Functional genetic variants of RUVBL1 predict overall survival of Chinese patients with epithelial ovarian cancer

Carcinogenesis. 2019 Oct 16;40(10):1209-1219. doi: 10.1093/carcin/bgz092.

Abstract

To date, the 5-year overall survival of epithelial ovarian cancer (EOC) remains poor. Because studies suggest that RUVBL1 may be a chemotherapeutic target for the treatment of cancer, in this study, therefore, we investigated the role of potentially functional single nucleotide polymorphisms (SNPs) of RUVBL1 in the survival of Chinese patients with EOC, and we subsequently performed functional prediction and validation of the identified significant SNPs. We found that RUVBL1 rs1057156 A>G and RUVBL1 rs149652370 A>G were associated with survival of EOC patients in the multivariate Cox proportional hazards regression analysis. Specifically, the RUVBL1 rs149652370 AG genotype was associated with a shorter progression-free survival ([adjusted hazards ratio (HR)] = 3.32, 95% confidence interval (CI) = 1.76-6.25 and P = 2.01E-04), compared with the AA genotype. The RUVBL1 rs1057156 AG (only nine had GG) genotype was also associated with a poor overall survival (adjusted HR = 1.73, 95% CI = 1.19-2.52, P = 0.004), compared with the AA genotype. Further experiments showed that the RUVBL1 rs1057156 A>G change lowered its binding affinity to microRNA-4294 and led to upregulation of the RUVBL1 expression. We further found that overexpression of RUVBL1 promoted cell proliferation and metastatic potential. Overall, RUVBL1 enhanced EOC cell proliferation, invasion and migration presumably by stimulating the process of glycolysis. Thus, this study provides evidence that functional variants of RUVBL1 may regulate its gene expression, a possible mechanism affecting survival of EOC patients and that RUVBL1 may be a potential chemotherapeutic target for the treatment of EOC patients.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis
  • Asian Continental Ancestry Group / genetics*
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Ovarian Epithelial / drug therapy
  • Carcinoma, Ovarian Epithelial / genetics
  • Carcinoma, Ovarian Epithelial / mortality*
  • Carcinoma, Ovarian Epithelial / pathology
  • Carrier Proteins / genetics*
  • Cell Proliferation
  • DNA Helicases / genetics*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Retrospective Studies
  • Survival Rate
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • Carrier Proteins
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL1 protein, human