Clinical and Translational Medicine (Aug 2022)

MiR‐192‐5p/RB1/NF‐κBp65 signaling axis promotes IL‐10 secretion during gastric cancer EMT to induce Treg cell differentiation in the tumour microenvironment

  • Jialin Song,
  • Zaihuan Lin,
  • Qing Liu,
  • Sihao Huang,
  • Lei Han,
  • Yan Fang,
  • Panyi Zhong,
  • Rongzhang Dou,
  • Zhenxian Xiang,
  • Jinsen Zheng,
  • Xinyao Zhang,
  • Shuyi Wang,
  • Bin Xiong

DOI
https://doi.org/10.1002/ctm2.992
Journal volume & issue
Vol. 12, no. 8
pp. n/a – n/a

Abstract

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Abstract Background Regulatory T (Treg) cells are important components of the tumour microenvironment (TME) that play roles in gastric cancer (GC) metastasis. Although tumour cells that undergo epithelial‐mesenchymal transition (EMT) regulate Treg cell function, their regulatory mechanism in GC remains unclear. Methods The miR‐192‐5p was identified by examining three Gene Expression Omnibus GC miRNA expression datasets. RNA immunoprecipitation (RIP) and dual‐luciferase reporter assays were conducted to identify interactions between miR‐192‐5p and RB1. The role of miR‐192‐5p/RB1 in GC progression was evaluated based on EdU incorporation, wound healing and Transwell assays. An in vitro co‐culture assay was performed to measure the effect of miR‐192‐5p/RB1 on Treg cell differentiation. In vivo experiments were conducted to explore the role of miR‐192‐5p in GC progression and Treg cell differentiation. Results MiR‐192‐5p was overexpressed in tumour and was associated with poor prognosis in GC. MiR‐192‐5p bound to the RB1 3′‐untranslated region, resulting in GC EMT, proliferation, migration and invasion. MiR‐192‐5p/RB1 mediated interleukin‐10 (IL‐10) secretion by regulating nuclear factor‐kappaBp65 (NF‐κBp65), affecting Treg cell differentiation. NF‐κBp65, in turn, promoted miR‐192‐5p expression and formed a positive feedback loop. Furthermore, in vivo experiments confirmed that miR‐192‐5p/RB1 promotes GC growth and Treg cell differentiation. Conclusion Collectively, our studies indicate that miR‐192‐5p/RB1 promotes EMT of tumour cells, and the miR‐192‐5p/RB1/NF‐κBp65 signaling axis induces Treg cell differentiation by regulating IL‐10 secretion in GC. Our results suggest that targeting miR‐192‐5p/RB1/NF‐κBp65 /IL‐10 may pave the way for the development of new immune treatments for GC.

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