TGFB1-mediated autophagy facilitates oxaliplatin resistance in stomach adenocarcinoma.

Abstract

Increasing evidence has indicated that transforming growth factor beta 1 (TGFB1) is engaged in tumorigenesis and progression. Nevertheless, the underlying role and mechanism of TGFB1 in stomach adenocarcinoma (STAD) chemotherapy remains unknown. TGFB1 levels in various types of cancers were first analyzed by the TCGA database. Next, the degree of cellular damage, apoptosis and autophagy were detected by lactate dehydrogenase kit, flow cytometry, autophagy fluorescence analysis, and Western blot assay. The gene highly correlated with TGFB1 expression was searched by LinkedOmics and KEGG. We disclosed TGFB1 was enhanced in STAD. Besides, TGFB1 was remarkably higher in STAD patients in oxaliplatin (OXA) chemoresistant group than sensitive group. Additionally, the half maximal inhibitory concentration (IC50) values of OXA-resistant cells were markedly elevated. Furthermore, TGFB1 reduced AGS-OXA and HGC27-OXA cell injury, inhibited apoptosis and induced cellular autophagy. The addition of the autophagy inhibitor 3-methyladenine hindered this phenomenon. Further studies revealed that muscle RAS oncogene homolog (MRAS) is a downstream target gene of TGFB1. TGFB1 accelerated MRAS level in OXA cells, and MRAS knockdown reversed the effects of TGFB1 on OXA cell function. TGFB1 induces cellular autophagy via MRAS, thereby promoting STAD OXA resistance.