50 results on '"Kin Tak Chan"'
Search Results
2. 1336 Cancer vaccine co-targeting PRAME and PD-L1 exerts significant tumor growth inhibition in syngeneic mouse hepatocellular carcinoma models
- Author
-
Kin-Tak Chan, Chen-Yi Chiang, Wing-Yan Ho, Melvin Toh, and Hsin-Wei Chen
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
3. Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer
- Author
-
Jun Zhang, Di Cui, Alfred King-Yin Lam, Simon Law, Yun Zhu, Nikki P. Lee, Kin Tak Chan, Sai Wah Tsao, Annie L.M. Cheung, Dong Dong Yan, Wen Wen Xu, Bin Li, and Daisy K Y Shum
- Subjects
Male ,0301 basic medicine ,Esophageal Neoplasms ,Carcinogenesis ,Serglycin ,Vesicular Transport Proteins ,Mice, Nude ,Medicine (miscellaneous) ,Proximity ligation assay ,midkine ,Metastasis ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,metastasis ,Animals ,Humans ,Autocrine signalling ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Midkine ,Mice, Inbred BALB C ,Tissue microarray ,biology ,Chemistry ,CD44 ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,esophageal squamous cell carcinoma ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Autocrine Communication ,Hyaluronan Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,biomarker ,Matrix Metalloproteinase 2 ,Female ,Proteoglycans ,Research Paper ,Signal Transduction - Abstract
Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.
- Published
- 2021
4. Identification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance
- Author
-
Can-Can Zheng, Wei Dai, Qing-Sheng Yang, Li Yan Xu, Xin Yuan Guan, Qing-Yu He, Simon Law, Wen-You Chen, Maria Li Lung, Yan Ru Qin, Kin Tak Chan, W Xu, Sai Wah Tsao, Pan Hong, Kwok Wah Chan, Annie L.M. Cheung, Nikki P. Lee, Liang Han, Bin Li, and En Min Li
- Subjects
0301 basic medicine ,Esophageal Neoplasms ,Medicine (miscellaneous) ,Antineoplastic Agents ,STAT5A ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,microRNA ,Tumor Cells, Cultured ,TaqMan ,Humans ,microRNA therapy ,Medicine ,Neoplasms, Squamous Cell ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Transcription factor ,p38 signaling ,diagnosis and prognosis ,business.industry ,F-Box Proteins ,Gene Expression Profiling ,Tumor Suppressor Proteins ,chemoresistance ,Cancer ,Models, Theoretical ,Esophageal cancer ,medicine.disease ,Biomarker (cell) ,MicroRNAs ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Fluorouracil ,business ,Research Paper - Abstract
Rationale: Dysregulated microRNA (miRNA) expressions in cancer can contribute to chemoresistance. This study aims to identify miRNAs that are associated with fluorouracil (5-FU) chemoresistance in esophageal squamous cell carcinoma (ESCC). The potential of miR-29c as a novel diagnostic, prognostic and treatment-predictive marker in ESCC, and its mechanisms and therapeutic implication in overcoming 5-FU chemoresistance were explored. Methods: The miRNA profiles of an ESCC cell model with acquired chemoresistance to 5-FU were analyzed using a Taqman miRNA microarray to identify novel miRNAs associated with 5-FU chemoresistance. Quantitative real-time PCR was used to determine miR-29c expression in tissue and serum samples of patients. Bioinformatics, gain- and loss-of-function experiments, and luciferase reporter assay were performed to validate F-box only protein 31 (FBXO31) as a direct target of miR-29c, and to identify potential transcription factor binding events that control miR-29c expression. The potential of systemic miR-29c oligonucleotide-based therapy in overcoming 5-FU chemoresistance was evaluated in tumor xenograft model. Results: MiR-29c, under the regulatory control of STAT5A, was frequently downregulated in tumor and serum samples of patients with ESCC, and the expression level was correlated with overall survival. Functional studies showed that miR-29c could override 5-FU chemoresistance in vitro and in vivo by directly interacting with the 3'UTR of FBXO31, leading to repression of FBXO31 expression and downstream activation of p38 MAPK. Systemically administered miR-29c dramatically improved response of 5-FU chemoresistant ESCC xenografts in vivo. Conclusions: MiR-29c modulates chemoresistance by interacting with FBXO31, and is a promising non-invasive biomarker and therapeutic target in ESCC.
- Published
- 2019
5. Preclinical Study of Novel Curcumin Analogue SSC-5 Using Orthotopic Tumor Xenograft Model for Esophageal Squamous Cell Carcinoma
- Author
-
Senchuan Song, Chung Man Chan, Hector K. Wang, Yanmin Huang, Lai Nar Tung, Ho Yu Lam, Hoi Ting Leung, Huacan Song, Zhiyong Chen, Mei Yuk Choi, Nikki P. Lee, Kin Tak Chan, and Simon Law
- Subjects
0301 basic medicine ,Cancer Research ,Curcumin ,Cell cycle checkpoint ,Esophageal Neoplasms ,Cell Survival ,Catechols ,Mice, Nude ,Cervix Uteri ,medicine.disease_cause ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Esophageal squamous cell carcinoma ,Cell Line, Tumor ,Abdomen ,medicine ,Animals ,Humans ,Abdominal Esophagus ,Esophagus ,Cell Proliferation ,Cell growth ,business.industry ,medicine.disease ,Xenograft Model Antitumor Assays ,Animal Cancer Model ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Esophageal stricture ,Cancer research ,Female ,Original Article ,Drug Screening Assays, Antitumor ,business ,Carcinogenesis ,Neoplasm Transplantation - Abstract
Purpose Tumor xenograft model is an indispensable animal cancer model. In esophageal squamous cell carcinoma (ESCC) research, orthotopic tumor xenograft model establishes tumor xenograft in the animal esophagus, which allows the study of tumorigenesis in its native microenvironment. Materials and methods In this study,we described two simple and reproducible methods to develop tumor xenograft at the cervical or the abdominal esophagus in nude mice by direct injection of ESCC cells in the esophageal wall. Results In comparing these two methods, the cervical one presented with more clinically relevant features, i.e., esophageal stricture, body weight loss and poor survival. In addition, the derived tumor xenografts accompanied a rapid growth rate and a high tendency to invade into the surrounding structures. This model was subsequently used to study the anti-tumor effect of curcumin, which is known for its potential therapeutic effects in various diseases including cancers, and its analogue SSC-5. SSC-5 was selected among the eight newly synthesized curcumin analogues based on its superior anti-tumor effect demonstrated in an MTT cell proliferation assay and its effects on apoptosis induction and cell cycle arrest in cultured ESCC cells. Treatment of orthotopic tumor-bearing mice with SSC-5 resulted in an inhibition in tumor growth and invasion. Conclusion Taken together, we have established a clinically relevant orthotopic tumor xenograft model that can serve as a preclinical tool for screening new anti-tumor compounds, e.g., SSC-5, in ESCC.
- Published
- 2018
6. Whole-exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma
- Author
-
Maria Li Lung, Kin Tak Chan, Sheyne Sta Ana Choi, Zhouyou Yu, Wei Dai, Josephine Mun Yee Ko, Hong Zheng, Luwen Ning, Vinod Gopalan, Kwok Wah Chan, Simon Law, Alfred King-Yin Lam, and Nikki P. Lee
- Subjects
0301 basic medicine ,Nucleosome organization ,Mutation ,Nucleosome assembly ,Biology ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,Pathology and Forensic Medicine ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,Cancer research ,medicine ,Missense mutation ,Metastasis suppressor ,Epigenetics ,neoplasms ,Exome sequencing - Abstract
Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10-5 ). The Cancer Genome Atlas data further showed that ZNF750 genetic alterations were associated with early disease relapse. Previous ESCC studies have demonstrated that ZNF750 knockdown strongly promotes proliferation, migration, and invasion. Collectively, these results suggest a role for ZNF750 as a metastasis suppressor. TP53 is highly mutated in ESCC, and missense mutations are associated with poor overall survival, independently of pathological stage, suggesting that these missense mutations have important functional impacts on tumour progression, and are thus likely to be gain-of-function (GOF) mutations. Additionally, mutations of epigenetic regulators, including KMT2D, TET2, and KAT2A, and chromosomal 6p22 and 11q23 deletions of histone variants, which are important for nucleosome assembly, were detected in 80% of LN metastases. Our study highlights the important role of critical genetic events including ZNF750 mutations, TP53 putative GOF mutations and nucleosome disorganization caused by genetic lesions seen with ESCC metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2017
7. MicroRNA-338-5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id-1
- Author
-
Liang Han, Di Cui, Stephanie Ma, Yun Zhu, Annie L.M. Cheung, Kwok Wah Chan, Simon Law, Nikki P. Lee, Wen Wen Xu, Bin Li, Alfred King Y. Lam, Xin Yuan Guan, Kin Tak Chan, Sai Wah Tsao, and Yan Ru Qin
- Subjects
0301 basic medicine ,Adult ,Inhibitor of Differentiation Protein 1 ,Male ,Cancer Research ,Esophageal Neoplasms ,Carcinogenesis ,miR‐338‐5p ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Cell Movement ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,esophageal cancer ,Id‐1 ,Aged ,Cisplatin ,Gene knockdown ,business.industry ,chemoresistance ,General Medicine ,Original Articles ,Esophageal cancer ,Middle Aged ,medicine.disease ,In vitro ,circulating miRNA ,MicroRNAs ,030104 developmental biology ,Oncology ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Original Article ,Esophageal Squamous Cell Carcinoma ,Fluorouracil ,business ,medicine.drug - Abstract
5‐Fluorouracil (5‐FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)‐338‐5p was underexpressed in ESCC cells with acquired 5‐FU chemoresistance. Forced expression of miR‐338‐5p in these cells resulted in downregulation of Id‐1, and restoration of both in vitro and in vivo sensitivity to 5‐FU treatment. The effects were abolished by reexpression of Id‐1. In contrast, miR‐338‐5p knockdown induced 5‐FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR‐338‐5p and Id‐1 resensitized the cells to 5‐FU. In addition, miR‐338‐5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR‐338‐5p and the 3′‐UTR of Id‐1. We also found that miR‐338‐5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR‐338‐5p expression level was associated with poorer survival and poor response to 5‐FU/cisplatin‐based neoadjuvant chemoradiotherapy. In summary, we found that miR‐338‐5p can modulate 5‐FU chemoresistance and inhibit invasion‐related functions in ESCC by negatively regulating Id‐1, and that serum miR‐338‐5p could be a novel noninvasive prognostic and predictive biomarker in ESCC., We found that microRNA (miR)‐338‐5p was underexpressed in esophageal squamous cell carcinoma cells with acquired 5‐fluorouracil (5‐FU) chemoresistance, and that reexpression of miR‐338‐5p could resensitize them to 5‐FU treatment through targeting Id‐1. MicroRNA‐338‐5p was significantly downregulated in tumor tissue and serum of patients with esophageal squamous cell carcinoma. Low serum miR‐338‐5p was predictive of poor response to 5‐FU/cisplatin‐based neoadjuvant chemoradiotherapy.
- Published
- 2019
8. BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese
- Author
-
Xin Song, Sheyne Sta Ana Choi, Pei-Nan Chen, Josephine Mun Yee Ko, Simon Law, Yun-Li Chang, Lvwen Ning, Anthony W.I. Lo, Li-Dong Wang, Nikki P. Lee, Annie Wai Yeeng Chai, Kin-Tak Chan, Lisa Chan Lei, Ava Kwong, Maria Li Lung, Zhao Xueke, and Lihua Tao
- Subjects
Adult ,Male ,Cancer Research ,China ,Esophageal Neoplasms ,Genes, BRCA2 ,Mutation, Missense ,Loss of Heterozygosity ,Penetrance ,Synthetic lethality ,Biology ,medicine.disease_cause ,Loss of heterozygosity ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Asian People ,Genetic predisposition ,medicine ,Missense mutation ,Humans ,Exome ,Genetic Predisposition to Disease ,neoplasms ,Germ-Line Mutation ,Genetic association ,Aged ,BRCA2 Protein ,Mutation ,Middle Aged ,digestive system diseases ,Pedigree ,Oncology ,MSH2 ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Esophageal Squamous Cell Carcinoma - Abstract
Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole-exome sequencing (WES) included 186 familial ESCC patients from high-risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate-risk Hong Kong Chinese. A WES approach identified BRCA2 loss-of-function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10-10 ). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild-type somatic allelic loss via loss of heterozygosity. Gene-based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10-5 ), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.
- Published
- 2019
9. Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation
- Author
-
Nikki P. Lee, Stella Chai, Stephanie Ma, Kwok Wah Chan, Mei Yuk Choi, Yan Ru Qin, Kin Tak Chan, Jin Na Chen, Sai Wah Tsao, Xin Yuan Guan, Tsun Ming Fung, KY Ng, Bin Li, Man Tong, Simon Law, and Annie L. Cheung
- Subjects
0301 basic medicine ,Gene knockdown ,Cadherin ,Angiogenesis ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,Pathology and Forensic Medicine ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Gene silencing ,Carcinogenesis - Abstract
Oesophageal squamous cell carcinoma (ESCC) is the most common histological subtype of oesophageal cancer. The disease is particularly prevalent in southern China. The incidence of the disease is on the rise and its overall survival rate remains dismal. Identification and characterization of better molecular markers for early detection and therapeutic targeting are urgently needed. Here, we report levels of transmembrane and soluble neuropilin-2 (NRP2) to be significantly up-regulated in ESCC, and to correlate positively with advanced tumour stage, lymph node metastasis, less favourable R category and worse overall patient survival. NRP2 up-regulation in ESCC was in part a result of gene amplification at chromosome 2q. NRP2 overexpression promoted clonogenicity, angiogenesis and metastasis in ESCC in vitro, while NRP2 silencing by lentiviral knockdown or neutralizing antibody resulted in a contrary effect. This observation was extended in vivo in animal models of subcutaneous tumourigenicity and tail vein metastasis. Mechanistically, overexpression of NRP2 induced expression of ERK MAP kinase and the transcription factor ETV4, leading to enhanced MMP-2 and MMP-9 activity and, as a consequence, suppression of E-cadherin. In summary, NRP2 promotes tumourigenesis and metastasis in ESCC through deregulation of ERK-MAPK-ETV4-MMP-E-cadherin signalling. NRP2 represents a potential diagnostic or prognostic biomarker and therapeutic target for ESCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2016
10. Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance
- Author
-
Annie L.M. Cheung, Qing-Yu He, YY Li, Hiu Fung Yuen, Simon Law, Kwok Wah Chan, Nikki P. Lee, Xin Yuan Guan, W Xu, Bin Li, Kin Tak Chan, Sai Wah Tsao, Yan Ru Qin, and Pui Ying Tam
- Subjects
Inhibitor of Differentiation Protein 1 ,0301 basic medicine ,endocrine system ,Cancer Research ,Esophageal Neoplasms ,Cdc20 Proteins ,Biology ,Binding, Competitive ,Thymidylate synthase ,03 medical and health sciences ,Downregulation and upregulation ,Insulin-Like Growth Factor II ,Cell Line, Tumor ,medicine ,Humans ,E2F1 ,Cell Proliferation ,Regulation of gene expression ,Cell growth ,Thymidylate Synthase ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Fluorouracil ,Proteolysis ,Carcinoma, Squamous Cell ,biology.protein ,Cancer research ,Esophageal Squamous Cell Carcinoma ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Chromatin immunoprecipitation ,E2F1 Transcription Factor ,Signal Transduction ,medicine.drug - Abstract
Purpose: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance. Experimental Design: In vitro and in vivo functional assays were performed to study the effects of Id1–E2F1–IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes. Results: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types. Conclusions: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1–E2F1–IGF2 regulatory axis has important implications for cancer prognosis and treatment. Clin Cancer Res; 22(5); 1243–55. ©2015 AACR.
- Published
- 2016
11. Survival Benefit of a Monoclonal Antibody against Cadherin-17 in an Orthotopic Liver Tumor Xenograft Model
- Author
-
Hector K. Wang, Edgar S. L. Liu, Zhaoxiang Bian, Lai Nar Tung, Ho Yu Lam, Mung Yee Wong, Winnie Tan, Kin Tak Chan, Nikki P. Lee, Mei Yuk Choi, Sarwat Fatima, and Pui Ying Tam
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Liver tumor ,medicine.drug_class ,Monoclonal antibody ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Medicine ,Cisplatin ,biology ,business.industry ,General Medicine ,medicine.disease ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,biology.protein ,Growth inhibition ,Antibody ,business ,Liver cancer ,Epirubicin ,medicine.drug - Abstract
Aims: Monoclonal antibodies against tumor-related molecules are therapeutic agents for cancers. Promising results support the use of monoclonal antibodies in several cancers such as lung and breast cancer. However, using monoclonal antibodies as therapeutic agents to treat hepatocellular carcinoma (HCC), a major type of liver cancer, is still at the beginning. We have previously generated a monoclonal antibody against cadherin-17 (CDH17), named Lic5. This antibody has proven anti-tumor and cisplatin-sensitizing effect in HCC using a subcutaneous tumor xenograft mouse model. Original Research Article Chan et al.; JALSI, 4(3): 1-10, 2016; Article no.JALSI.22188 2 Study Design and Methodology: To further consolidate our previous finding, we tested the effect of Lic5 alone or in combination with cisplatin or epirubicin on tumor growth inhibition and animal survival using a more advanced orthotopic tumor xenograft model. Results: Single Lic5, cisplatin and epirubicin treatment inhibited growth of cultured HCC cells using cell proliferation assay, while more significant reductions were observed when cisplatin or epirubicin was used together with Lic5. Similar trends of growth inhibition were observed when the same experimental grouping was applied to treat orthotopic tumor-bearing nude mice. Treatment of Lic5 enhanced survivals of orthotopic tumor-bearing nude mice when compared to the control group. Among all experimental groups, combined Lic5 and epirubicin group yielded the best survival. For next phase antibody humanization, we also identified the complementarity determining regions (CDRs) on variable regions on the light and heavy chain of Lic5. Conclusion: Together, we have validated the preclinical use of Lic5 in an orthotopic HCC xenograft model. Our successful identification of CDRs constitutes the first step in synthesizing
- Published
- 2016
12. Role of AMPK signaling in mediating the anticancer effects of silibinin in esophageal squamous cell carcinoma
- Author
-
Yan Ru Qin, Simon Law, Annie L.M. Cheung, Nikki P. Lee, Bin Li, Jin Li, Kin Tak Chan, Kwok Wah Chan, Sai Wah Tsao, Xin Yuan Guan, and Wen Wen Xu
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Esophageal Neoplasms ,Clinical Biochemistry ,Mice, Nude ,Silibinin ,Antineoplastic Agents ,Apoptosis ,AMP-Activated Protein Kinases ,Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,AMP-activated protein kinase ,Cell Line, Tumor ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Drug Discovery ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Protein kinase A ,neoplasms ,Cell Proliferation ,Pharmacology ,Cell growth ,AMPK ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,030104 developmental biology ,Endocrinology ,chemistry ,Silybin ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Cancer research ,biology.protein ,Molecular Medicine ,Esophageal Squamous Cell Carcinoma ,Fluorouracil ,Signal transduction ,Signal Transduction ,Silymarin - Abstract
Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK) may suppress cancer growth. Identification of novel AMPK activators is therefore crucial to exploit AMPK as a potential target for cancer prevention and treatment.We determined the expression status and role of AMPK in esophageal squamous cell carcinoma (ESCC) and investigated whether silibinin, a nontoxic natural product, could activate AMPK to inhibit ESCC development.Our results from 49 pairs of human ESCC and normal tissues showed that AMPK was constitutively inactive in the majority (69.4%) of ESCC. We found that silibinin induced apoptosis, and inhibited ESCC cell proliferation in vitro and tumorigenicity in vivo without any adverse effects. Silibinin also markedly suppressed the invasive potential of ESCC cells in vitro and their ability to form lung metastasis in nude mice. The anticancer effects of silibinin were abrogated by the presence of compound C or shRNA against AMPK. More importantly, silibinin enhanced the sensitivity of ESCC cells and tumors to the chemotherapeutic drugs, 5-fluorouracil and cisplatin.This preclinical study supports that AMPK is a valid therapeutic target and suggests that silibinin may be a potentially useful therapeutic agent and chemosensitizer for esophageal cancer.
- Published
- 2015
13. Abstract A29: Anticancer effects of polo-like kinase-4 inhibitor (CFI-400945) in ovarian cancer
- Author
-
Vincent Wai-Hin Yuen, Bray Mark R, Carmen Chai Lui Wong, Hextan Yeung Sheung Ngan, Misty Shuo Zhang, Philip P.C. Ip, Tak W. Mak, Ka Yu Tse, and Kin Tak Chan
- Subjects
0301 basic medicine ,Cancer Research ,Cell division ,DNA repair ,Cancer ,Cell cycle ,Biology ,medicine.disease_cause ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,Cancer research ,Carcinogenesis ,Ovarian cancer ,Mitosis - Abstract
Background: Dysregulation of cell cycle and mitosis plays a pivotal role in carcinogenesis. Polo-like kinase (PLK) regulates centriole duplication and mitosis and is crucial in maintaining the genomic stability in cancer cells. Disruption of this process may affect cancer cell growth and so PLK represents a druggable target in cancer therapy. CFI-400945 is a small molecule against PLK4 activity, and this study aims to investigate its anticancer efficacy and mechanisms in ovarian cancer cells. Methods: Expression of PLK4 in ovarian cancer patients was determined by Taqman quantitative PCR (qPCR) at transcriptional level. To assess the in vitro growth inhibition effect of CFI-400945, XTT cell viability assay was employed to compare the IC50 of CFI-400945 in a panel of 25 ovarian cancer cell lines of different histologic origins, and the antiproliferative results were assessed by direct cell counting assay. The anticancer activity of CFI-400945 in ovarian cancer cells were further studied by (1) propidium iodide (PI) staining to assess its impact on cell cycle and cell division, (2) annexin V staining to determine the level of apoptosis, (3) gH2AX Western blotting and gH2AX/RAD51 co-immunofluorescence to reveal its effect on DNA damage and repair, and (4) beta-galactosidase activity staining to study the outcome of senescence induced by CFI-400945. To study the change of gene expression induced by CFI-400945 at molecular level, poly-A capture RNA sequencing (RNAseq) was performed in OCC1 and ES2. Results: The qPCR assay significantly demonstrated overexpression of PLK4 in ovarian cancer tumor tissue when compared to nontumor. The growth inhibition effect of CFI-400945 varied among different ovarian cancer cell lines, with IC50 ranging from 0.7 to 68.2nmol. PI-based cell cycle analysis clearly demonstrated the presence of aneuploidy up to 16N, indicating the failure of cell division after S phase DNA duplication. In addition to its impact on cell division, gH2AX immunofluorescent staining and Western blotting also revealed CFI-400945 induced DNA damage. However, induction of apoptosis was only rarely seen in the cell lines tested. The aneuploidy formation and low level of apoptosis was followed by cellular senescence, which was evidenced by 3-fold increase in the number of cells having positive beta-galactosidase staining after CFI-400945 treatment as compared to control. RNAseq of OCC1 and ES2 showed an induction of senescence-associated secretory phenotypes, like IL6 and P21, and suppression of DNA repair gene expression, like RAD51 and BRCA1, which were in agreement with our in vitro observation. Conclusion: CFI-400945 had antiproliferative effect in ovarian cancer cell lines of different histologic origins, and its anticancer activity was attributable to DNA damage, its suppressive effect on DNA repair, failure of cell division, and subsequent cell senescence. Further study would focus on enhancing the anticancer activity of CFI-400945 through drug combination against DNA damage repair. Citation Format: Ka Yu Tse, Kin Tak Chan, Vincent Yuen, Misty Shuo Zhang, Philip Pun Ching Ip, Hextan Yeung Sheung Ngan, Mark Bray, Carmen Chai Lui Wong, Tak Wah Mak. Anticancer effects of polo-like kinase-4 inhibitor (CFI-400945) in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A29.
- Published
- 2020
14. Elevated levels of serum nidogen-2 in esophageal squamous cell carcinoma
- Author
-
Maria Li Lung, Wei Dai, Arthur Kwok Leung Cheung, Josephine Mun Yee Ko, Simon Law, Kin Tak Chan, Annie Wai Yeeng Chai, and Nikki P. Lee
- Subjects
0301 basic medicine ,Adult ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,Enzyme-Linked Immunosorbent Assay ,Kaplan-Meier Estimate ,Gastroenterology ,Esophageal squamous cell carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,Biomarkers, Tumor ,Medicine ,Humans ,Survival analysis ,Aged ,Neoplasm Staging ,Basement membrane ,Receiver operating characteristic ,business.industry ,Calcium-Binding Proteins ,Area under the curve ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,ROC Curve ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Case-Control Studies ,Carcinoma, Squamous Cell ,Esophageal Squamous Cell Carcinoma ,Nidogen-2 ,Neoplasm Grading ,business ,Ovarian cancer ,Cell Adhesion Molecules - Abstract
BACKGROUND Nidogen-2 (NID2), a secretory basement membrane protein, has been implicated as a potential biomarker in ovarian cancer and hepatocellular carcinoma. OBJECTIVE In this study, we aimed to investigate the utility of detecting serum NID2 levels for identification of esophageal squamous cell carcinoma (ESCC) patients and prediction of poor survival outcome. METHODS Using an in-house NID2 enzyme-linked immunosorbent assay (ELISA), serum samples from 101 ESCC patients and 50 healthy controls were screened for their NID2 levels. RESULTS The serum NID2 levels in ESCC patients (median 24.4 μg/L) are significantly higher (p= 4.3e-09) than that of the healthy controls (median 15.85 μg/L). The receiver operating characteristic (ROC) curve demonstrated an area under the curve of 0.756. At the threshold of 17.95 μg/L, the sensitivity and specificity achieved are 0.76 and 0.63, respectively. Kaplan-Meier survival analysis revealed that patients with high serum NID2 levels (⩾ 32.6 μg/L) have significantly higher risk of death (HR = 1.984, 95% CI: 1.175-3.349; log-rank p-value = 0.012) compared to those with low serum NID2 levels (< 20.0 μg/L). CONCLUSIONS In conclusion, we show that detecting the elevation of serum NID2 levels has potential diagnostic and prognostic value for ESCC patients.
- Published
- 2017
15. Serum microRNA-193b as a promising biomarker for prediction of chemoradiation sensitivity in esophageal squamous cell carcinoma patients
- Author
-
Hector K. Wang, TT Law, Chung Man Chan, Daniel K. Tong, Nikki P. Lee, Simon Law, Kin Tak Chan, Kenneth K. Y. Lai, Enders K.O. Ng, Tiffany W. H. Kwok, Kwok Wah Chan, and Mei Na Kiang
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Receiver operating characteristic ,Oncogene ,business.industry ,Cancer ,Articles ,Cell cycle ,Esophageal cancer ,medicine.disease ,Molecular medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,microRNA ,Medicine ,Biomarker (medicine) ,business - Abstract
Esophageal squamous cell carcinoma (ESCC) is the most predominantly occurring type of esophageal cancer worldwide. Locally advanced ESCC patients are treated by neoadjuvant chemoradiation for tumor downstaging prior to tumor resection. Patients receiving this treatment have an increased expectation of cure via the following tumor resection and have better survival outcomes. However, not all patients respond well to chemoradiation and poor responders suffer from treatment-associated toxicity and complications without benefits. No method is currently available to predict patient chemoradiation response and to exclude poor responders from ineffective treatment. To address this clinical limitation, the present study aimed to identify non-invasive biomarkers for predicting patient chemoradiation response. Due to the features of microRNA (miRNA) in cancer diagnosis, prognosis and treatment response prediction, serum miRNA arrays were performed to identify potential miRNA(s) that may be used for chemoradiation response prediction in ESCC. Using an miRNA array to compare pre-treatment serum sample pools from 10 good responders and 10 poor responders, the present study identified miR-193b, miR-942 and miR-629* as candidate miRNAs for predicting chemoradiation response. Subsequent validation using reverse transcription-quantitative polymerase chain reaction confirmed that miR-193b, however not miR-942 and miR-629*, were significantly increased in sera from 24 good responders, compared with 23 poor responders. Further analyses using the receiver operating characteristic curve revealed a strong predictive power of serum miR-193b on discriminating good responders from poor responders to chemoradiation. In addition, a high serum level of miR-193b was significantly associated with better survival outcomes. Therefore, serum miR-193b may be considered a promising biomarker for predicting chemoradiation response and post-therapy survival of ESCC patients.
- Published
- 2017
16. Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.
- Author
-
Yun Zhu, Lam, Alfred K. Y., Shum, Daisy K. Y., Di Cui, Jun Zhang, Dong Dong Yan, Bin Li, Wen Wen Xu, Lee, Nikki P. Y., Kin Tak Chan, Law, Simon, Sai Wah Tsao, and Cheung, Annie L. M.
- Published
- 2021
- Full Text
- View/download PDF
17. Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma
- Author
-
Hector K. Wang, Ruibang Luo, Wing-Kin Sung, John M. Luk, Felix H. Shek, Kin Tak Chan, Nikki P. Lee, Ronnie T.P. Poon, Ming Sum Leung, Brian Y.H. Lam, Chung Man Chan, and Tak-Wah Lam
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Carcinoma, Hepatocellular ,Biology ,Cell Line ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,neoplasms ,beta Catenin ,Cadherin ,Effector ,Gene Expression Profiling ,Liver Neoplasms ,General Medicine ,Hep G2 Cells ,HCCS ,medicine.disease ,Cadherins ,digestive system diseases ,In vitro ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Trypsin Inhibitor, Kazal Pancreatic ,030220 oncology & carcinogenesis ,Catenin ,Hepatocellular carcinoma ,Cancer research ,Molecular Medicine ,RNA Interference ,Liver cancer ,Signal Transduction - Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients. We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/β-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in β-catenin expression (a core component of the CDH17/β-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway. Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/β-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.
- Published
- 2017
18. Whole-exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma
- Author
-
Wei, Dai, Josephine Mun Yee, Ko, Sheyne Sta Ana, Choi, Zhouyou, Yu, Luwen, Ning, Hong, Zheng, Vinod, Gopalan, Kin Tak, Chan, Nikki Pui-Yue, Lee, Kwok Wah, Chan, Simon Ying-Kit, Law, Alfred King-Yin, Lam, and Maria Li, Lung
- Subjects
DNA Copy Number Variations ,Esophageal Neoplasms ,Tumor Suppressor Proteins ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,Genes, p53 ,Epigenesis, Genetic ,Nucleosomes ,Editorial ,Lymphatic Metastasis ,Mutation ,Carcinoma, Squamous Cell ,Humans ,Point Mutation ,Exome ,Esophageal Squamous Cell Carcinoma ,Transcriptome ,Telomerase ,Transcription Factors - Abstract
Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10
- Published
- 2017
19. Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression
- Author
-
Yang Wang, Yim Ling Yip, Sookja K. Chung, En Min Li, Qing-Yu He, Simon Law, Li Yan Xu, W Xu, Xin Yuan Guan, Nikki P. Lee, Kwok Wah Chan, Annie L.M. Cheung, Kin Tak Chan, Sai Wah Tsao, and Bin Li
- Subjects
Inhibitor of Differentiation Protein 1 ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,animal structures ,Esophageal Neoplasms ,Science ,Transplantation, Heterologous ,Mice, Nude ,General Physics and Astronomy ,Bone Marrow Cells ,Kaplan-Meier Estimate ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Insulin-Like Growth Factor II ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Progenitor cell ,Cells, Cultured ,Mice, Knockout ,Multidisciplinary ,Stem Cells ,Cancer ,General Chemistry ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor A ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,Disease Progression ,Cancer research ,Bone marrow ,Stem cell - Abstract
Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression.
- Published
- 2017
20. Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma
- Author
-
Nikki P. Lee, Daniel K. H. Tong, Mei Yuk Choi, Kin Tak Chan, Kenneth K. Y. Lai, Lai Nar Tung, Ho Yu Lam, Winnie Tan, and Simon Law
- Subjects
Male ,MAPK/ERK pathway ,Cancer Research ,Esophageal Neoplasms ,Carcinogenesis ,MAP Kinase Signaling System ,Cell ,Gene Expression ,Transferrin receptor ,Biology ,medicine.disease_cause ,Downregulation and upregulation ,Antigens, CD ,Cell Line, Tumor ,Receptors, Transferrin ,medicine ,Humans ,RNA, Small Interfering ,Aged ,Neoplasm Staging ,Oncogene ,Cell growth ,General Medicine ,Middle Aged ,Cell cycle ,medicine.anatomical_structure ,Oncology ,Gene Knockdown Techniques ,Carcinoma, Squamous Cell ,Cancer research ,Female ,Esophageal Squamous Cell Carcinoma - Abstract
Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in endemic Asian regions. In the present study, we investigated the clinical implication and role of transferrin receptor CD71 in ESCC. CD71 has a physiological role in cellular iron intake and is implicated in the carcinogenesis of various types of tumors. In our cohort, more than a 2-fold upregulation of the CD71 transcript was detected in 61.5% of patients using quantitative polymerase chain reaction. Immunohistochemical analysis also showed strong membranous and cytoplasmic localization of CD71 in paraffin-embedded tumors. Staining parallel tumor sections with the proliferative marker Ki-67 revealed that the pattern of Ki-67 staining was associated with CD71 expression. Analysis of clinicopathological data indicated that CD71 overexpression can be used as an indicator for advanced T4 stage (p=0.0307). These data suggested a strong link between CD71 and ESCC. Subsequent in vitro assays using short interfering RNA (siRNA) to suppress CD71 expression confirmed the tumorigenic properties of CD71 in ESCC; cell growth inhibition and cell cycle arrest at S phase were observed in CD71-suppressed cells. The underlying mechanism involved activation of the MEK/ERK pathway. In summary, the present study provides evidence showing the tumorigenic properties of CD71 in ESCC with clinical correlations and suggests targeting CD71 as a strategy for the treatment of ESCC.
- Published
- 2014
21. The triterpenoid cucurbitacin B augments the antiproliferative activity of chemotherapy in human breast cancer
- Author
-
Melvin Toh, Dhong Hyun Lee, Ngan B. Doan, H. Phillip Koeffler, Sigal Gery, Gabriela B. Thoennissen, Quoc Ho, Ahmed M. Aribi, Rocio Alvarez, Nils H. Thoennissen, Kunik Lee, Jonathan W. Said, and Kin Tak Chan
- Subjects
Cancer Research ,medicine.medical_treatment ,Apoptosis ,Bone Marrow Cells ,Breast Neoplasms ,Docetaxel ,Pharmacology ,Deoxycytidine ,Article ,Mice ,Breast cancer ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Cytotoxicity ,Cell Proliferation ,Chemotherapy ,business.industry ,fungi ,Cancer ,Drug Synergism ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,Gemcitabine ,Triterpenes ,Tumor Burden ,Oncology ,Toxicity ,Female ,Taxoids ,business ,medicine.drug - Abstract
Despite recent advances in therapy, breast cancer remains the second most common cause of death from malignancy in women. Chemotherapy plays a major role in breast cancer management, and combining chemotherapeutic agents with non-chemotherapeutic agents is of considerable clinical interest. Cucurbitacins are triterpenes compounds found in plants of the Cucurbitaceae family, reported to have anti-cancer and anti-inflamatory activities. Previously, we have shown antiproliferative activity of cucurbitacin B (CuB) in breast cancer, and we hypothesized that combining CuB with chemotherapeutic agents can augment their anti-tumor effect. Here, we show that a combination of CuB with either docetaxel (DOC) or gemcitabine (GEM) synergistically inhibited the proliferation of MDA-MB-231 breast cancer cells in vitro. This antiproliferative effect was accompanied by an increase in apoptosis rates. Furthermore, in vivo treatment of human breast cancer orthotopic xenografts in immunodeficient mice with CuB at either low (0.5 mg/kg) or high (1 mg/kg) doses in combination with either DOC (20 mg/kg) or GEM (12.5 mg/kg) significantly reduced tumor volume as compared to monotherapy of each drug. Importantly, no significant toxicity was noted with low dose CuB in combination with either DOC or GEM. In conclusion, combination of CuB at a relatively low concentration with either of the chemotherapeutic agents, DOC or GEM, shows prominent antiproliferative activity against breast cancer cells without increased toxicity. This promising combination should be examined in therapeutic trials of breast cancer.
- Published
- 2012
22. Tri-band optical coherence tomography for lipid and vessel spectroscopic imaging
- Author
-
Jiqiang Kang, Xie Wang, Kenneth K. Y. Wong, Xiaoming Wei, Nikki P. Lee, Luoqin Yu, and Kin-Tak Chan
- Subjects
Materials science ,genetic structures ,medicine.diagnostic_test ,business.industry ,Amplifier ,Phase (waves) ,02 engineering and technology ,Laser ,01 natural sciences ,Multiplexing ,law.invention ,010309 optics ,Wavelength ,020210 optoelectronics & photonics ,Optics ,Mode-locking ,Optical coherence tomography ,law ,Wavelength-division multiplexing ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,sense organs ,business - Abstract
Optical coherence tomography (OCT) has been utilized for various functional imaging applications. One of its highlights comes from spectroscopic imaging, which can simultaneously obtain both morphologic and spectroscopic information. Assisting diagnosis and therapeutic intervention of coronary artery disease is one of the major directions in spectroscopic OCT applications. Previously Tanaka et al. have developed a spectral domain OCT (SDOCT) to image lipid distribution within blood vessel [1]. In the meantime, Fleming et al. have demonstrated optical frequency domain imaging (OFDI) by a 1.3-μm swept source and quadratic discriminant analysis model [2]. However, these systems suffered from burdensome computation as the optical properties’ variation was calculated from a single-band illumination that provided limited contrast. On the other hand, multi-band OCT facilitates contrast enhancement with separated wavelength bands, which further offers an easier way to distinguish different materials. Federici and Dubois [3] and Tsai and Chan [4] have demonstrated tri-band OCT systems to further enhance the image contrast. However, these previous work provided under-explored functional properties. Our group has reported a dual-band OCT system based on parametrically amplified Fourier domain mode-locked (FDML) laser with time multiplexing scheme [5] and a dual-band FDML laser OCT system with wavelength-division multiplexing [6]. Fiber optical parametric amplifier (OPA) can be ideally incorporated in multi-band spectroscopic OCT system as it has a broad amplification window and offers an additional output range at idler band, which is phase matched with the signal band. The sweeping ranges can thus overcome traditional wavelength bands that are limited by intra-cavity amplifiers in FDML lasers. Here, we combines the dual-band FDML laser together with fiber OPA, which consequently renders a simultaneous tri-band output at 1.3, 1.5, and 1.6 μm, for intravascular applications. Lipid and blood vessel distribution can be subsequently visualized with the tri-band OCT system by ex vivo experiments using porcine artery model with artificial lipid plaques.
- Published
- 2016
23. Tri-band optical coherence tomography via optical parametric amplifier for endoscopic application
- Author
-
Jin Li, Xiaoming Wei, Kenneth K. Y. Wong, William Kongto Hau, Xie Wang, Aimin Xu, Luoqin Yu, Nikki P. Lee, Kin-Tak Chan, Jiqiang Kang, and Chandra Jinata
- Subjects
Optical amplifier ,Optical fiber ,Materials science ,genetic structures ,medicine.diagnostic_test ,business.industry ,02 engineering and technology ,01 natural sciences ,Optical parametric amplifier ,eye diseases ,law.invention ,010309 optics ,020210 optoelectronics & photonics ,Optics ,Optical coherence tomography ,law ,0103 physical sciences ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,sense organs ,business ,Fiber optical parametric amplifier - Abstract
A novel tri-band optical coherence tomography (OCT) system based on fiber optical parametric amplifier (FOPA) has been proposed and subsequently demonstrated for endoscopic functional spectroscopic imaging of aorta and lipid plaques in mouse models.
- Published
- 2016
24. Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration
- Author
-
Qian Li, Miao Li, Melvin Toh, Tsz Shan Lam, Kin Tak Chan, Kee Hung Chu, Wai Him Lee, Fan Yan Meng, Yu To, and Cheong Yip Ho
- Subjects
STAT3 Transcription Factor ,Cancer Research ,Carcinoma, Hepatocellular ,Blotting, Western ,Transplantation, Heterologous ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,S Phase ,Mice ,chemistry.chemical_compound ,Cyclin D1 ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,STAT3 ,Cytotoxicity ,biology ,business.industry ,Cell Cycle ,Liver Neoplasms ,Cell cycle ,Flow Cytometry ,medicine.disease ,Triterpenes ,Proto-Oncogene Proteins c-raf ,Oncology ,chemistry ,Hepatocellular carcinoma ,biology.protein ,Growth inhibition ,business ,Cell Division - Abstract
Cucurbitacin B is an anti-cancer drug candidate and its efficacy has been demonstrated in hepatocellular carcinoma (HCC). To explore its mechanism against HCC, BEL-7402 cells were treated with cucurbitacin B in vitro. Treatment with cucurbitacin B induced S phase arrest and apoptosis. The growth inhibition effect was associated with cyclin D1 and cdc-2 down regulations. Western blotting analysis of cell signaling molecules indicated that cucurbitacin B inhibited c-Raf activation without affecting STAT3 phosphorylation. Moreover, in vivo study demonstrated that cucurbitacin B is effective against BEL-7402 xenograft when administrated orally.
- Published
- 2010
25. Multiple coding and non-coding RNAs in the Hoxb3 locus and their spatial expression patterns during mouse embryogenesis
- Author
-
Mai Har Sham, Kin Tak Chan, and Jie Qi
- Subjects
Central Nervous System ,RNA, Untranslated ,Transcription, Genetic ,Biophysics ,Embryonic Development ,Biology ,Biochemistry ,Mice ,Transcription (biology) ,Animals ,RNA, Messenger ,Small nucleolar RNA ,Promoter Regions, Genetic ,Molecular Biology ,Homeodomain Proteins ,Regulation of gene expression ,Genetics ,Alternative splicing ,Gene Expression Regulation, Developmental ,RNA ,Promoter ,Cell Biology ,Non-coding RNA ,Long non-coding RNA ,Alternative Splicing ,Genetic Code ,Genetic Loci ,Transcription Initiation Site - Abstract
Hoxb3 plays important roles in embryogenesis and it has a complex transcription profile of mRNAs, non-coding RNAs and anti-sense RNAs. Characterization of the spatial expression patterns of these RNAs is important to understand their functions. We investigated the regulation and spatial expression patterns of multiple RNA transcripts derived from the Hoxb3 gene locus. By 5'-RACE we identified four novel transcription initiation sites and initiating exons, and by luciferase activity assay we identified a new promoter region. Expression pattern analysis of the alternative transcripts containing specific initiation exons in mouse embryos suggests that there are co-operations between the initiation exons, their adjacent promoters and enhancer elements to orchestrate overlapping neural tube specific transcription profiles for Hoxb3. Furthermore, we showed that anti-sense transcripts derived from the Hoxb3 locus were expressed in the hindbrain with distinct rhombomere boundaries, in a pattern complementary to the sense coding mRNA transcripts. Our results suggest that the multiple non-coding RNAs could be involved in the regulation of Hoxb3.
- Published
- 2010
26. Induction of cytotoxic T cell response against HCA661 positive cancer cells through activation with novel HLA-A∗0201 restricted epitopes
- Author
-
Paul Ha-Sang Pang, Ray Chun-Fai Chan, Yong Xie, Fion Wan-Yee Sin, Kin-Tak Chan, Zhihong Guo, Luigi Ying-Wai Tse, and Ying-Kit Cheung
- Subjects
Fetal Proteins ,Cancer Research ,Carcinoma, Hepatocellular ,Cell Survival ,Cell Adhesion Molecules, Neuronal ,medicine.medical_treatment ,T cell ,Enzyme-Linked Immunosorbent Assay ,Lymphocyte Activation ,Epitope ,Interferon-gamma ,Interleukin 21 ,Antigen ,Antigens, CD ,Cell Line, Tumor ,HLA-A2 Antigen ,medicine ,Humans ,Cytotoxic T cell ,Antigen-presenting cell ,HLA-A Antigens ,Immunodominant Epitopes ,Chemistry ,Liver Neoplasms ,Computational Biology ,Immunotherapy ,Dendritic cell ,Molecular biology ,medicine.anatomical_structure ,Oncology ,Feasibility Studies ,Epitope Mapping ,T-Lymphocytes, Cytotoxic - Abstract
HCA661 is a cancer-testis (CT) antigen frequently expressed in human hepatocellular carcinoma (HCC). To search for immunogenic peptides of HCA661, bioinformatics analysis and CD8(+) T cell IFN-gamma ELISPOT assay were employed, and two HLA-A *0201 restricted peptides, H110 and H246, were identified. These two HCA661 peptides are naturally processed in dendritic cells (DCs) and when used for DCs loading, they are sufficient to prime autologous CD8(+) T cells to elicit cytotoxic response against HCA661(+) human cancer cells. The HCA661 peptides, H110 and H246, are hence attractive candidates for human cancer immunotherapy.
- Published
- 2007
27. Induction of T-cell response by a DNA vaccine encoding a novel HLA-A*0201 severe acute respiratory syndrome coronavirus epitope
- Author
-
Fion Wan-Yee Sin, Samuel Chak-Sum Cheng, Yong Xie, Ying-Kit Cheung, and Kin-Tak Chan
- Subjects
DNA vaccine ,Severe acute respiratory syndrome (SARS) ,T-Lymphocytes ,Epitopes, T-Lymphocyte ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Biology ,Severe Acute Respiratory Syndrome ,medicine.disease_cause ,Article ,Epitope ,Cell Line ,DNA vaccination ,Mice ,Immune system ,HLA-A2 Antigen ,MHC class I ,Vaccines, DNA ,medicine ,Animals ,Coronavirus Nucleocapsid Proteins ,Humans ,Cytotoxic T cell ,Coronavirus ,HLA-A Antigens ,General Veterinary ,General Immunology and Microbiology ,Viral Vaccine ,Public Health, Environmental and Occupational Health ,Viral Vaccines ,Nucleocapsid Proteins ,medicine.disease ,Virology ,Infectious Diseases ,Severe acute respiratory syndrome-related coronavirus ,Immunology ,biology.protein ,Molecular Medicine ,Single-chain-trimers (SCT) ,Severe acute respiratory syndrome ,T-Lymphocytes, Cytotoxic - Abstract
The severe acute respiratory syndrome coronavirus nucleocapsid protein (SARS-CoV N) is one of the major targets for SARS vaccine due to its high potency in triggering immune responses. In this study, we have identified a novel HLA-A*0201 restricted epitope, N220 (LALLLLDRL), of the SARS-CoV N-protein through bioinformatics analysis. The N-protein peptide N220 shows a high binding affinity towards human MHC class I in T2-cells, and is capable of activating cytotoxic T-cells in human peripheral blood mononuclear cells (PBMCs). The application of using the N220 peptide sequence with a single-chain-trimer (SCT) approach to produce a potential DNA vaccine candidate was investigated in HLA-A2.1K(b) transgenic mice. Cytotoxicity assay clearly showed that the T-cells obtained from the vaccinated animals were able to kill the N-protein expressing cells with a cytotoxicity level of 86% in an effector cells/target cells ratio of 81:1 one week after the last vaccination, which is significantly higher than other N-protein peptides previously described. The novel immunogenic N-protein peptide revealed in the present study provides valuable information for therapeutic SARS vaccine design.
- Published
- 2007
28. Characterization of the pathogenic mechanism of a novel BRCA2 variant in a Chinese family
- Author
-
Kin-Tak Chan, Edmond S. K. Ma, Ui-Soon Khoo, L. P. Wong, Ava Kwong, and James M. Ford
- Subjects
Adult ,Proband ,Cancer Research ,Genetic counseling ,Genes, BRCA2 ,Genes, BRCA1 ,Breast Neoplasms ,Biology ,Gene mutation ,Frameshift mutation ,Unknown Significance ,Breast cancer ,Germline mutation ,Asian People ,Risk Factors ,Genetics ,medicine ,Humans ,Point Mutation ,Chinese family ,skin and connective tissue diseases ,Germ-Line Mutation ,Genetics (clinical) ,Base Sequence ,Mechanism (biology) ,business.industry ,Cancer ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Pedigree ,Oncology ,Mutation (genetic algorithm) ,Mutation ,RNA splicing ,Identification (biology) ,Female ,business - Abstract
10541 Background: Despite the identification of a large number of sequences in BRCA1/2 mutation analyses, many genetic alterations are classified as variants of unknown significance (VUS). Increasing data demonstrates ethnic variation of BRCA mutation. We report a novel BRCA2 VUS in a Chinese family with multiple breast cancers and characterized it as pathogenic by RNA analysis. Method: Peripheral blood was collected from the breast cancer proband and her family who were suspected to have a pathogenic mutation due the segregation of the disease phenotype and the young age of presentation of breast cancer. DNA and RNA was extracted from the blood. The entire coding regions and flanking introns of BRCA1/2 were screened for germline mutations using full gene sequencing and Multiplex Ligation -dependent Probe Amplification. Variant DNA alteration leading to an aberrant BRCA transcript was demonstrated by RT-PCR of the RNA and Polyacrylamide Gel Electrophoresis. Abnormal bands were cloned and direct sequencing conducted. Results: A germline mutation c.7806–9T>G was identified in the proband at the BRCA2 intron 16. This mutation was also found in 3 of her 4 sibling sisters with early breast cancer. The proband's mother harbored the same BRCA2 mutation in DNA extracted from archival gastric tumor tissues. Computational analyses showed that this mutation might give rise to a cryptic splice site for alternative RNA splicing. To confirm the pathogenicity, RT- PCR using specific primers flanking the cryptic splice site and sequencing was performed on RNA extracted from the proband's blood. Four different sizes of transcripts were found: wild type, r.7806_7874del , r.7806_7976del and r.7806–8_7806-lins. The latter 3 aberrant transcripts were not found in the 30 controls therefore polymorphism is unlikely. The r.7806–8_7806-lins transcript caused a frameshift which created a truncated protein; whereas the other two short transcripts produced shorter BRCA2 protein isoforms. Conclusion: We identified a novel BRCA2 VUS and classified it as pathogenic. Classification of VUS as neutral or pathogenic, particularly in ethnic groups where limited knowledge is known is a challenge. Research on the spectrum of mutations in diversed ethnic groups has important implications on management. [Genbank: DQ889340 ] No significant financial relationships to disclose.
- Published
- 2007
29. Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation
- Author
-
Tsun Ming, Fung, Kai Yu, Ng, Man, Tong, Jin-Na, Chen, Stella, Chai, Kin-Tak, Chan, Simon, Law, Nikki P, Lee, Mei Yuk, Choi, Bin, Li, Annie L, Cheung, Sai Wah, Tsao, Yan-Ru, Qin, Xin-Yuan, Guan, Kwok Wah, Chan, and Stephanie, Ma
- Subjects
Esophageal Neoplasms ,Proto-Oncogene Proteins c-ets ,Carcinogenesis ,MAP Kinase Signaling System ,Cadherins ,Neuropilin-2 ,Up-Regulation ,Cohort Studies ,Gene Expression Regulation, Neoplastic ,Antigens, CD ,Cell Line, Tumor ,Lymphatic Metastasis ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,Carcinoma, Squamous Cell ,Animals ,Humans ,Adenovirus E1A Proteins ,Esophageal Squamous Cell Carcinoma ,Transcriptome - Abstract
Oesophageal squamous cell carcinoma (ESCC) is the most common histological subtype of oesophageal cancer. The disease is particularly prevalent in southern China. The incidence of the disease is on the rise and its overall survival rate remains dismal. Identification and characterization of better molecular markers for early detection and therapeutic targeting are urgently needed. Here, we report levels of transmembrane and soluble neuropilin-2 (NRP2) to be significantly up-regulated in ESCC, and to correlate positively with advanced tumour stage, lymph node metastasis, less favourable R category and worse overall patient survival. NRP2 up-regulation in ESCC was in part a result of gene amplification at chromosome 2q. NRP2 overexpression promoted clonogenicity, angiogenesis and metastasis in ESCC in vitro, while NRP2 silencing by lentiviral knockdown or neutralizing antibody resulted in a contrary effect. This observation was extended in vivo in animal models of subcutaneous tumourigenicity and tail vein metastasis. Mechanistically, overexpression of NRP2 induced expression of ERK MAP kinase and the transcription factor ETV4, leading to enhanced MMP-2 and MMP-9 activity and, as a consequence, suppression of E-cadherin. In summary, NRP2 promotes tumourigenesis and metastasis in ESCC through deregulation of ERK-MAPK-ETV4-MMP-E-cadherin signalling. NRP2 represents a potential diagnostic or prognostic biomarker and therapeutic target for ESCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.
- Published
- 2015
30. Oxygen carrier YQ23 can enhance the chemotherapeutic drug responses of chemoresistant esophageal tumor xenografts
- Author
-
Lai Nar Tung, Kin Tak Chan, Ho Yu Lam, Fei Chuen Tzang, Sze Hang Lau, Sui Yi Kwok, Ian P. Y. Lam, Cornelia Man, Simon Law, Heron Han, Daniel K. Tong, Nikki P. Lee, Mei Yuk Choi, and Bing L. Wong
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,Cell Survival ,Mice, Nude ,Vimentin ,Antineoplastic Agents ,Toxicology ,Hemoglobins ,Internal medicine ,Cell Line, Tumor ,medicine ,Chemosensitizing agent ,Animals ,Humans ,Pharmacology (medical) ,Pharmacology ,Cisplatin ,Tumor hypoxia ,biology ,business.industry ,Mesenchymal stem cell ,Drug Synergism ,Xenograft Model Antitumor Assays ,digestive system diseases ,Tumor Burden ,Oxygen ,Cell culture ,Fluorouracil ,Drug Resistance, Neoplasm ,biology.protein ,Carcinoma, Squamous Cell ,Chemotherapeutic drugs ,business ,medicine.drug - Abstract
Adjunct chemoradiation is offered to unresectable esophageal squamous cell carcinoma (ESCC) patients, while its use is limited in tumors with strong resistance. Oxygen carriers or anti-hypoxic drugs belong to an emerging class of regulators that can alleviate tumor hypoxia. We investigate the potential use of a novel oxygen carrier YQ23 in sensitizing chemoresistant ESCC in a series of subcutaneous tumor xenograft models developed using ESCC cell lines with different strengths of chemosensitivities. Tumor xenografts were developed using SLMT-1 and HKESC-2 ESCC cell lines with different strengths of resistance to two chemotherapeutic drugs, 5-fluorouracil and cisplatin. More resistant SLMT-1 xenografts responded better to YQ23 treatment than HKESC-2, as reflected by the induced tumor oxygen level. YQ23 sensitized SLMT-1 xenografts toward 5-fluorouracil via its effect on reducing the level of a hypoxic marker HIF-1α. Furthermore, a derangement of tumor microvessel density and integrity was demonstrated with a concurrent decrease in the level of a tumor mesenchymal marker vimentin. Similar to the 5-fluorouracil sensitizing effect, YQ23 also enhanced the response of SLMT-1 xenografts toward cisplatin by reducing the tumor size and the number of animals with invasive tumors. Chemosensitive HKESC-2 xenografts were irresponsive to combined YQ23 and cisplatin treatment. In all, YQ23 functions selectively on chemoresistant ESCC xenografts, which implicates its potential use as a chemosensitizing agent for ESCC patients.
- Published
- 2015
31. Tri-band spectroscopic optical coherence tomography based on optical parametric amplification for lipid and vessel visualization
- Author
-
Kin Tak Chan, Xiaoming Wei, Xie Wang, Nikki P. Lee, Kenneth K. Y. Wong, Luoqin Yu, Jiqiang Kang, and Chandra Jinata
- Subjects
Optics and Photonics ,Materials science ,Swine ,Biomedical Engineering ,Imaging phantom ,law.invention ,Biomaterials ,Mice ,Optics ,Optical coherence tomography ,law ,Fiber laser ,medicine ,Image Processing, Computer-Assisted ,Animals ,Optical amplifier ,medicine.diagnostic_test ,Amplifiers, Electronic ,Fourier Analysis ,business.industry ,Phantoms, Imaging ,Attenuation ,Lasers ,Signal Processing, Computer-Assisted ,Arteries ,Equipment Design ,Laser ,Optical parametric amplifier ,Lipids ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials ,Mice, Inbred C57BL ,Wavelength ,Spectrophotometry ,Blood Vessels ,Female ,business ,Tomography, Optical Coherence - Abstract
A tri-band spectroscopic optical coherence tomography (SOCT) system has been implemented for visualization of lipid and blood vessel distribution. The tri-band swept source, which covers output spectrum in 1.3, 1.5, and 1.6 μm wavelength windows, is based on a dual-band Fourier domain mode-locked laser and a fiber optical parametric amplifier. This tri-band SOCT can further differentiate materials, e.g., lipid and artery, qualitatively by contrasting attenuation coefficients difference within any two of these bands. Furthermore, ex vivo imaging of both porcine artery with artificial lipid plaque phantom and mice with coronary artery disease were demonstrated to showcase the capability of our SOCT.
- Published
- 2015
32. 14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules
- Author
-
Lai Nar Tung, Daniel K. H. Tong, Ho Yu Lam, Nikki P. Lee, Hector K. Wang, Raymond Wai-Yin Sun, Winnie Tan, Eva Yi Man Fung, Simon Law, Kenneth K. Y. Lai, Kin Tak Chan, and Mei Yuk Choi
- Subjects
0301 basic medicine ,DNA Repair ,Esophageal Neoplasms ,DNA repair ,Blotting, Western ,Antineoplastic Agents ,HMGB1 ,Bioinformatics ,Polymerase Chain Reaction ,Mass Spectrometry ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,medicine ,Biomarkers, Tumor ,Humans ,HMGB1 Protein ,Chromatography, High Pressure Liquid ,Cisplatin ,Gene knockdown ,biology ,medicine.diagnostic_test ,General Medicine ,Esophageal cancer ,medicine.disease ,Xeroderma Pigmentosum Group A Protein ,030104 developmental biology ,14-3-3 Proteins ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Exoribonucleases ,biology.protein ,Cancer research ,Carcinoma, Squamous Cell ,Ectopic expression ,Esophageal Squamous Cell Carcinoma ,Transcriptome ,medicine.drug - Abstract
Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.
- Published
- 2015
33. Investigations of p53 mutations and effects on drug resistance
- Author
-
Kin Tak Chan
- Published
- 2014
34. Humanization, expression and characterization of an anti-hepatocellular carcinoma monoclonal antibody
- Author
-
Kin Tak Chan
- Published
- 2014
35. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line
- Author
-
Maria Li Lung and Kin-Tak Chan
- Subjects
Cancer Research ,Carcinoma, Hepatocellular ,Paclitaxel ,Tumor suppressor gene ,Cell Survival ,Mutant ,Apoptosis ,Drug resistance ,Transfection ,Toxicology ,Gene product ,Cell Line, Tumor ,In Situ Nick-End Labeling ,Humans ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,P-glycoprotein ,Pharmacology ,biology ,Liver Neoplasms ,DNA, Neoplasm ,Flow Cytometry ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Multiple drug resistance ,Oncology ,Doxorubicin ,Drug Resistance, Neoplasm ,Cell culture ,Mutation ,Cancer cell ,Cancer research ,biology.protein ,Tumor Suppressor Protein p53 - Abstract
Chemoresistance is a major problem in the treatment of hepatocellular carcinoma. Certain p53 mutants may enhance drug resistance in cancer cells. To determine whether two frequently occurring p53 mutants, R248Q and R273C, would increase the drug resistance of liver cancer cells, stable cell lines expressing these specific p53 mutants were established by transfecting the p53-null Hep3B cells with mutant p53 expression vectors, and then treating them with the anticancer drugs doxorubicin and paclitaxel. The cells expressing the p53 mutant, R248Q, but not R273C, displayed cross-resistance to both drugs, in contrast to the control cells expressing the vector alone. Moreover, both the expression and the activity of the multiple drug resistance gene product, P-glycoprotein, were elevated in p53 mutant R248Q-expressing cells. Reduced uptake of doxorubicin was also observed in the R248Q-expressing cells. These results suggest that expression of the p53 mutant, R248Q, in liver cancer cells may enhance their drug resistance and that upregulation of P-glycoprotein activity may contribute to this protective effect.
- Published
- 2004
36. Differential Expression of a Stress-modulating Gene, BRE, in the Adrenal Gland, in Adrenal Neoplasia, and in Abnormal Adrenal Tissues
- Author
-
Ningshao Xia, John Y.H. Chan, Nirmal S. Panesar, Ji Miao, Yingbin Wang, Philip J. Johnson, Fernand M.M. Lai, and Kin-Tak Chan
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Histology ,Immunoblotting ,Adrenal Gland Neoplasms ,Nerve Tissue Proteins ,Biology ,03 medical and health sciences ,Internal medicine ,Cortex (anatomy) ,Adrenal Glands ,medicine ,Animals ,Humans ,RNA, Messenger ,Northern blot ,Biological response modifiers ,Gene ,In Situ Hybridization ,Nitrites ,Nitrates ,030102 biochemistry & molecular biology ,Adrenal gland ,Blotting, Northern ,Immunohistochemistry ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Organ Specificity ,Tumor necrosis factor alpha ,Anatomy ,Signal transduction ,Hormone - Abstract
Genes that modulate the action of hormones and cytokines play a critical role in stress response, survival, and in growth and differentiation of cells. Many of these biological response modifiers are responsible for various pathological conditions, including inflammation, infection, cachexia, aging, genetic disorders, and cancer. We have previously identified a new gene, BRE, that is responsive to DNA damage and retinoic acid. Using multiple-tissue dot-blotting and Northern blotting, BRE was recently found to be strongly expressed in adrenal cortex and medulla, in testis, and in pancreas, whereas low expression was found in the thyroid, thymus, small intestine and stomach. In situ hybridization and immunohistochemical staining indicated that BRE was strongly expressed in the zona glomerulosa of the adrenal cortex, which synthesizes and secretes the mineralocorticoid hormones. It is also highly expressed in the glial and neuronal cells of the brain and in the round spermatids, Sertoli cells, and Ledig cells of the testis, all of which are associated with steroid hormones and/or TNF synthesis. However, BRE expression was downregulated in human adrenal adenoma and pheochromocytoma, whereas its expression was enhanced in abnormal adrenal tissues of rats chronically treated with nitrate or nitrite. These data, taken together, indicate that the expression of BRE is apparently associated with steroids and/or TNF production and the regulation of endocrine functions. BRE may play an important role in the endocrine and immune system, such as the cytokine–endocrine interaction of the adrenal gland.
- Published
- 2001
37. Role of AMPK signaling in mediating the anticancer effects of silibinin in esophageal squamous cell carcinoma
- Author
-
Jin Li, Bin Li, Kwok Wah Chan, Simon Law, Sai Wah Tsao, Wen Wen Xu, Xin Yuan Guan, Yan Ru Qin, Nikki Pui Yue Lee, Kin Tak Chan, Annie LM Cheung, Jin Li, Bin Li, Kwok Wah Chan, Simon Law, Sai Wah Tsao, Wen Wen Xu, Xin Yuan Guan, Yan Ru Qin, Nikki Pui Yue Lee, Kin Tak Chan, and Annie LM Cheung
- Published
- 2015
- Full Text
- View/download PDF
38. Circulating Biomarkers for Esophageal Squamous Cell Carcinoma
- Author
-
Nikki P. Lee, Simon Law, Sarwat Fatima, Kin Tak Chan, and Kenneth K. Y. Lai
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Cancer ,Esophageal cancer ,medicine.disease ,Asymptomatic ,Esophageal squamous cell carcinoma ,digestive system diseases ,Circulating biomarkers ,Internal medicine ,microRNA ,medicine ,Cancer biomarkers ,medicine.symptom ,business ,neoplasms ,Chemoradiotherapy - Abstract
Esophageal cancer is the eighth most common cancer worldwide and esophageal squamous cell carcinoma (ESCC) is the predominant type in Asia. Surgical resection of the tumor is the mainstay treatment for ESCC. Recent advances in neoadjuvant or adjuvant chemotherapy/chemoradiotherapy for treatment of ESCC have significantly improved prognosis. Despite these advancements, survival of some patients still remains poor in particular for those diagnosed at a late stage. In view of the asymptomatic nature of early ESCC and the limitations of currently used diagnostic methods, there is a pressing need to identify circulatory biomarkers to allow noninvasive and early detection of ESCC. In this chapter, we summarize circulating cancer biomarkers including circulatory proteins, microRNAs, and tumor cells that are found to have elevated level in serum and plasma of ESCC patients when compared to healthy subjects. These biomarkers could help improve the diagnostic efficiency of ESCC.
- Published
- 2013
39. Fucoidin enhances dendritic cell-mediated T-cell cytotoxicity against NY-ESO-1 expressing human cancer cells
- Author
-
Samuel Chak-Sum Cheng, Chenjie Zeng, Kin-Tak Chan, Fion Wan-Yee Sin, Yaling Hu, Yan Ke, Yong Xie, and Bofu Xue
- Subjects
Cytotoxicity, Immunologic ,Biophysics ,Membrane Proteins ,Antineoplastic Agents ,Cell Biology ,Dendritic cell ,Dendritic Cells ,Biology ,Biochemistry ,Cell biology ,Cross-Priming ,Antigen ,Cell culture ,Antigens, Neoplasm ,Polysaccharides ,Cell Line, Tumor ,Neoplasms ,Cancer/testis antigens ,Cytotoxic T cell ,Humans ,NY-ESO-1 ,Cytotoxicity ,Molecular Biology ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Scavenger receptor A (SR-A) plays a crucial role in affecting the dendritic cell-mediated presentation of cancer testis antigens to T cells against human cancer cells. Here we use a dendritic cell-mediated model to verify that a sulphated polysaccharide, fucoidin, can regulate the adverse regulatory function of SR-A, and lead to the up-regulation of the anti-tumor immunological response. SR-A is a receptor of calreticulin (CRT) existing on the surface of dendritic cells (DCs). CRT is a specific receptor for a NY-ESO-1 cancer testis antigen, and CRT itself is responsible for the cross-presentation of NY-ESO-1 to CD8+ cells and the induction of anti-tumor immunity. Flow cytometrical analysis (FACS) showed that fucoidin was able to significantly enhance the binding ratio of NY-ESO-1 to human DCs in a concentration dependent manner, and that the addition of fucoidin promoted the DC maturation upon stimulation of NY-ESO-1. Results from a cytotoxicity assay indicated that fucoidin-treated DCs stimulated the CD8+ T cells more effectively than non-treated DCs via a cross-presentation pathway. Furthermore, it was found that after stimulated by fucoidin-treated DCs, the CD8+ T cells can release more IFN-gamma than non-fucoidin-treated cells as detected by intracellular IFN-gamma staining. We conclude that fucoidin enhances the cross-presentation of NY-ESO-1 to T cells leading to an increase of T-cell cytotoxicity against NY-ESO-1 expressing human cancer cells.
- Published
- 2010
40. Cucurbitacin B inhibits STAT3 and the Raf/MEK/ERK pathway in leukemia cell line K562
- Author
-
Wei Dong Xie, Kwan Li, Shiu Lam Liu, Kee Hung Chu, Kin Tak Chan, and Melvin Toh
- Subjects
MAPK/ERK pathway ,STAT3 Transcription Factor ,Cancer Research ,MAP Kinase Signaling System ,Blotting, Western ,Antineoplastic Agents ,Apoptosis ,Biology ,Pharmacology ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,Humans ,Extracellular Signal-Regulated MAP Kinases ,Mitogen-Activated Protein Kinase Kinases ,Cucurbitacin ,Cell growth ,medicine.disease ,Flow Cytometry ,Molecular biology ,Triterpenes ,Leukemia ,Oncology ,chemistry ,Cell culture ,raf Kinases ,Growth inhibition ,K562 Cells ,K562 cells ,Signal Transduction - Abstract
Cucurbitacin B is a natural anti-cancer compound found in Cucurbitaceae. Although the anti-cancer activity of cucurbitacin B in human leukemia cells has been reported, the underlining mechanism is still unclear. To clarify its anti-cancer activity and the mechanism of action, five different leukemia cell lines (CCRF-CEM, K562, MOLT-4, RPMI-8226 and SR) of the National Cancer Institute panel were treated with cucurbitacin B. Leukemia cell growth was inhibited by cucurbitacin B with GI(50) ranged from 15.6 nM to 35.3 nM and the growth inhibition effect was attributable to G2/M phase arrest and apoptosis. Western blotting analysis of cell signaling molecules indicated that cucurbitacin B inhibits STAT3 activation and the Raf/MEK/ERK pathway in the K562 cells.
- Published
- 2009
41. Activation of cytotoxic T lymphocytes against CML28-bearing tumors by dendritic cells transduced with a recombinant adeno-associated virus encoding the CML28 gene
- Author
-
Yi Xie, Yong Xie, Ying-Kit Cheung, Fion Wan-Yee Sin, Kin-Tak Chan, Li-Hua Xie, and Samuel Chak-Sum Cheng
- Subjects
Cancer Research ,viruses ,medicine.medical_treatment ,Immunology ,Genes, MHC Class I ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Adenoviridae ,Multiplicity of infection ,Antigen ,Cancer immunotherapy ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,RNA, Messenger ,Antigen-presenting cell ,Exosome Multienzyme Ribonuclease Complex ,RNA-Binding Proteins ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,Virology ,Oncology ,Antigens, Surface ,Exoribonucleases ,B7-1 Antigen ,Feasibility Studies ,Cancer vaccine ,T-Lymphocytes, Cytotoxic - Abstract
Induction of anti-tumor immune responses by dendritic cells (DCs) transduced with a recombinant adeno-associated virus type 2 (rAAV2) encoding tumor antigens is considered a promising approach for cancer vaccine development. CML28, a novel antigen with the properties of cancer/ testis (CT) antigens, is an attractive target for antigen-specific immunotherapy. Here we investigated the feasibility of inducing CML28-specific cytotoxic T lymphocyte (CTL) responses using DCs transduced with the rAAV2 vectors containing the CML28 gene (rAAV/CML28). Using an adenovirus-free packaging system, rAAV/CML28 was generated. The transduction efficiency of rAAV/CML28 in DCs increased in a multiplicity of infection (MOI)-dependent manner. The rAAV/CML28 transduction did not impair DC maturation, but even enhanced the CD80 expression. The rAAV/CML28-transduced DCs induced CML28-specific CTLs which exhibited a MHC class I-mediated antigen-specific lytic activity against CML28-bearing tumor cell lines (HepG2 and MCF-7) as well as the primary leukemia blasts. These findings suggest that rAAV/CML28-transduced DCs vaccine may serve as a feasible approach for the treatment of CML28-associated cancers.
- Published
- 2007
42. Abstract 3989: MicroRNA-16 and microRNA-193b as serological predictors for chemoradiation response in esophageal squamous cell carcinoma patients
- Author
-
Nikki P. Lee, Kenneth K. Y. Lai, Kin Tak Chan, Simon Law, and Daniel K. Tong
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Esophageal cancer ,medicine.disease ,Malignancy ,Esophageal squamous cell carcinoma ,Surgery ,Serology ,medicine.anatomical_structure ,Internal medicine ,microRNA ,Cohort ,medicine ,Esophagus ,business - Abstract
Esophageal cancer is one of the most deadly malignancies along the gastrointestinal tract. Esophageal squamous cell carcinoma (ESCC) is the most common cell type occurring at the upper and middle part of the esophagus. Surgery remains the mainstay treatment for this malignancy, however the long-term prognosis is modest with a 5-year overall survival of approximately 30%. To improve the treatment outcome of this cancer, multimodal treatment strategies including neoadjuvant chemoradiation have been implemented. Such pre-surgery treatment indeed leads to better clinical outcome and increases the chance for cure. Unfortunately patients who do not respond may have to undergo prolonged, unnecessary and potentially toxic treatments with no benefits. Currently, there is no reliable method for chemoradiation response prediction. To address this clinical limitation, we have established a non-invasive assay to stratify chemoradiation responders from non-responders. This study is systematically divided into three phases. In the discovery phase (phase I), we found 23 human microRNAs (out of 742 human microRNAs) with more than 2.5-fold elevation in serum from chemoradiation responders when compared to non-responders. In the selection and small-scale validation phase (phase II), small-scale validation in an independent cohort showed that microRNA-16 and microRNA-193b were two most powerful candidates for indicating chemoradiation responders. In the large-scale validation phase (phase III), we have further validated and confirmed the feasibility of microRNA-16 and miroRNA-193b as discriminators for chemoradiation response in a large cohort of more than a hundred patients. Standard curves were also constructed for these two microRNAs for copy number quantitation. In all, we have newly established a highly sensitive and specific blood-based assay with specific cut-offs for discriminating ESCC patients who are responsive to chemoradiation. This assay works by quantitating the serum level of microRNA-16 and microRNA-193b in ESCC patients, such that patients would be advised to receive pre-surgery chemoradiation if they have elevated levels of circulatory microRNA-16 and microRNA-193b. The development of this assay will benefit patient care by formulating individualized treatment plans. Note: This abstract was not presented at the meeting. Citation Format: Nikki P. Lee, Kenneth K. Lai, Kin Tak Chan, Daniel K. Tong, Simon Law. MicroRNA-16 and microRNA-193b as serological predictors for chemoradiation response in esophageal squamous cell carcinoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2015-3989
- Published
- 2015
43. Simultaneous dual-band optical coherence tomography for endoscopic applications
- Author
-
P. C. Chui, Nikki P. Lee, Jianbing Xu, Xie Wang, Kin Tak Chan, Xiaoming Wei, Edmund Y. Lam, Luoqin Yu, and Kenneth K. Y. Wong
- Subjects
Materials science ,genetic structures ,Biomedical Engineering ,law.invention ,Fingers ,Biomaterials ,Mice ,Esophagus ,Optics ,Optical coherence tomography ,law ,Wavelength-division multiplexing ,medicine ,Medical imaging ,Endomicroscopy ,Animals ,Humans ,Fourier Analysis ,medicine.diagnostic_test ,business.industry ,Endoscopy ,Laser ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials ,Imaging spectroscopy ,Mode-locking ,Optoelectronics ,sense organs ,business ,Tomography, Optical Coherence ,Preclinical imaging - Abstract
Dual-band optical coherence tomography (OCT) can greatly enhance the imaging contrast with potential applications in functional (spectroscopic) analysis. A new simultaneous dual-band Fourier domain mode-locked swept laser configuration for dual-band OCT is reported. It was based on a custom-designed dual-channel driver to synchronize two different wavelength bands at 1310 and 1550 nm, respectively. Two lasing wavelengths were swept simultaneously from 1260 to 1364.8 nm for the 1310-nm band and from 1500 to 1604 nm for the 1550-nm band at an A-scan rate of 45 kHz. Broadband wavelength-division multiplexing was utilized to couple two wavelength bands into a common catheter for circumferential scanning to form dual-band OCT. The proposed dual-band OCT scheme was applied to endoscopic OCT imaging of mouse esophageal wall ex vivo and human fingertip in vivo to justify the feasibility of the proposed imaging technique. The proposed dual-band OCT system is fast and easy to be implemented, which allows for in vivo high-speed biomedical imaging with potential applications in spectroscopic investigations for endoscopic imaging. © 2014
- Published
- 2014
44. In vitro aflatoxin B1-induced p53 mutations
- Author
-
Maria Li Lung, Dennis P.H. Hsieh, and Kin-Tak Chan
- Subjects
Cancer Research ,Aflatoxin B1 ,DNA, Complementary ,Guanine ,Saccharomyces cerevisiae ,Biology ,Polymerase Chain Reaction ,DNA sequencing ,chemistry.chemical_compound ,Codon ,Gene ,DNA Primers ,Base Sequence ,Nucleic acid sequence ,Methylation ,Templates, Genetic ,DNA Methylation ,Genes, p53 ,Molecular biology ,Oncology ,CpG site ,chemistry ,DNA methylation ,Cancer research ,Carcinogens ,DNA ,Dinucleoside Phosphates ,Mutagens ,Plasmids - Abstract
The tumor suppressor gene p53 is commonly mutated with high frequencies at certain hot spots in human cancers. In liver cancers there is an especially high frequency of mutations at codon 249. To study the impact of carcinogen targeting and the role of cytosine methylation on the mutation spectrum, a common liver cancer carcinogen aflatoxin B1 (AFB1), was studied using the p53 cDNA template to examine mutation induction. Subsequent mutations were detected with a yeast p53 functional assay and identified by DNA sequencing. The results indicated that cytosine methylation enhances AFB1-induced guanine mutations at CpG sites. However, no mutations were detected at codon 249.
- Published
- 2003
45. Su1928 Comparison of Effects of Sleeve Gastrectomy, Duodenal-Jejunal Bypass and Ileal Transposition for the Treatment of Type II Diabetes
- Author
-
Nikki P. Lee, Kwan Man, Kin-Tak Chan, Daniel K. Tong, Kenneth K. Y. Lai, and Simon Law
- Subjects
medicine.medical_specialty ,Matrigel ,Hepatology ,business.industry ,Crypt ,Gastroenterology ,Transfection ,Molecular biology ,In vitro ,Viral vector ,Transplantation ,Epidermal growth factor ,Internal medicine ,medicine ,Stem cell ,business - Abstract
Background: Porcine models are important tools for preclinical studies of stem cell transplantation. However, methods for the long-term culture and genetic manipulation of small intestinal crypt stem cells from adult pigs are lacking. Methods: Two-cm segments of jejunum were procured from 10-14 week-old Yorkshire pigs (n=17). Crypts were isolated by EDTA chelation, suspended in Matrigel and grown in various culture media. We first used murine media containing only epidermal growth factor, noggin, and R-spondin 1 ("ENR medium") and then tested supplementation of Wnt3a, nicotinamide and small molecule inhibitors of GSK3 (CHIR99021), p160ROCK (Y27632), p38MAP kinase (SB202190), and TGFβ receptor (LY2157299). We also isolated intestinal subepithelial myofibroblasts (ISEMFs), cultured them in DMEM with 10% FBS and added ISEMF or Wnt3a-conditioned medium (CM) to crypt cultures in a 1:1 ratio. We evaluated all media for enterosphere-forming efficiency and assessed cell lineage differentiation by immunohistology and fluorescence microscopy (FM). After we found that enteroids could be grown long-term in ENR medium with nicotinamide, Wnt3a-CM, SB202190 and LY2157299, we passaged enteroids while adding various compounds, e.g., PGE2 and the Notch ligand Jagged1, and testedmedia combinations to produce transducible cells. When crypts were grown in ENR medium with ISEMF-CM, CHIR99021 and Y27632, spheroids formed in culture that could be transduced using a lentiviral vector encoding a GFP reporter. Spheroids were maintained in this medium for 2 days and reporter activity was assessed by FM. Results: ENR medium did not sustain adult porcine enterospheres beyond 5 days in culture. Addition of nicotinamide and small molecule inhibitors drastically improved 2-5 day survival of enterospheres but did not support long-term culture. Crypts grown in presence of porcine ISEMF-CM or co-cultured with porcine ISEMFs formed large, thin-walled spheroids. In contrast, Wnt3a-CM resulted in complex enteroids with budding extensions. Passaged enteroids continued to proliferate well for up to 5 weeks in culture when PGE2 was added at time of passage to enhance growth whereas Jagged1 had no discernible effect. Successful lentiviral transfection of spheroids was demonstrated with reporter activity present in >90% of transduced spheroids compared to controls. Discussion: We describe a novel method to maintain adult porcine crypt cells in culture over several weeks. Porcine crypts can be induced by specific supplements to form enteroids which can be repeatedly passaged in vitro. Porcine ISEMFs produce factors that induce formation of spheroids which can be successfully transduced with >90% efficiency using lentiviral vectors. Acknowledgment: This work was conducted by the Intestinal Stem Cell Consortium. The ISCC is supported by the NIDDK and NIAID (grant #DK085535).
- Published
- 2014
46. A humanized monoclonal antibody constructed from intronless expression vectors targets human hepatocellular carcinoma cells
- Author
-
Hong Xie, Samuel Chak-Sum Cheng, Kin-Tak Chan, and Yong Xie
- Subjects
Carcinoma, Hepatocellular ,medicine.drug_class ,Genetic Vectors ,Molecular Sequence Data ,Biophysics ,Cytomegalovirus ,Fluorescent Antibody Technique ,Enzyme-Linked Immunosorbent Assay ,CHO Cells ,Biology ,Humanized antibody ,Monoclonal antibody ,Biochemistry ,Binding, Competitive ,Chromatography, Affinity ,Immunoglobulin kappa-Chains ,Mice ,Affinity chromatography ,Antibody Specificity ,Complementary DNA ,Cricetinae ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Serologic Tests ,Amino Acid Sequence ,Molecular Biology ,Peptide sequence ,Expression vector ,Base Sequence ,Dose-Response Relationship, Drug ,Liver Neoplasms ,Antibodies, Monoclonal ,Cell Biology ,Molecular biology ,Introns ,Immunoglobulin G ,biology.protein ,Antibody ,Protein A ,Immunoglobulin Heavy Chains - Abstract
An anti-human hepatocellular carcinoma (HCC) monoclonal antibody, hHP-1, was genetically humanized from a murine monoclonal antibody. In this study, a concept of positional template approach was applied to design the amino acid sequence of hHP-1's variable region, and synthetic DNA fragments for protein expression were produced through overlapping PCR from single strand oligonucleotides. Synthetic DNA fragments and human antibody constant region cDNA were used to construct two CMV promotor-based expression vectors for the antibody light and heavy chains, in which the variable region was connected directly to the constant region without an intron sequence. Completely assembled humanized antibody was successfully expressed in mammalian cells as IgG1 kappa molecules and purified using protein A affinity column. The immunogenicity of the hHP1 was estimated by the amino acid sequence and determined through a HAMA (human anti-murine antibody) serum reaction assay. Results indicated that the immunogenicity of hHP-1 was significantly reduced. In vitro binding activity assay showed that the hHP-1 had retained its binding function to a human HCC SMMC-7721 cell-line, without cross binding to other human normal tissues. Immunofluorescence staining showed that hHP-1 had a strong binding activity to SMMC cells. A competitive binding assay showed that the relative binding activity of hHP-1 was approximately 25% binding activity of the original murine antibody. Our results indicate that a humanized antibody could be produced using intronless vectors and expressed as a complete IgG1 kappa antibody. Hence we believe that hHP-1 could be a potential candidate for HCC treatment.
- Published
- 2001
47. Tri-band spectroscopic optical coherence tomography based on optical parametric amplification for lipid and vessel visualization.
- Author
-
Luoqin Yu, Jiqiang Kang, Jinata, Chandra, Xie Wang, Xiaoming Wei, Kin Tak Chan, Lee, Nikki P., and Wong, Kenneth K. Y.
- Subjects
OPTICAL coherence tomography ,OPTICAL parametric amplifiers ,SPECTROMETRY ,BLOOD vessels ,CORONARY disease - Abstract
A tri-band spectroscopic optical coherence tomography (SOCT) system has been implemented for visualization of lipid and blood vessel distribution. The tri-band swept source, which covers output spectrum in 1.3, 1.5, and 1.6 μmwavelength windows, is based on a dual-band Fourier domain mode-locked laser and a fiber optical parametric amplifier. This tri-band SOCT can further differentiate materials, e.g., lipid and artery, qualitatively by contrasting attenuation coefficients difference within any two of these bands. Furthermore, ex vivo imaging of both porcine artery with artificial lipid plaque phantom and mice with coronary artery disease were demonstrated to showcase the capability of our SOCT. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
48. Abstract LB-231: Decoding complex patterns of structural variations in hepatocellular carcinoma
- Author
-
Sheung Tat Fan, Kin Tak Chan, Ronnie T.P. Poon, Nikki P. Lee, Winnie Tan, Xiao Liu, Zhengyan Kan, Shiyong Li, Keith A. Ching, Huan Gao, Mao Mao, Wing Kin Sun, Paul A. Rejto, and Julio Fernandez-Banet
- Subjects
Genetics ,Cancer Research ,Chromothripsis ,Breakpoint ,Cancer ,Biology ,medicine.disease ,Genome ,Oncology ,Chromosome instability ,Hepatocellular carcinoma ,medicine ,Copy-number variation ,Gene - Abstract
Elucidating the molecular basis of Hepatocellular Carcinoma (HCC) is crucial to developing targeted diagnostics and therapies for this deadly disease. Somatically acquired structural variations (SVs) can lead to oncogenic gene fusions and gene expression deregulation in tumors. Although recent studies have delineated HCC genomic alterations including copy number variations, somatic mutations and HBV integrations, the landscape of SVs remains poorly characterized in HCC. We have predicted 4,314 SVs including large-scale insertions, deletions, inversions and translocations based on the whole-genome sequencing data for 88 primary HCC tumor/non-tumor tissues. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. TP53 and RB1 alterations appear to cause increased levels of genomic arrangement and chromosomal instability. Albumin (ALB) was found to be the most significantly affected by SVs and harbor genomic alterations including deactivating mutations and deletions in 10.2% of cohort. Integrative analysis revealed a causal link between genomic rearrangements and copy number variations, such as focal amplifications of the CCND1/FGF19 loci, and distinctive patterns of copy number variation flanking SV breakpoints. Furthermore, we predicted 260 gene fusions which frequently result in aberrant over-expression of the 3′ genes in tumors. Citation Format: Julio Fernandez-Banet, Nikki P. Lee, Kin Tak Chan, Huan Gao, Xiao Liu, Wing Kin Sun, Winnie Tan, Sheung Tat Fan, Ronnie T. Poon, Shiyong Li, Keith Ching, Paul Rejto, Mao Mao, Zhengyan Kan. Decoding complex patterns of structural variations in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-231. doi:10.1158/1538-7445.AM2013-LB-231
- Published
- 2013
49. Activation of cytotoxic T lymphocytes against CML28-bearing tumors by dendritic cells transduced with a recombinant adeno-associated virus encoding the CML28 gene.
- Author
-
Li-HuaXie, Fion Sin, Samuel Cheng, Ying-Kit Cheung, Kin-Tak Chan, Yi Xie, and Yong Xie
- Subjects
IMMUNE response ,T cells ,CELL-mediated cytotoxicity ,TUMORS ,RECOMBINANT viruses ,ANTIGENS ,ADENOVIRUSES - Abstract
Induction of anti-tumor immune responses by dendritic cells (DCs) transduced with a recombinant adeno-associated virus type 2 (rAAV2) encoding tumor antigens is considered a promising approach for cancer vaccine development. CML28, a novel antigen with the properties of cancer/testis (CT) antigens, is an attractive target for antigen-specific immunotherapy. Here we investigated the feasibility of inducing CML28-specific cytotoxic T lymphocyte (CTL) responses using DCs transduced with the rAAV2 vectors containing the CML28 gene (rAAV/CML28). Using an adenovirus-free packaging system, rAAV/CML28 was generated. The transduction efficiency of rAAV/CML28 in DCs increased in a multiplicity of infection (MOI)-dependent manner. The rAAV/CML28 transduction did not impair DC maturation, but even enhanced the CD80 expression. The rAAV/CML28-transduced DCs induced CML28-specific CTLs which exhibited a MHC class I-mediated antigen-specific lytic activity against CML28-bearing tumor cell lines (HepG2 and MCF-7) as well as the primary leukemia blasts. These findings suggest that rAAV/CML28-transduced DCs vaccine may serve as a feasible approach for the treatment of CML28-associated cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
50. Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma
- Author
-
Zhengyan Kan, Nikki P. Lee, Kin Tak Chan, Wing-Kin Sung, Ronnie T.P. Poon, Keith A. Ching, Julio Fernandez-Banet, Paul A. Rejto, Xiao Liu, Mao Mao, Huan Gao, Winnie Tan, Shiyong Li, and Sheung Tat Fan
- Subjects
Male ,Carcinoma, Hepatocellular ,Hepatocellular carcinoma ,Chromosomal translocation ,Biology ,Genome ,Translocation, Genetic ,Cohort Studies ,Genetics ,Humans ,Copy-number variation ,ABCB11 ,Gene ,Whole genome sequencing ,Gene Rearrangement ,Whole-genome sequencing ,Chromothripsis ,Genome, Human ,Copy number variation ,Breakpoint ,Liver Neoplasms ,Genomic rearrangement ,Chromosomes, Human, Pair 1 ,Female ,Chromosomes, Human, Pair 8 ,Genome-Wide Association Study - Abstract
Elucidating the molecular basis of hepatocellular carcinoma (HCC) is crucial to developing targeted diagnostics and therapies for this deadly disease. The landscape of somatic genomic rearrangements (GRs), which can lead to oncogenic gene fusions, remains poorly characterized in HCC. We have predicted 4314 GRs including large-scale insertions, deletions, inversions and translocations based on the whole-genome sequencing data for 88 primary HCC tumor/non-tumor tissues. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. Albumin (ALB) was found to harbor GRs, deactivating mutations and deletions in 10% of cohort. Integrative analysis identified a pattern of paired intra-chromosomal translocations flanking focal amplifications and asymmetrical patterns of copy number variation flanking breakpoints of translocations. Furthermore, we predicted 260 gene fusions which frequently result in aberrant over-expression of the 3′ genes in tumors and validated 18 gene fusions, including recurrent fusion (2/88) of ABCB11 and LRP2.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.