MST4 as a novel therapeutic target for autophagy and radiosensitivity in gastric cancer.

Abstract

Mammalian ste20-like kinase 4 (MST4) and autophagy have been implicated in ailments such as inflammatory and cancers. In this study, the expression of MST4 data was extracted from TCGA, GTEx, and GEPIA. The infiltration of immune cells and methylation level of MST4 in tumor and normal tissues were extracted from GEPIA 2021, TISIDB, UALCAN, EWAS, MethSurv, and MEXPRESS database. We also predict the efficacy of outcome prediction with receiver operating characteristic curve (ROC). All proteins expressions of MST4, P62, and LC3 were detected by immunohistochemistry (IHC) in paired Gastric cancer (GC) and para-cancerous normal tissue samples. We verify the effects of MST4 on irradiation-induced gastric death, and also investigate effects of MST4 activating autophagy in GC cell lines with various in vitro assays using western blotting. We have confirmed the high transcription level of MST4 from TCGA, USLCAN, HPA, and other portals, but a rapid decrease in protein level. More, MST4 can be considered as an independent prognostic molecule, which has significant prognostic significance in tumor grade, anti-tumor treatment, histological type, and time-dependent ROC curve. The methylation degree of MST4 promoter region in tumor is much lower than that in normal tissue, which may be the main reason for the remarkably high transcription level of MST4. In addition, MST4 transcription level was significantly inversely proportional to the infiltration level of most immune cells. The MST4 up-regulation and the positive association of MST4 with autophagy expression were cross-validated in open-access datasets. MST4, as an autophagy-associated protein, plays a potential role in inducing cell death by increasing protein content in radiotherapy.