MiRNA-195-5p Functions as a Tumor Suppressor and a Predictive of Poor Prognosis in Non-small Cell Lung Cancer by Directly Targeting CIAPIN1

Pathol Oncol Res. 2019 Jul;25(3):1181-1190. doi: 10.1007/s12253-018-0552-z. Epub 2019 Jan 12.

Abstract

Accumulating evidence suggests that microRNAs (miRNAs) has been proven to be a critical regulator in the tumor progression, of which miR-195-5p was reported to function as tumor suppressor in prostate cancer and oral squamous cell carcinoma. However, studies on the clinical significance and biological function of miR-195-5p in non-small cell lung cancer (NSCLC) were still unavailable. Here, we reported that the expression of miR-195-5p was decreased in NSCLC tissues and cell lines. Downregulation of miR-195-5p was significantly associated with TNM stage, tumor size and lymph node metastasis. The Kaplan-Meier survival analysis demonstrated that the survival time of NSCLC patients with high expression of miR-195-5p was longer than those with low expression during the 5-year follow up period (p = 0.0410). COX regression analysis indicated that miR-195-5p expression was an independent prognostic indicator for the survival of NSCLC patients (HR = 2.45, 95% CI: 1.53-4.63; p = 0.007). Results of functional analyses revealed that overexpression of miR-195-5p in A549 cells inhibited cell proliferation, induced cell cycle G0/G1 phase arrest and apoptosis using MTT and flow cytometry analysis. Furthermore, bioinformatics and luciferase reporter assays demonstrated that cytokine-induced apoptosis inhibitor 1 (CIAPIN1), an anti-apoptotic molecule was a direct target of miR-195-5p in NSCLC cells. Meta-analysis based on Oncomine database showed CIAPIN1 was significantly up-regulated in human lung cancer tissues. Consistently, knockdown of CIAPIN1 phenocopied the inhibitory effects of miR-195-5p overexpression in NSCLC cell function. These findings suggest that miR-195-5p could be used as a potential prognostic predictor and tumor suppressor in NSCLC.

Keywords: CIAPIN1; Non-small cell lung cancer; Overall survival; Prognosis; miR-195-5p.

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / secondary*
  • Adenocarcinoma of Lung / surgery
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Non-Small-Cell Lung / surgery
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / secondary*
  • Carcinoma, Squamous Cell / surgery
  • Cell Proliferation
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / surgery
  • Lymphatic Metastasis
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Prognosis
  • Survival Rate

Substances

  • Biomarkers, Tumor
  • CIAPIN1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • MIRN195 microRNA, human
  • MicroRNAs