A study of molecular signals deregulating mismatch repair genes in prostate cancer compared to benign prostatic hyperplasia

PLoS One. 2015 May 4;10(5):e0125560. doi: 10.1371/journal.pone.0125560. eCollection 2015.


Prostate cancer is one of the leading causes of mortality among aging males. There is an unmet requirement of clinically useful biomarkers for early detection of prostate cancer to reduce the liabilities of overtreatment and accompanying morbidity. The present population-based study investigates the factors disrupting expression of multiple functionally related genes of DNA mismatch repair pathway in prostate cancer patients to identify molecular attributes distinguishing adenocarcinoma from benign hyperplasia of prostate. Gene expression was compared between tissue samples from prostate cancer and benign prostatic hyperplasia using real-time-PCR, western blot and immunohistochemistry. Assessment of genotypes of seven single-nucleotide-polymorphisms of three MMR genes was conducted using PCR-coupled RFLP and sequencing. Promoter methylation was interrogated by methylation-specific-PCR and bisulfite-sequencing. Interaction between microRNAs and MMR genes was verified by 3'UTR-based dual luciferase assays. Concurrent reduction of three MMR genes namely hMLH1, hMSH6 and hMSH2 (34-85%, P<0.05) was observed in prostate cancer tissues. hMSH6 polymorphism rs1800932(Pro92Pro) conferred a borderline protection in cancer patients (OR = 0.33, 95% CI = 0.15-0.75). Relative transcript level of hMLH1 was inversely related (r = -0.59, P<0.05) with methylation quotient of its promoter which showed a significantly higher methylation density (P = 0.008, Z = -2.649) in cancer patients. hsa-miR-155, hsa-miR-141 and hsa-miR-21 gene expressions were significantly elevated (66-85%, P<0.05) in tumor specimens and negatively correlated (r = -0.602 to -0.527, P<0.05) with that of MMR genes. hsa-miR-155 & hsa-miR-141 and hsa-miR-155 & hsa-miR-21 were demonstrated to bind to their putative seed sequences in hMLH1 and hMSH6 3'UTRs respectively. Relatively higher expression of DNA methyl-transferases (DNMT1 and DNMT3b) and HIF-1α genes (34-50%, P<0.05) were also detected in tumor tissues. This study provides statistical evidence that MMR deficiency is correlated with hypermethylation of hMLH1 promoter and upregulation of hsa-miR-155, hsa-miR-141 and hsa-miR-21 in prostate cancer. This comparative study reflects that microRNA expression level, particularly hsa-miR-155, exhibits predictive signature of prostate adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Aged
  • Alleles
  • Base Sequence
  • Binding Sites
  • Biomarkers, Tumor
  • CpG Islands
  • DNA Methylation
  • DNA Mismatch Repair / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Frequency
  • Genotype
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • MicroRNAs / chemistry
  • MicroRNAs / genetics
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Prostatic Hyperplasia / diagnosis
  • Prostatic Hyperplasia / genetics*
  • Prostatic Hyperplasia / metabolism*
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism*
  • RNA Interference
  • Sequence Analysis, DNA
  • Signal Transduction*


  • 3' Untranslated Regions
  • Biomarkers, Tumor
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MicroRNAs

Grants and funding

This work was supported by the Council of Scientific and Industrial Research, New Delhi, India, Grant No. 27/(0206)/09/EMR-II (www.csirhrdg.res.in). SS received the funding.