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Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor‐promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell‐cell and cell‐extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15‐knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15‐deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen‐presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15‐derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy. [ABSTRACT FROM AUTHOR]

Due to the heterogeneity of colon cancer, surgery, chemotherapy, and radiation are ineffective in all cases. The genomic profile and biomarkers associated with the process are considered in personalized medicine, along with the patient's personal history. It is based on the response of the targeted therapies to specific genetic variations. The patient's genetic transcriptomic and epigenetic features are evaluated, and the best therapeutic approach and diagnostic testing are identified through personalized medicine. This review aims to summarize all the necessary, updated information on colon cancer related to personalized medicine. Personalized medicine is gaining prominence as generalized treatments are finding it challenging to contain colon cancer cases which currently rank fourth among global cancer incidence while being the fifth largest in total death cases worldwide. In personalized therapy, patients are grouped into specific categories, and the best therapeutic approach is chosen based on evaluating their molecular features. Various personalized strategies are currently being explored in the treatment of colon cancer involving immunotherapy, phytochemicals, and other biomarker-specific targeted therapies. However, significant challenges must be overcome to integrate personalized medicine into healthcare systems completely. We look at the various signaling pathways and genetic and epigenetic alterations associated with colon cancer to understand and identify biomarkers useful in targeted therapy. The current personalized therapies available in colon cancer treatment and the strategies being explored to improve the existing methods are discussed. This review highlights the advantages and limitations of personalized medicine in colon cancer therapy. The current scenario of personalized medicine in developed countries and the challenges faced in middle- and low-income countries are also summarized. Finally, we discuss the future perspectives of personalized medicine in colon cancer and how it could be integrated into the healthcare systems. [ABSTRACT FROM AUTHOR]

The role of microRNA 122 (miR-122) in colorectal cancer (CRC) has not been widely investigated. In the current study, we aimed to identify the prominent gene and protein interactors of miR122 in CRC. Based on their binding affinity, these targets were chosen as candidate genes for the creation of miR122–mRNA duplexes. Following this, we examined the miRNA-mediated silencing mechanism using the gene-silencing complex protein Argonaute (AGO). Public databases, STRING, and GeneMANIA were utilized to identify major proteins and genes interacting with miR-122. DAVID, PANTHER, UniProt, FunRich, miRwalk, and KEGG were used for functional annotation, pathway enrichment, binding affinity analysis, and expression of genes in different stages of cancer. Three-dimensional duplexes of hub genes and miR-122 were created using the RNA composer, followed by molecular interaction analysis using molecular docking with the AGO protein. We analyzed, classified, and scrutinized 93 miR-122 interactors using various bioinformatic approaches. A total of 14 hub genes were categorized as major interactors of miR-122. The study confirmed the role of various experimentally documented miR-122 interactors such as MTDH (Q86UE4), AKT1 (P31749), PTPN1 (P18031), MYC (P01106), GSK3B (P49841), RHOA (P61586), and PIK3CG (P48736) and put forth several novel interactors, with AKT3 (Q9Y243), NCOR2 (Q9Y618), PIK3R2 (O00459), SMAD4 (P61586), and TGFBR1 (P36897). Double-stranded RNA duplexes of the strongest interactors were found to exhibit higher binding affinity with AGO. In conclusions, the study has explored the role of miR-122 in CRC and has identified a closely related group of genes influencing the prognosis of CRC in multiple ways. Further, these genes prove to be targets of gene silencing through RNA interference and might serve as effective therapeutic targets in understanding and treating CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: The identification of effective novel biomarkers is emergently needed in colon cancer patients. In the present study, firstly we predicted that CHGA could be a biomarker for colon cancer based on the protein–protein interaction network of all the reported biomarkers that were collected from our colorectal cancer biomarker database (CBD). Then we verified our results using a diagnostic test in gene expression data and an immunohistochemistry test. The results of this study suggest that a loss of CHGA expression from the normal colon and adjacent mucosa to colon cancer may be used as a valuable biomarker for early diagnosis of colon cancer patients. Background. The incidence of colorectal cancers has been constantly increasing. Although the mortality has slightly decreased, it is far from satisfaction. Precise early diagnosis for colorectal cancer has been a great challenge in order to improve patient survival. Patients and Methods. We started with searching for protein biomarkers based on our colorectal cancer biomarker database (CBD), finding differential expressed genes (GEGs) and non-DEGs from RNA sequencing (RNA-seq) data, and further predicted new biomarkers of protein–protein interaction (PPI) networks by machine learning (ML) methods. The best-selected biomarker was further verified by a receiver operating characteristic (ROC) test from microarray and RNA-seq data, biological network, and functional analysis, and immunohistochemistry in the tissue arrays from 198 specimens. Results. There were twelve proteins (MYO5A, CHGA, MAPK13, VDAC1, CCNA2, YWHAZ, CDK5, GNB3, CAMK2G, MAPK10, SDC2, and ADCY5) which were predicted by ML as colon cancer candidate diagnosis biomarkers. These predicted biomarkers showed close relationships with reported biomarkers of the PPI network and shared some pathways. An ROC test showed the CHGA protein with the best diagnostic accuracy (AUC = 0.9 in microarray data and 0.995 in RNA-seq data) among these candidate protein biomarkers. Furthermore, immunohistochemistry examination on our colon cancer tissue microarray samples further confirmed our bioinformatical prediction, indicating that CHGA may be used as a potential biomarker for early diagnosis of colon cancer patients. Conclusions. CHGA could be a potential candidate biomarker for diagnosing earlier colon cancer in the patients. [ABSTRACT FROM AUTHOR]

Background: Rectal cancer is a disease characterized with tumor heterogeneity. The combination of surgery, radiotherapy, and chemotherapy can reduce the risk of local recurrence. However, there is a significant difference in the response to radiotherapy among rectal cancer patients even they have the same tumor stage. Despite rapid advances in knowledge of cellular functions affecting radiosensitivity, there is still a lack of predictive factors for local recurrence and normal tissue damage. The tumor protein DNp73 is thought as a biomarker in colorectal cancer, but its clinical significance is still not sufficiently investigated, mainly due to the limitation of human-based pathology analysis. In this study, we investigated the predictive value of DNp73 in patients with rectal adenocarcinoma using image-based network analysis. Methods: The fuzzy weighted recurrence network of time series was extended to handle multi-channel image data, and applied to the analysis of immunohistochemistry images of DNp73 expression obtained from a cohort of 25 rectal cancer patients who underwent radiotherapy before surgery. Two mathematical weighted network properties, which are the clustering coefficient and characteristic path length, were computed for the image-based networks of the primary tumor (obtained after operation) and biopsy (obtained before operation) of each cancer patient. Results: The ratios of two weighted recurrence network properties of the primary tumors to biopsies reveal the correlation of DNp73 expression and long survival time, and discover the non-effective radiotherapy to a cohort of rectal cancer patients who had short survival time. Conclusion: Our work contributes to the elucidation of the predictive value of DNp73 expression in rectal cancer patients who were given preoperative radiotherapy. Mathematical properties of fuzzy weighted recurrence networks of immunohistochemistry images are not only able to show the predictive factor of DNp73 expression in the patients, but also reveal the identification of non-effective application of radiotherapy to those who had poor overall survival outcome. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) biomarker database (CBD) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data were collected, sorted, displayed and analysed. The CBD with the credible contents as a powerful and time-saving tool provide more comprehensive and accurate information for further CRC biomarker research. The CBD was constructed under MySQL server. HTML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD could provide to users the multiple individual biomarker information and categorized into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the average age of cohort, gender, race, the number of tumours, tumour location and stage. We only collect data from the articles with clear and credible results to prove the biomarkers are useful in the diagnosis, treatment or prognosis of CRC. The CBD can also provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high-quality research in CRC. They can submit their new findings to our database via the submission page and communicate with us in the CBD. Database URL: http://sysbio.suda.edu.cn/CBD/ [ABSTRACT FROM AUTHOR]

Aim: To demonstrate the radiation responses of tafazzin (TAZ) protein in colon cancer. Methods: TAZ expression was examined in colon cancer cell lines SW480, KM12C, SW620 and KM12L4a. KM12C and KM12L4a cell lines were used for this experiment with exposure to X- and UV rays (mW/cm2). HCT15 cell line was used to test the expression of TAZ by using an anti-TAZ drug, namely 9-fluorenone, which is a Hippo-YAP/TAZ signaling inhibitor. The experimentation also involved exposing HCT15 cell line, to UV radiation. Cell proliferation and apoptosis studies were carried out. TAZ interactions with oncoproteins were screened and the oncoproteins Livin, MAC30 and FXYD-3 were considered for in silico protein-protein interaction studies. Results: TAZ protein was significantly downregulated after 2 Gy radiations. 9-Fluorenone inhibited the expression of TAZ. Action of 9-fluorenone along with radiation, decreased the percentage of proliferation and increased apoptosis. Computational studies predicted that TAZ interacts with the oncoproteins Livin, MAC30 and FXYD-3. Conclusions: Our results suggest that TAZ plays a significant role in non-metastatic KM12C cells and is predominantly seen in the colon cancer cells isolated from primary stages of cancer. Thus, use of TAZ protein as a biomarker will be an efficient way to detect tumors in the early stages and treatment may be modulated with radiation before surgery/therapy. [ABSTRACT FROM AUTHOR]

Background: Mucinous adenocarcinoma (MAC) represents 6-19 % of all colorectal carcinoma. It is associated with poorer response to chemotherapy and chemoradiotherapy.Case Presentation: A 27-year-old Swedish woman presented with stomach pain and weight loss, and was diagnosed with locally advanced MAC in the transverse colon as well as 3 liver metastases. Neoadjuvant treatment with fluorouracil, folinic acid and oxaliplatin (FLOX) failed due to several infections, pulmonary embolism and deteriorated performance status. The patient was therefore considered palliative. Palliative treatment with metronomic capecitabine 500 mg × 2 daily and bevacizumab every other week were initiated. After 4 months of treatment the tumors had regressed and the patient was able to undergo radical surgery, thereby changing the treatment intention from palliative to curative. No adjuvant chemotherapy was given. There were no signs of recurrence 9 months later.Conclusions: The role of the combination of metronomic capecitabine and bevacizumab in patients with MAC merits further investigation. [ABSTRACT FROM AUTHOR]

Objective: Currently, little is known regarding the role of peroxisome proliferator-activated receptor-β (PPAR β) in the vascular endothelial cells (VECs) of colorectal cancers (CRCs). The aim of this study was to investigate the relationship of PPAR β expression in the VECs of CRCs in terms of the prognosis and clinicopathological features of CRC patients. Design: The expression and localization of PPAR β in the primary cancers and the matched normal mucosal samples of 141 Swedish CRC patients were analyzed in terms of its correlation with clinicopathological features and the expression of angiogenesis-related genes. This study also included 92 Chinese CRC patients. Results: PPAR β was predominantly localized in the cytoplasm and was significantly downregulated in the VECs of CRC compared to that of the normal mucosa. The low expression levels of PPAR β in the VECs of CRC were statistically correlated with enhanced differentiation, early staging and favorable overall survival and were associated with the increased expression of VEGF and D2-40. The patients exhibiting elevated expression of PPAR β in CRC cells but reduced expression in VECs exhibited more favorable survival compared with the other patients, whereas the patients with reduced expression of PPAR β in CRC cells but increased expression in VECs exhibited less favorable prognosis. Conclusions: PPAR β might play a tumor suppressor role in CRC cells in contrast to a tumor promoter role in the VECs of CRCs. [ABSTRACT FROM AUTHOR]

The role of matrix metalloproteinase-7 (MMP-7) in the pathogenesis of colon cancer is not understood thoroughly. Previous studies from our group have shown that the expression levels of MMP-7 were highly elevated in colorectal cancer patient specimens and were correlated with Dukes Staging, histological differentiation grade and CEA level. The goal of this study was to investigate the cellular impact of MMP-7 in colon cancer. In this study, we used the SW480 colon cancer cell lines of MMP-7 knockdown by lentivirus-mediated RNA interference as a model system to investigate the impact of MMP-7 on cell proliferation and sensitivity to 5-Fluorouracil (5-FU) and X-ray irradiation (IR). Cell proliferation and sensitivity to 5-FU and IR were measured by MTT assay and colony formation assay. Cell cycle was evaluated by flow cytometry. We showed that the down regulation of MMP-7 inhibits colon cancer cell proliferation and sensitizes tumour cells to 5-FU and IR ( P < 0.05). Decreased MMP-7 expression in SW480 cells by RNA interference triggered cell cycle arrest at G1 phase ( P < 0.05). Down regulation of MMP-7 may inhibit the cell proliferation of colon cancer cells and increase tumour cells sensitivity to radiotherapy and chemotherapy. RNAi-mediated silencing of MMP-7 may represent a powerful therapeutic approach for controlling human colorectal cancer growth. [ABSTRACT FROM AUTHOR]

Purpose: Recently, microRNA-124 (miR-124) has been demonstrated as a potential tumor suppressor in several types of cancers. However, the role of miR-124 in colorectal cancer remains unclear. This study was aimed at investigating the clinicopathological significance of miR-124 expression in colorectal cancer. Methods: Quantitative real-time PCR was used to analyze miR-124 expression in 96 colorectal cancers and individual-matched normal mucosa samples. The expression of miR-124 was assessed for associations with clinicopathological characteristics using chi-square test. The survival curves were calculated by the Kaplan-Meier method. The influence of each variable on survival was examined by the Cox multivariate regression analysis. Results: The miR-124 expression was significantly downregulated in colorectal cancer compared to normal mucosa ( P = 0.001). In colorectal cancer, miR-124 decreased expression correlated significantly with the grade of differentiation ( P = 0.021). Univariate survival analysis showed that the downregulated miR-124 was significantly correlated with worse prognosis, both in terms of overall survival ( P = 0.017) and disease-free survival (DFS) ( P = 0.014). Further, the downregulated miR-124 was demonstrated as a prognostic factor for overall survival (hazard ratio, HR = 4.634; 95 % confidence interval, CI, 1.731-12.404; P = 0.002) and DFS (HR = 4.533, 95 % CI 1.733-11.856, P = 0.002), independently of gender, age, location, maximum tumor size, depth of invasion, differentiation, and TNM stage. Conclusions: MiR-124 may play a certain role in the development of colorectal cancer. The downregulation expression of miR-124 is an independent prognostic factor in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Objective: Particularly interesting new cysteine-histidine rich protein (PINCH) is an important component of the local adhesion complexes and upregulated in several types of malignancies, and involved in the incidence and development of tumours. PINCH expression is also independently correlated with poorer survival in patients with colorectal cancer. However, there is no study of PINCH in gastric cancer, therefore, the aim of this project was to investigate PINCH expression and its clinicopathological significance in gastric adenocarcinoma. Patients and methods: PINCH expression was immunohistochemically examined in normal gastric mucous (n=30) and gastric adenocarcinoma (n=73), from gastric cancer patients. Results: PINCH expression in the associated-stroma of gastric cancers was heterogeneous, and its positive rate (75%) was higher than that of normal gastric mucosa (43%, X^{2} =9.711, p=0.002). The stronger staining was observed at the invasive edge of tumour when compared to the inner area of tumour. The rate of positive PINCH (88%) in the cases with lymph node metastasis was higher than that (52%) in the cases without metastasis (X^{2}=11.151, p=0.001). PINCH expression was not correlated with patients' gender, age, tumour size, differentiation and invasion depth (p> 0.05). Comclusion: PINCH protein might play an important role in the tumourigenesis and metastasis of gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

Introduction: The NF-κB transcription factor protein family has diverse cellular and biological functions, and posttranslational modification is important to regulate these functions. An important site of phosphorylation of NF-κB p65 subunit is at serine-536 (phospho-Ser536-p65), and this phosphorylation is involved in regulation of transcriptional activity, nuclear localization, and protein stability. Patients and Methods: In this study, we investigated expression of phospho-Ser536-p65 in colorectal cancers and its relationships with clinicopathological factors. The expression of phospho-Ser536-p65 was examined by immunohistochemistry in 203 primary colorectal cancers, 156 normal mucosa specimens, and 18 metastases in the lymph nodes. Results: The expression of phospho-Ser536-p65 increased from normal mucosa to primary tumor ( p < 0.0001). Further, the increased expression of phospho-Ser536-p65 in the cytoplasm of the primary tumors correlated with worse survival of the patients independently of gender, age, tumor location, stage, and differentiation ( p = 0.04; hazard ratio, 1.89; 95% CI 1.03-3.47). Conclusion: The NF-κB p65 subunit phosphorylated at serine-536 is an independent prognostic factor in colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Background: Meningioma-associated protein (MAC30), first described to be overexpressed in meningiomas, exhibits altered expression in certain human tumors. The aim of our study was to investigate the expression of MAC30 mRNA and its correlation with clinicopathological variables in human colorectal cancer (CRC). Methods: MAC30 mRNA expression was first examined in 55 CRCs, along with the samples from the matched distant normal and adjacent noncancerous tissue by RT-PCR, further verified in 18 CRCs by quantitative RT-PCR. MAC30 protein expression was detected by Western blot in 10 CRCs, and DNA sequencing was performed in 1 case of the paired CRC and the matched noncancerous specimen. MAC30 mRNA expression in two colon cancer cell lines, HCT-116p53-/- and HCT-116p53+/+, was detected by quantitative RT-PCR. Results: The mRNA expression of MAC30 was increased in CRC when compared with distant normal (p < 0.01) and adjacent noncancerous mucosa (p < 0.01). The mean value of MAC30 mRNA expression in the tumor located in the colon was higher than in the rectum (0.677 ± 0.419 vs. 0.412 ± 0.162, p = 0.005). As the tumor penetrated the wall of the colon/rectum, MAC30 mRNA expression notably increased in tumors with T3+T4 stage compared to tumors with T1+T2 stage (0.571 ± 0.364 vs. 0.404 ± 0.115, p = 0.014). MAC30 protein expression in CRCs was also remarkably elevated compared to the adjacent noncancerous mucosa. There was no mutation in the coding region of the MAC30 gene either in CRC or in the noncancerous mucosa. mRNA expression of p53 was notably decreased in HCT-116p53-/- compared to HCT-116p53+/+, while MAC30 did not vary greatly. Conclusion: The overexpression of MAC30 might be involved in the development and aggressiveness of CRCs, especially in the colon. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the prevalence and clinical significance of caspase-10 mRNA expression in stage II colorectal cancer. Methods: Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze caspase-10 expression in cancer tissue and corresponding normal mucosa from 120 patients with stage II colorectal cancer. Variables were analyzed by Chi-square test or Fisher's exact test. Survival was evaluated with method of Kaplan-Meier. Multivariate analysis was performed with Cox's proportional hazards model. Results: The expression of caspase-10 mRNA was found to be downregulated in cancer tissue compared to normal mucosa ( P = 0.001). Poorly differentiated cancer showed lower mRNA expression than cancer with greater differentiation ( P = 0.031). Univariate survival curves, estimated using the method of Kaplan-Meier, defined a significant association between caspase-10 expression and both overall survival ( P = 0.012) and disease-free survival ( P = 0.021). A multivariate analysis, performed by Cox's proportional hazards regression model, confirmed that a low caspase-10 expression was the only significant factor to predict poor prognosis in patients with stage II colorectal cancer. Conclusion: Our data indicate that caspase-10 expression, measured by quantitative real-time RT-PCR, is a possible prognostic factor in patients with stage II colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Expression of the meningioma-associated protein (MAC30) was increased in several types of tumors, including esophageal, gastric and colon tumors, compared to normal tissue. MAC30 expression levels gradually increased from normal colorectal mucosa to primary colorectal cancer and colorectal cancer spreading to the lymph nodes. MAC30 expression was related to survival in patients with colorectal cancer. However, there is no study on MAC30 in oral squamous cell carcinoma (OSCC). Methods: Therefore, MAC30 expression in OSCC was investigated and possible associations of MAC30 expression with clinicopathological variables in OSCC have been analyzed. MAC30 expression was immunohistochemically examined in 20 normal oral mucosa and 43 OSCC specimens. Results: Expression levels of MAC30 in the cytoplasm markedly increased from normal oral epithelial cells to primary OSCC. Strong cytoplasmic staining was significantly higher in primary OSCC compared to normal oral mucosa samples (51 vs. 20%, p = 0.019). Furthermore, MAC30 expression levels in primary tumors of patients with lymph node metastasis exceeded levels in those without metastasis (65 vs. 35%, p = 0.048), and MAC30 expression in poorly differentiated tumors was higher than in well-differentiated ones (90 vs. 39%, p = 0.005). Conclusion: Overexpression of MAC30 in the cytoplasm of OSCC may predict nodal metastasis and poor differentiation. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: FXYD3 is up-/down-regulated in different types of cancers. We examined FXYD3 expression in colorectal cancers and its relationship to biological and clinicopathological variables. Patients and Methods: Expression of FXYD3 protein was immunohistochemically examined in distant normal mucosa (n = 34), adjacent normal mucosa (n = 72), primary tumour (n = 150) and lymph node metastasis (n = 35) from colorectal cancer patients. Results: FXYD3 was highly expressed in primary tumour compared to adjacent normal mucosa (p = 0.02). FXYD3 was or tended to be positively related to the expression of ras (p = 0.02), p53 (p = 0.06), legumain (p = 0.02) and proliferating cell nuclear antigen (p = 0.03). Moreover, there was a higher frequency of strong FXYD3 expression in Dukes A–C tumours than in D tumours (p = 0.04). The strong FXYD3 expression tended to predict worse survival in the patients with Dukes A + B tumour (p = 0.07), while there was no such tendency in the patients with Dukes C + D tumour (p = 0.94). The tumours located in the colon had a higher degree of FXYD3 expression than the tumours located in the rectum (p = 0.05). Conclusion: The FXYD3 was associated with certain biological variables and may be involved in the development of the relative earlier stages of colorectal cancers. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective. An insertion/deletion polymorphism (-94ins/delATTG) in the promoter region of the NFKB1 gene correlates to an increased risk of ulcerative colitis, a known risk factor for colorectal cancer, but this polymorphism has not been studied in colorectal cancer patients. The purpose of this study was to investigate whether this polymorphism is related to colorectal cancer risk and clinicopathological variables. Material and methods. Case samples were taken from four groups of Swedish patients: 193 unselected patients, 90 patients with ≥3 affected 1st-degree relatives, 85 patients with 2 affected 1st-degree relatives, and 109 sporadic cancer patients, and one group of 193 unselected Chinese patients. Controls included 439 Swedish and 458 Chinese healthy individuals. Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Results. The deletion increased the risk of colorectal cancer among Swedish unselected patients (OR=3.81, 95% CI: 2.17-6.69, p<0.0001 for heterozygote deletion, and OR=4.65, 95% CI: 2.43-8.89, p<0.0001 for homozygote deletion) and sporadic cancer patients (OR=7.73, 95% CI: 3.06-19.57, p<0.0001 for heterozygote deletion, and OR=6.58, 95% CI: 2.35-18.43, p<0.0001 for homozygote deletion) compared to homozygote insertion (wild-type), but not among the other Swedish or Chinese patients (p>0.05). Similar evidence was seen in age-adjusted analyses (p<0.0001). The polymorphism did not correlate to clinicopathological variables (p>0.05). Conclusions. Deletion of the polymorphism was associated with increased susceptibility to sporadic colorectal cancers in the Swedish population, but not in the Swedish patients with a family history of colorectal cancer or in Chinese patients. [ABSTRACT FROM AUTHOR]

Noxa is a BH3-only member of the Bcl-2 family, upregulated by p53 as a response to DNA damage. Mutations in the BH3-only region of other BH3-only members lead to an inactive protein. We have investigated the mRNA expression of Noxa with real-time PCR in 94 unselected colorectal adenocarcinomas and the corresponding normal mucosa. Among them, Noxa protein expression was investigated with immunohistochemistry in 16 tumors and six corresponding normal mucosa samples. Further, we searched for Noxa mutations in all the cases using single-stranded conformation polymorphism and DNA sequencing. The mRNA expression of Noxa was weak in 9% and strong in 2% of the tumors, and decreased in 9% and increased in 16% of the tumors compared with the normal mucosa; however, these changes did not have any clinical or pathological significance. The protein level in most of the cases investigated was correlated with the mRNA level. We did not find any mutations in the Noxa gene. Thus, we suggest that Noxa may not be of importance in the development of colorectal cancer.Oncogene (2003) 22, 4675-4678. doi:10.1038/sj.onc.1206655 [ABSTRACT FROM AUTHOR]

OBJECTIVE:We aimed to investigate the associations of cyclooxygenase-2 (COX-2) with pathological features and survival in patients with colorectal cancer.METHODS:The expression of COX-2 was examined by immunohistochemistry in 112 primary colorectal cancers, with 64 samples from the corresponding normal mucosa and 16 metastases in the regional lymph nodes of patients with colorectal cancer. The associations of COX-2 expression with clinicopathological features, including survival, were analyzed.RESULTS:The frequency and intensity of COX-2 staining were remarkably increased from the normal samples (17%) to the primary tumors (72%) and to the metastases (100%). Expressions of COX-2 were 25%, 74%, 78%, and 67% in Dukes’ A, B, C, and D tumors, respectively (p = 0.005), and positively related to proliferative activity (p = 0.003). COX-2 expressions were 80% in colonic tumors and 60% in rectal tumors (p = 0.03). The expression of COX-2 was positively related to the better differentiated tumors in the colon (p = 0.04). We were unable to find any relationship of COX-2 with patient age, sex, tumor growth pattern, apoptosis, and patient survival (p > 0.05).CONCLUSION:We found that the expression of COX-2 was upregulated from normal cells to primary tumors and to metastases, and related to proliferative activity, tumor location, Dukes’ stage, and differentiation. These results further support the evidence that COX-2 may be involved in tumorigenesis and development of colorectal cancer. [Copyright &y& Elsevier]

Colon cancer is one of the major causes of cancer death worldwide. The five-year survival rate for the early-stage patients is more than 90%, and only around 10% for the later stages. Moreover, half of the colon cancer patients have been clinically diagnosed at the later stages. It is; therefore, of importance to enhance the ability for the early diagnosis of colon cancer. Taking advantages from our previous studies, there are several potential biomarkers which have been associated with the early diagnosis of the colon cancer. In order to investigate these early diagnostic biomarkers for colon cancer, human chromogranin-A (CHGA) was further analyzed among the most powerful diagnostic biomarkers. In this study, we used a logistic regression-based meta-analysis to clarify associations of CHGA expression with colon cancer diagnosis. Both healthy populations and the normal mucosa from the colon cancer patients were selected as the double normal controls. The results showed decreased expression of CHGA in the early stages of colon cancer as compared to the normal controls. The decline of CHGA expression in the early stages of colon cancer is probably a new diagnostic biomarker for colon cancer diagnosis with high predicting possibility and verification performance. We have also compared the diagnostic powers of CHGA expression with the typical oncogene KRAS, classic tumor suppressor TP53, and well-known cellular proliferation index MKI67, and the CHGA showed stronger ability to predict early diagnosis for colon cancer than these other cancer biomarkers. In the protein–protein interaction (PPI) network, CHGA was revealed to share some common pathways with KRAS and TP53. CHGA might be considered as a novel, promising, and powerful biomarker for early diagnosis of colon cancer. [ABSTRACT FROM AUTHOR]

The polymorphism at codon 201 of the “deleted in colorectal carcinoma” (DCC) gene has been liked to susceptibility to colorectal cancer. However, its clinicopathological significance has not been reported. We examined the codon 201 polymorphism and loss of heterozygosity (LOH) by PCR-restriction fragment length polymorphism (PCR-RFLP) in 59 colorectal cancers, 48 samples from transitional mucosa and 67 samples from normal mucosa. The frequencies of the polymorphism did not significantly differ from normal to transitional mucosa and to tumor, but LOH was increased from transitional mucosa to tumor. Almost all of the LOH cases showed the polymorphism. The polymorphism was increased from well/moderately to poorly differentiated and to mucinous carcinoma (P=0.03). The polymorphism was more frequently seen in advanced stages than in earlier stages (P=0.02), and further predicted worse survival (P=0.04). The data suggest that the codon 201 polymorphism of the DCC gene was a target of LOH, and predicted prognosis in colorectal cancer patients. [Copyright &y& Elsevier]

Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients. Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT. Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p = 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes’ stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01). Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT. [Copyright &y& Elsevier]