Search

Cervical cancer is a common female malignancy worldwide, and the molecular mechanism of cervical tumorigenesis remains poorly understood. A large piece of evidence have demonstrated the important roles of long noncoding RNAs (lncRNAs) in tumorigenesis, cancer progression and drug resistance. In this study, we comprehensively analyzed the lncRNAs expression pattern in cervical cancer using RNA sequencing and microarray data from the cancer genome atlas, gene expression omnibus and Genotype Tissue Expression. Moreover, we assessed the correlation between lncRNA expression levels and cervical cancer patient's survival. We uncovered hundreds of lncRNAs that are upregulated or downregulated in cervical cancer tissues. Among these aberrantly lncRNAs, some are significantly associated with cervical patients' poorer prognosis, such as ALOX12-AS1 and LINC00173. ALOX12-AS1 expression is downregulated in cervical cancer, and over-expression of ALOX12-AS1 could inhibit cervical cancer cells proliferation in vitro. Further, mechanistically investigation revealed that ALOX12-AS1 could interact with AGO2 and sponge miR-3171, thereby antagonizing its' repression of tumor suppressor phosphatase and tensin homolog expression in cervical cancer cell. Taken together, this study provides lncRNA candidates in cervical cancer and highlights the critical role of ALOX12-AS1 in cervical cancer.

Background: Carcinoma ex pleomorphic adenoma (CXPA), a very rare malignancy found mostly in the major salivary glands, has no established standardized treatment. Case presentation: This report describes a 67-year-old male with advanced CXPA who was effectively treated by anlotinib. Pleomorphic adenoma of the submandibular gland was first diagnosed in 1976 after a surgical resection of a mass underneath the jaw. The patient underwent re-excision 3 years later due to a recurrent pleomorphic adenoma. CXPA was first diagnosed in 2016 after a surgical removal of the left submandibular mass. A lung nodule was found on a chest CT scan in January 2018. Following a CT-guided lung biopsy that demonstrated findings consistent with pulmonary metastasis, the patient underwent local therapy (microwave ablation and radioactive seed implantation) but suffered a recurrence of disease approximately 6 months later. Anlotinib was administered orally at a dose of 12 mg daily on a 2 weeks on/1 week off schedule. A partial response was observed after two cycles of treatment. The disease remains in continued partial response after completion of his sixth cycle. Conclusion: This is the first report for anlotinib in treating CXPA. Further pre-clinical and clinical studies are needed to validate the efficacy and safety of anlotinib in the treatment of CXPA.

Thyroid cancer is the most common endocrine malignancy, and its incidence continues to rise. For clinicians with cancer patients, choosing and interpreting diagnostic laboratory studies has become increasingly important. Previously, changes in plasma free mitochondrial DNA levels have been found in colorectal, breast, lung, and urinary cancers, and have demonstrated diagnostic value. In this study, we investigated whether the occurrence and development of thyroid cancer might be predicted using mtDNA copy number (ND1), mtDNA integrity (ND4/ND1) and levels of cell-free nDNA (GAPDH). We analyzed ND1, ND4, and GAPDH levels in plasma and blood cells from 75 patients with thyroid cancer, 40 patients with nodular goiter, and 107 normal controls using real-time PCR. Although both the thyroid nodule and thyroid cancer patients had significantly increased ND1 levels, the ND4/ND1 ratio in the thyroid cancer group was higher than the thyroid nodule group (P < 0.05), and significantly higher than the normal control group (P < 0.01). Plasma levels of nuclear DNA (GAPDH) in the thyroid cancer group were also higher compared to normal (P < 0.05). These results indicate that increased intactness of plasma free mtDNA is associated with increased levels of plasma cell-free nDNA, and that the ND4/ ND1 ratio has the potential to be a new detection indicator in thyroid cancer. Furthermore, we classified thyroid cancer patients according to clinical data including age, tumor size, and metastasis. We found significantly higher levels of GAPDH in malignant tissues. Because ND4/ND1 correlated with plasma GAPDH in the plasma studies, this also suggests a potential relationship between ND4 intactness and thyroid tumor tissue size. Taken together, our findings suggest a tumor-specific process involving increased release of intact mtDNA, detectable in the plasma, which differentiates normal patients from patients with thyroid cancer.

e22500 Background: Breast cancer susceptibility genes BRCA1 and 2 are tumor suppressor genes and they play an important role in DNA damage response and repair during homologous recombination. Hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominant disease due to BRCA1 and 2 germline mutation. Germline mutations of BRCA1 and 2 genes significantly increase the risk of developing breast cancer, ovarian cancer, prostate cancer and a broad range of cancers. PARP inhibitor (PARPi) monotherapy and combinations have shown promising efficacy against a variety of cancer types with BRCA mutations. Nevertheless, the knowledge of incidence of BRCA1 and 2 germline mutations in solid tumor remains poorly understood. Herein, next generation sequencing of 539-gene profiling was performed to explore the incidence of BRCA1 and 2 germline mutations in Chinese solid tumors. Methods: We retrospectively analyzed the BRCA1 and BRCA2 germline mutations from a comprehensive 539-gene profiling of 8535 Chinese patients with pan-cancer. 539-gene profiling contains the somatic mutations in tumor tissue or blood ctDNA and the germline mutations in blood leukocyte. We screened out the pathogenic and likely pathogenic mutations in BRCA germline mutations, and calculated the mutation frequency and the median age in every cancer type. Results: In 8535 patients with pan-cancer, 110 patients were found pathogenic or likely pathogenic germline mutations in BRCA gene and the mutation frequency was 1.29%, of which 40 BRCA1 mutations and 70 BRCA2 mutations were found in patients, respectively. The total median age was 58.15. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained ovarian cancer (14.78%, media age 58), prostatic cancer (6%, media age 58.33), breast cancer (5.2% media age 57.33). The details of the top 8 cancer types with mutation frequency and media age were shown in Table. Conclusions: This was the first report of the incidence of BRCA1 and 2 germline mutations in Chinese solid tumors, which expanded the understanding of BRCA1/2 and provided a direction for clinical trial design of PARPi monotherapy and combinations.[Table: see text]

// Chaoyi Xu 1, * , Jinhong Zhu 3, * , Wen Fu 2, * , Zongwen Liang 1 , Shujie Song 4 , Yuan Zhao 1 , Lihua Lyu 4 , Anqi Zhang 1 , Jing He 1, 2 , Ping Duan 1 1 Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China 2 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China 3 Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China 4 Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China * These authors contributed equally to this work Correspondence to: Ping Duan, email: dppddpp@126.com Jing He, email: hejing198374@gmail.com Keywords: MDM4, polymorphism, cancer susceptibility, meta-analysis Received: June 15, 2016 Accepted: September 21, 2016 Published: September 28, 2016 ABSTRACT Mouse double minute 4 (MDM4) is a p53-interacting oncoprotein that plays an important role in the p53 tumor suppressor pathway. The common rs4245739 A > C polymorphism creates a miR-191 binding site in the MDM4 gene transcript. Numerous studies have investigated the association between this MDM4 polymorphism and cancer risk, but have failed to reach a definitive conclusion. To address this issue, we conducted a meta-analysis by selecting eligible studies from MEDLINE, EMBASE, and Chinese Biomedical databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. We also performed genotype-based mRNA expression analysis using data from 270 individuals retrieved from public datasets. A total of 15 studies with 19796 cases and 49681 controls were included in the final meta-analysis. The pooled results revealed that the MDM4 rs4245739C allele is associated with a decreased cancer risk in the heterozygous (AC vs. AA: OR = 0.82, 95% CI = 0.73−0.93), dominant (AC/CC vs. AA: OR = 0.82, 95% CI = 0.72−0.93), and allele contrast models (C vs. A: OR = 0.84, 95% CI = 0.76−0.94). The association was more prominent in Asians and population-based studies. We also found that the rs4245739C allele was associated with decreased MDM4 mRNA expression, especially for Caucasians. Thus the MDM4 rs4245739 A > C polymorphism appears to be associated with decreased cancer risk. These findings would be strengthened by new studies with larger sample sizes and encompassing additional ethnicities.

Epstein&ndash, Barr virus (EBV) is a major contributor to nasopharyngeal carcinoma (NPC) tumorigenesis. Mitochondria have been shown to be a target for tumor viral invasion, and to mediate viral tumorigenesis. In this study, we detected that mitochondrial morphological changes in tumor tissues of NPC patients infected with EBV were accompanied by an elevated expression of BHRF1, an EBV encoded protein homologue to Bcl-2. High expression of BHRF1 in human NPC cell lines enhanced tumorigenesis and metastasis features. With BHRF1 localized to mitochondria, its expression induced cyclophlin D dependent mitochondrial membrane permeabilization transition (MMPT). The MMPT further modulated mitochondrial function, increased ROS production and activated mitophagy, leading to enhanced tumorigenesis. Altogether, our results indicated that EBV-encoded BHRF1 plays an important role in NPC tumorigenesis through regulating cyclophlin D dependent MMPT.

In this study, the antimicrobial activity of milk-derived peptide αS2-casein151-181 against Bacillus subtilis ATCC6633 was evaluated. The minimum inhibitory concentration of αS2-casein151-181 against B. subtilis was between 3.10 and 6.67 μ m and the minimum bactericidal concentration was below 16.00 μ m . Peptide αS2-casein151-181 generated pores in the cytoplasmic membrane of B. subtilis and resulted in PI uptake and leakage of cell constituents. Treatment with αS2-casein151-181 also caused a loss of membrane potential as measured by DiOC2 fluorescence. These data suggest that αS2-casein151-181 kills B. subtilis through the disruption of cell membrane, allowing cell constituents to leak out of the cell, which is followed by a loss of membrane potential and cell death. Furthermore, αS2-casein151-181 also acted against B. subtilis spores (1 × 106 spores mL−1) with an IC50 and an IC90 of 8.07 μ m and 16.22 μ m , respectively.

Mitochondria play important roles in multiple aspects of viral tumorigenesis. Mitochondrial genomes contribute to the host's genetic background. After viruses enter the cell, they modulate mitochondrial function and thus alter bioenergetics and retrograde signaling pathways. At the same time, mitochondria also regulate and mediate viral oncogenesis. In this context, oncogenesis by oncoviruses like Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human papilloma virus (HPV), Human Immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) will be discussed.

The SWI/SNF chromatin-remodeling complex regulates gene expression and alters chromatin structures in an ATP-dependent manner. Recent sequencing efforts have shown mutations in BRG1 (SMARCA4), one of two mutually exclusive ATPase subunits in the complex, in a significant number of human lung tumor cell lines and primary non–small cell lung carcinoma (NSCLC) clinical specimens. To determine how BRG1 loss fuels tumor progression in NSCLC, molecular profiling was performed after restoration of BRG1 expression or treatment with a histone deacetylase inhibitor or a DNA methyltransferase (DNMT) inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 reexpression led to substantial changes in the expression of CDH1, CDH3, EHF, and RRAD that commonly undergo silencing by other epigenetic mechanisms during NSCLC development. Furthermore, treatment with DNMT inhibitors did not restore expression of these transcripts, indicating that this common mechanism of gene silencing did not account for their loss of expression. Collectively, BRG1 loss is an important mechanism for the epigenetic silencing of target genes during NSCLC development. Implications: Inactivation of the SWI/SNF complex provides a novel mechanism to induce gene silencing during NSCLC development. Mol Cancer Res; 12(4); 560–70. ©2014 AACR.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous studies have addressed the safety and feasibility of endoscopic band ligation (EBL) for the treatment of small gastric GISTs. However, published reports comparing EBL with other interventions are limited. This current study evaluates the efficacy of EBL and compares EBL to both endoscopic submucosal dissection (ESD) and laparoscopic resection (LAP) for small gastric GISTs less than 15 mm.A total of 339 patients who underwent endoscopic therapy or laparoscopic resection for gastric GISTs between 1998 and 2012 were retrospectively identified and collected from medical records in our hospital. The parameters measured for each procedure type includes clinicopathological characteristics, length of stay, hospitalization expense and surgical outcomes.Among the 147 patients included in our study, 72 (48.98 %) received EBL, 27 (18.37 %) received ESD, and 48 (32.65 %) received LAP. The demographic and clinical characteristics of the patients such as gender, age, tumor site and size were well balanced between the study groups. There was also no significant difference in follow-up time between the study groups. The mean operating time was significantly shorter in the patients receiving EBL than patients receiving ESD and LAP (p 0.001). The estimated blood loss was significantly different between the three groups (p 0.001). Complications occurred in 1.39 % of the patients receiving EBL, 18.52 % of the patients receiving ESD and 4.17 % of the patients receiving LAP (p = 0.004), and recurrence rate in 15.00, 9.10 and 11.76 %, respectively (p = 0.705). There was also significant difference about mean hospital stay and hospital cost between three groups (p 0.001).Our results show a significant advantage in the short-term outcome for EBL compared to ESD and LAP. However, long-term randomized controlled trials are needed to compare the three methods for the treatment of small GISTs.

Background: Exposure to environmental carcinogens can cause damages to DNA. If not properly repaired, the DNA damages may increase the risk of carcinogenesis. Xeroderma pigmentosum group G (XPG) gene is an essential gene in the nucleotide excision repair (NER) pathway. The association between XPG polymorphisms and cancer susceptibility has been the focus of attention in the molecular epidemiology of cancer. However, the conclusions have been divergent. Therefore, we conducted a comprehensive meta-analysis to precisely evaluate the association of 3 frequently investigated XPG polymorphisms (rs751402, rs873601, and rs2296147) with cancer risk. Methods: Pubmed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies in English and Chinese. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the association between XPG polymorphisms (rs751402, rs873601, and rs2296147) and cancer risk. Results: Twenty-three studies were included. Overall, there was no significant association between rs751402 polymorphism and overall cancer risk under the 5 gene models. However, we observed strong correlation between rs751402 polymorphism and gastric cancer (C vs T: OR=1.21, 95% CI = 1.00–1.26, P = .045; TC vs CC: OR = 1.12, 95% CI = 1.00–1.24, P = .041; TC/TT vs CC: OR = 1.13, 95% CI = 1.02–1.26, P = .020). There was a significant correlation between rs873601 polymorphism and cancer risk under the homozygous model (GG vs AA: OR = 1.16, 95% CI = 1.07–1.26, P = .001). Moreover, significant association with breast cancer was detected for rs873601 polymorphism under the allele contrast model (G vs A: OR = 1.10, 95% CI = 1.02–1.20, P = .021). In the subgroup of Asian, rs873601 polymorphism was related to the susceptibility to cancer (G vs A: OR = 1.07, 95% CI = 1.03–1.12, P = .010; GG vs AA: OR = 1.15, 95% CI = 1.06–1.26, P = .001; AG/AA vs GG: OR = 1.08, 95% CI = 1.01–1.15, P = .031; AA vs AG/GG: OR = 1.13, 95% CI = 1.05–1.21, P = .001). Significant association between rs2296147 polymorphism and cancer risk were observed in Asian population (CT vs TT: OR = 0.93, 95% CI = 0.87–0.99, P = .036). Conclusions: Our meta-analysis suggested that the rs873601 polymorphism was significantly associated with overall cancer risk. The moderate effects of rs751402 and rs2296147 polymorphism on cancer susceptibility might be highly dependent on cancer type and ethnicity, respectively. Large studies are needed to validate our findings, especially in Caucasian and African population.

Malignant rhabdoid tumors (MRT), a pediatric cancer that most frequently appears in the kidney and brain, generally lack SNF5 (SMARCB1/INI1), a subunit of the SWI/SNF chromatin-remodeling complex. Recent studies have established that multiple SWI/SNF complexes exist due to the presence or absence of different complex members. Therefore, the effect of SNF5 loss upon SWI/SNF complex formation was investigated in human MRT cells. MRT cells and primary human tumors exhibited reduced levels of many complex proteins. Furthermore, reexpression of SNF5 increased SWI/SNF complex protein levels without concomitant increases in mRNA. Proteomic analysis, using mass spectrometry, of MRT cells before and after SNF5 reexpression indicated the recruitment of different components into the complex along with the expulsion of others. IP–Western blotting confirmed these results and demonstrated similar changes in other MRT cell lines. Finally, reduced expression of SNF5 in normal human fibroblasts led to altered levels of these same complex members. These data establish that SNF5 loss during MRT development alters the repertoire of available SWI/SNF complexes, generally disrupting those associated with cellular differentiation. These findings support a model where SNF5 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones. Therefore, restoration of these complexes in tumors cells provides an attractive approach for the treatment of MRTs. Implications: SNF5 loss dramatically alters SWI/SNF complex composition and prevents formation of complexes required for cellular differentiation. Mol Cancer Res; 12(11); 1574–85. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 1533][1] [1]: /lookup/volpage/12/1533?iss=11

NF-E2-related factor 2 (NRF2), negatively regulated by KEAP1, modulates induction of a battery of cytoprotective genes against oxidative stress via binding to the antioxidant responsive element (ARE) sequence. Recent NGS studies have shown a significant number of mutations in the KEAP1-NRF2-ARE signaling pathway, implicating aberrant activation of this pathway in lung cancer carcinogenesis and chemoresistance. The SWI/SNF chromatin-remodeling complex, employing either BRG1 or BRM as a catalytic subunit, regulates gene expression and alters chromatin structures in an ATP-dependent manner. Loss of complex function often occurs in lung cancers, via mutations in complex subunits. Since KEAP1/NRF2 mutations and BRG1/BRM loss occur frequently in non-small cell lung cancers (NSCLCs) in a mutually exclusive fashion, we hypothesized that BRG1 and/or BRM play(s) a role in the regulation of NRF2 target genes. To test this hypothesis, we developed a series of isogenic H358 NSCLC lines with reduced BRG1 and/or BRM expression using shRNA technology. We observed a significant increase in the levels of HMOX1 (heme oxygenase1) and GSTM4 (Glutathione S-transferase Mu 4) with a concomitant decrease in NQO1 (NAD(P)H dehydrogenase, quinone 1) in the BRG1-deficient H358 cell lines. However, GCLM (Glutamate–cysteine ligase regulatory subunit) was elevated only in the BRM-reduced H358 cells. Interestingly, BRG1 loss, either alone or combined with BRM loss, promoted SDS-resistant KEAP1 dimerization. We are currently examining whether BRG1 and/or BRM loss increases ROS levels. Chromatin immunoprecipitation (ChIP) showed that NRF2 were enriched at NRF2 downstream genes in both H358 parental and vector control cells, whereas BRG1 knockdown led to a moderate increase (HMOX1) or decrease (NQO1) in NRF2 binding. These results provide evidence that loss of SWI/SNF chromatin remodeling complex activity alters the NRF2 pathway in NSCLC. Furthermore, novel drugs targeting NRF2 downstream genes might provide a therapeutic approach for BRG1 deficient NSCLC patients. Citation Format: Shujie Song, Tess Orvis, Yanfang Zheng, Michael B. Major, Bernard E. Weissman. KEAP1-NRF2-ARE signaling interacts with the SWI/SNF chromatin remodeling complex in non-small cell lung cancer. [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 1299. doi:10.1158/1538-7445.AM2013-1299