STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

J Exp Clin Cancer Res. 2022 Oct 11;41(1):297. doi: 10.1186/s13046-022-02513-z.

Abstract

Background: Aberrantly activated mammalian target of rapamycin complex 1 (mTORC1) plays a vital role in tumor angiogenesis, but its precise mechanisms are still unclear.

Methods: Micro-RNA-130b-3p (miR-130b-3p) expression in mTORC1-activated and control cells was examined by quantitative real-time PCR (qRT-PCR). MiR-130b-3p levels and their correlation with mTORC1 activity were evaluated by analyzing publicly available databases and in-house head and neck squamous cell carcinoma (HNSCC) tissues. The role of miR-130b-3p in mTORC1-mediated angiogenesis and tumor growth was examined using tube formation assay, chicken chorioallantoic membrane assay, cell line - derived xenograft models, and an HNSCC patient-derived xenograft (PDX) model. The regulatory mechanisms among signal transducer and activator of transcription 3 (STAT3), miR-130b-3p, and muscleblind-like protein 1 (MBNL1) were investigated via bioinformatics analyses, qRT-PCR, western blot, RNA immunoprecipitation, immunofluorescence, luciferase reporter assay, and chromatin immunoprecipitation assay.

Results: Elevated miR-130b-3p enhanced the angiogenic and tumorigenic abilities of mTORC1-activated cells both in vitro and in vivo. STAT3, a downstream effector of mTORC1, transactivated miR-130b-3p by direct binding promoter of the miR-130b gene. MBNL1 was identified as a direct target of miR-130b-3p. MBNL1 depletion rescued the compromised angiogenesis and tumor growth caused by miR-130b-3p inhibition. MiR-130b-3p levels were significantly upregulated and positively correlated with mTORC1 signaling in multiple cancers. MiR-130b-3p inhibition attenuated tumor angiogenesis and growth in an HNSCC PDX model. MBNL1 feedback inhibited STAT3 activation in mTORC1-activated cells.

Conclusions: The STAT3/miR-130b-3p/MBNL1 feedback loop plays a vital role in mTORC1-mediated angiogenesis and tumor progression. This pathway could be targeted for therapeutic intervention of mTORC1-related cancers.

Keywords: Angiogenesis; MBNL1; STAT3; Tumor growth; mTOR; miR-130b-3p.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Feedback
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms* / genetics
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Neovascularization, Pathologic / genetics
  • RNA-Binding Proteins* / genetics
  • STAT3 Transcription Factor* / genetics
  • STAT3 Transcription Factor* / metabolism
  • Squamous Cell Carcinoma of Head and Neck* / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MBNL1 protein, human
  • MIRN130 microRNA, human
  • MicroRNAs
  • RNA-Binding Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases