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.

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.