Dicer suppresses MMP-2-mediated invasion and VEGFA-induced angiogenesis and serves as a promising prognostic biomarker in human clear cell renal cell carcinoma

Oncotarget. 2016 Dec 20;7(51):84299-84313. doi: 10.18632/oncotarget.12520.

Abstract

Dicer, a key component of the microRNA processing machinery, has been reported to exert discrepant prognostic values and biological roles in different types of cancers. Here, we investigated the function and prognostic value of Dicer in clear cell renal cell carcinoma (ccRCC). Using the retrospective ccRCC patients' cohorts with tissue microarray (TMA), we demonstrated that Dicer expression was significantly down-regulated in ccRCC compared with renal non-tumor tissues, and negatively associated with pN status (P = 0.005), pM status (P = 0.009) and TNM stage (P =0.013). Multivariate Cox proportional hazards regression analyses showed that positive Dicer expression was an independent favorable factor for prognosis of ccRCC patients (hazard ratio (HR) = 0.709, P = 0.025 for 5-year overall survival; HR = 0.655, P = 0.008 for disease specific survival). Moreover, we found that Dicer decreased the abilities of cell migration, invasion and angiogenesis through suppressing MMP-2 and VEGFA expression. Tumor metastasis model in vivo showed much more metastatic nodules of lung in the Dicer knockdown group than the control group via increased MMP-2 expression. Our findings imply that Dicer inhibits ccRCC metastasis and may serve as promising prognostic biomarkers for ccRCC patients.

Keywords: angiogenesis; dicer; metastasis; prognostic biomarker; renal cell carcinoma.

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / therapy
  • Cell Line, Tumor
  • Cells, Cultured
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / therapy
  • Matrix Metalloproteinase 2 / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Prognosis
  • RNA Interference
  • RNAi Therapeutics
  • Retrospective Studies
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Biomarkers, Tumor
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • DICER1 protein, human
  • Ribonuclease III
  • Matrix Metalloproteinase 2
  • DEAD-box RNA Helicases