TNF-α-induced miR-450a mediates TMEM182 expression to promote oral squamous cell carcinoma motility

PLoS One. 2019 Mar 20;14(3):e0213463. doi: 10.1371/journal.pone.0213463. eCollection 2019.

Abstract

Distant metastasis leads oral cancer patients into a poor survival rate and a high recurrence stage. During tumor progression, dysregulated microRNAs (miRNAs) have been reported to involve tumor initiation and modulate oral cancer malignancy. MiR-450a was significantly upregulated in oral squamous cell carcinoma (OSCC) patients without functional reports. This study was attempted to uncover the molecular mechanism of novel miR-450a in OSCC. Mir-450a expression was examined by quantitative RT-PCR, both in OSCC cell lines and patients. Specific target of miR-450a was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-450a and TMEM182 were accessed by adhesion and transwell invasion analyses. Determination of the expression and cellular localization of TMEM182 was examined by RT-PCR and by immunofluorescence staining. The signaling pathways involved in regulation of miR-450a were investigated using the kinase inhibitors. Overexpression of miR-450a in OSCC cells impaired cell adhesion ability and induced invasiveness, which demonstrated the functional role of miR-450a as an onco-miRNA. Interestingly, tumor necrosis factor alpha (TNF-α)-mediated expression of TMEM182 was regulated by miR-450a induction. MiR-450a-reduced cellular adhesion was abolished by TMEM182 restoration. Furthermore, the oncogenic activity of TNF-α/miR-450a/TMEM182 axis was primarily through activating extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. ERK1/2 inhibitor prevented the TNF-α-induced miR-450a expression and enhanced adhesion ability. Our data suggested that TNF-α-induced ERK1/2-dependent miR-450a against TMEM182 expression exerted a great influence on increasing OSCC motility. Overall, our results provide novel molecular insights into how TNF-α contributes to oral carcinogenesis through miR-450a that targets TMEM182.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / secondary
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Female
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / pathology
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • MIRN450 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • TMEM182 protein, human
  • Tumor Necrosis Factor-alpha

Grants and funding

This work was supported by: National Health Research Institutes NHRI-CA105-PP03; National Health Research Institutes NHRI-CA106-PP03; Ministry of Science and Technology, Taiwan MOST-104-2314-B-400-018-MY2; and Ministry of Health and Welfare MOHW 106-TDU-B-212-122015 to SGS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.