miR-128-3p suppresses tumor growth and enhances chemosensitivity in tongue squamous cell carcinoma through MAP2K7 targeting

Mol Biol Rep. 2024 Oct 30;51(1):1107. doi: 10.1007/s11033-024-10040-7.

Abstract

Background: MicroRNAs (miRNAs), which are key players in cancer cell resistance to chemotherapy, notably target genes associated with drug resistance. While miRNA-128-3p is recognized for its involvement in various cancers, its specific role in tumorigenesis and cisplatin (CIS) resistance in tongue cancer remains unclear. Therefore, in the present study, we endeavoured to elucidate the significance of miR-128-3p in tongue squamous cell carcinoma (TSCC), shedding light on its intricate functions and underlying mechanisms.

Methods and results: We quantified the expression of miR-128-3p and its target genes using qRT-PCR, followed by a series of functional assays in vitro, such as proliferation and migration assays, flow cytometry analysis, and western blotting to unravel the mechanisms underlying the functions of miR-128-3p. Additionally, we validated the ability of miR-128-3p to target MAP2K7 genes through luciferase reporter assays. We observed that increased expression of miR-128-3p significantly inhibited TSCC cell migration, proliferation, and epithelial-mesenchymal transition (EMT), possibly by regulating MAP2K7 in the JNK/MAP kinase pathway through miRNA target binding. Furthermore, we showed that increased miR-128-3p levels enhanced the sensitivity of TSCC cells to CIS through the JNK/c-Jun cascade. We observed that miR-128-3p reduces the expression of c-Jun and ABC transporter genes by targeting MAP2K7, affecting JNK1/2. This inhibition possibly decreases drug efflux and thus enhances the TSCC sensitivity to CIS treatment.

Conclusions: Our findings demonstrate oncosuppressive behaviour of miR-128-3p, which also potentially enhances the sensitivity of TSCC cells to CIS by suppressing MAP2K7 and JNK1/2, leading to evasion of apoptosis.

Keywords: Cisplatin resistance; MAP2K7; Tongue cancer; miR-128-3p; microRNA.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Carcinoma, Squamous Cell* / drug therapy
  • Carcinoma, Squamous Cell* / genetics
  • Carcinoma, Squamous Cell* / metabolism
  • Carcinoma, Squamous Cell* / pathology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Movement* / genetics
  • Cell Proliferation* / drug effects
  • Cell Proliferation* / genetics
  • Cisplatin* / pharmacology
  • Drug Resistance, Neoplasm* / genetics
  • Epithelial-Mesenchymal Transition* / drug effects
  • Epithelial-Mesenchymal Transition* / genetics
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Tongue Neoplasms* / drug therapy
  • Tongue Neoplasms* / genetics
  • Tongue Neoplasms* / metabolism
  • Tongue Neoplasms* / pathology

Substances

  • MicroRNAs
  • Cisplatin
  • MIRN128 microRNA, human
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase Kinases