Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

Abstract

Abstract. Changes in the expression of the mismatch repair (MMR) genes hMSH2, hMLH1, hMSH6 and hPMS2 reflect dysfunction of the DNA repair system that may allow the malignant transformation of tissue cells. The aim of the present study was to address the mRNA expression profiles of the mismatch DNA repair system in cancerous and precancerous urothelium. This is the first study to quantify MMR mRNA expression by applying quantitative real-time PCR (qPCR) and translate the results to mRNA phenotypic profiles (r, reduced; R, regular or elevated) in bladder tumors [24 urothelial cell carcinomas (UCCs) and 1 papillary urothelial neoplasm of low malignant potential (PUNLMP)] paired with their adjacent normal tissues (ANTs). Genetic instability analysis was applied at polymorphic sites distal or close to the hMSH2 and hMLH1 locus. Presenting our data, reduced hMSH2, hMSH6 and hPMS2 mRNA expression profiles were observed in cancerous and precancerous urothelia. Significantly, the ANTs of UCCs revealed the highest percentages of reduced hMSH2 (r 2 ), hMSH6 (r 6 ) and hPMS2 (p 2 ) mRNA phenotypes relative to their tumors (P<0.03). In particular, combined r 2 r 6 (P<0.02) presented a greater difference between ANTs of low-grade UCCs vs. their tumors compared with ANTs of high-grade UCCs (P= 0.000). Reduced hMLH1 (r 1 ) phenotype was not expressed in precancerous or cancerous urothelia. The hMSH6 mRNA was the most changed in UCCs (47.8%), while hMSH2, hMLH1 and hPMS2 showed overexpression (47.8, 35 and 30%, respectively) that was associated with gender and histological tumor grading or staging. Genetic instability was rare in polymorphic regions distal to hMLH1. Our data reveal a previously unrecognized hMSH2 and hMSH6 mRNA combined phenotype (r 2 r 6 ) correlated with a precancerous urothelium and show that hMLH1 is transcriptionally activated in precancerous or cancerous urothelium. In the present study, it is demonstrated that reduction of hMSH6 mRNA is a frequent event in bladder tumorigenesis and reflects a common mechanism of suppression with hMSH2, while alterations of hMSH2 or hMLH1 mRNA expression in UCCs does not correlate with the allelic imbalance of polymorphic regions harboring the genes. IntroductionThe most common histological type of bladder cancer is urothelial cell carcinoma (UCC) or transitional cell carcinoma (TCC). Papillary urothelial neoplasm of low malignant potential (PUNLMP) may also arise from urothelium of bladder (1,2). The urothelium of a patient with a bladder cancer is at risk as the cancer often recurrs in the urinary bladder following treatment (1,3). Numerous genetic and epigenetic factors have been implicated in the carcinogenesis of the urinary bladder that involved in its mutator phenotype (4-7). The DNA repair mechanism is essential to prevent DNA mutations that may be lethal for cells (8). Mismatch repair (MMR) genes encode a number of DNA repair enzymes that cooperate to recognize and repair DNA mismatches (8,9). These enzymes act as complexes. A crucial complex that recognizes base...

Inhibition of MicroRNA-21-5p Promotes the Radiation Sensitivity of Non-Small Cell Lung Cancer Through HMSH2

“…These findings suggest that miR-21-5p and hMSH2 might play roles in the radiation sensitivity of NSCLC and that inhibition of miR-21-5p might promote the radiation sensitivity of NSCLC through hMSH2. hMSH2 is an MMR gene, the dysfunction of which may cause malignant transformation of tumor cells [21]. In line with our results, Zhong Z reported that miR-21-5p is a key regulator of hMSH2 and modulates the cell cycle and viability by targeting hMSH2 in human lung cancer [16].…”

Genomic Instability Promoted by Overexpression of Mismatch Repair Factors in Yeast: A Model for Understanding Cancer Progression

“…Again, the authors did not test if MSH6 was overexpressed as well. However, a number of studies suggest that MSH2 and MSH6 mRNA and protein expression in cancers are correlated to each other (Vageli et al 2013;Wagner et al 2016), as we found in certain tumors overexpressing both MSH2 and MSH6 ( Figure S2). Additionally, in their study of 115 oral squamous cell carcinoma samples, Wagner et al (2016) showed that many of these cancers exhibited overexpression of MSH2 or MSH6 alone, and a significant fraction showed cooverexpression of MSH2 and MSH6.…”

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

“…Although multiple diagnostic and prognostic markers have been identified for both lung and head and neck cancers [18,19], the precise molecular mechanisms involved in the development and progression of these malignancies remain unclear.We understand that a functional DNA repair mechanism that includes the recognition and repair of mismatch DNA errors during DNA replication is essential in eliminating the harmful effect of several environmental risk factors, such as NNK, on the exposed cells [20][21][22][23]. A number of studies have shown that reduced expression of mismatch DNA repair (MMR) genes increases the incidence of microsatellite instability [24][25][26][27], which is often found in head and neck cancer [28][29][30][31]. Other studies have also shown that reduced expression of MSH2 or MLH1 genes at the protein or mRNA levels is associated with poor survival and MSI in lung cancer [32][33][34].In addition, MMR deficiency appears to affect the effectiveness of chemotherapy in these cancers [34,35].…”