Up to now, the molecular mechanisms underlying the stemness of prostate cancer stem cells (PCSCs) are still poorly understood. In this study, we demonstrated that microRNA-7 (miR-7) appears to be a novel tumor-suppressor miRNA, which abrogates the stemness of PCSCs and inhibits prostate tumorigenesis by suppressing a key stemness factor KLF4. MicroRNA-7 is down-regulated in prostate cancer cells compared to non-tumorigenic prostate epithelial cells. Restoration of miR-7 suppresses the expression of the stemness factor KLF4 in PCSCs and inhibits prostate tumorigenesis both in vitro and in vivo. Interestingly, the suppression of the stemness of PCSCs by miR-7 is sustained for generations in xenografts. Analysis of clinical samples also revealed a negative correlation between miR-7 expression and prostate tumor progression. Mechanistically, overexpression of miR-7 may lead to a cell cycle arrest but not apoptosis, which seems achieved via suppressing the KLF4/PI3K/Akt/p21 pathway. This study identifies miR-7 as a suppressor of PCSCs' stemness and implicates its potential application for PCa therapy.
Androgen receptor (AR) plays a critical role during the development and progression of prostate cancer in which microRNA miR-375 is overexpressed and correlated with tumor progression. Although DNA methylation is a key mechanism for the repression of gene expression, the relationship between AR and the expression or the hypermethylation of miR-375 is unknown. In this study, we found that AR-positive prostate cancer (PCa) cells showed high expression levels and hypomethylation of the miR-375. In contrast, AR-negative PCa cells displayed low levels and hypermethylation of the miR-375. Addition of 5-Aza-2′-deoxycytidine, a specific inhibitor of DNA methylation, into the culture medium reversed the low expression levels of miR-375 in the AR negative PCa cells. In addition, the total activity levels of DNA methyltransferases (DNMTs) were high in AR-negative PCa cells, in which hypermethylation of miR-375 promoter and low expression levels of miR-375 were observed. Taken together, these findings indicate that the negative correlation between AR and total DNMT activity is one of mechanisms to influence the methylation status of miR-375 promoter, which in turn regulates the expression of miR-375.
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.
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