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

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.

• Authors: Hongwu Li, Ping Liu, Dapeng Li, Zixi Wang, Zhao Ding, Meng Zhou, Xu Chen, Manli Miao, Junli Ding, Wei Lin, Yehai Liu, Xiaojun Zha
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 41 Issue 1 Pg. 297 (Oct 11 2022) ISSN: 1756-9966 [Electronic] England
• PMID: 36217202 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• 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

Topics

• 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, metabolism)
• Neovascularization, Pathologic (genetics)
• RNA-Binding Proteins (genetics)
• STAT3 Transcription Factor (genetics, metabolism)
• Squamous Cell Carcinoma of Head and Neck (genetics)
• TOR Serine-Threonine Kinases (metabolism)