MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway

Oncogene. 2015 Jan 22;34(4):413-23. doi: 10.1038/onc.2013.574. Epub 2014 Jan 27.

Abstract

The metastatic cascade is a complex and multistep process with many potential barriers. Recent evidence has shown that microRNAs (miRNAs) are involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). In this study, by comparing the miRNA expression profiles of SPC-A-1sci (high metastatic) and SPC-A-1 (weakly metastatic) cells, we demonstrated that the downregulation and function of miR-193a-3p and miR-193a-5p in NSCLC metastasis and the expression of these miRNAs was suppressed in NSCLC compared with corresponding non-tumorous tissues. Decreased miR-193a-3p/5p expression was significantly associated with tumor node metastasis (TNM) and lymph node metastasis. Furthermore, functional assays showed that the overexpression of miR-193a-3p/5p inhibited NSCLC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and lung metastasis formation in vivo. In addition, we discovered that ERBB4 and S6K2 were the direct targets of miR-193a-3p and that PIK3R3 and mTOR were the direct targets of miR-193a-5p in NSCLC. We also observed that miR-193a-3p/5p could inactivate the AKT/mTOR signaling pathway. Thus, miR-193a-3p/5p functions as a tumor suppressor and has an important role in NSCLC metastasis through ERBB signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Cell Line, Tumor
  • Down-Regulation
  • Epithelial-Mesenchymal Transition
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / physiology*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / prevention & control
  • Phosphatidylinositol 3-Kinases / physiology*
  • Receptor, ErbB-4 / physiology*
  • Ribosomal Protein S6 Kinases / physiology*
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • MIRN193 microRNA, human
  • MicroRNAs
  • MTOR protein, human
  • PIK3R3 protein, human
  • ERBB4 protein, human
  • Receptor, ErbB-4
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases