MST4 as a novel therapeutic target for autophagy and radiosensitivity in gastric cancer
Xiuhua Shi1,2, Junwei Zou3, Yinhua Wang2
1Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Institute of Radiotherapy and Oncology, Soochow University, Suzhou, China.
Background:
Mammalian ste20-like kinase 4 (MST4) and autophagy have been implicated in ailments such as inflammatory and cancers.
Methods:
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.
Results:
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.
Conclusions:
MST4, as an autophagy-associated protein, plays a potential role in inducing cell death by increasing protein content in radiotherapy.
Insights
Mammalian ste20-like kinase 4 (MST4) is linked to cancer and inflammation. This study found MST4 protein levels decrease in tumors despite high transcription, suggesting a prognostic role in gastric cancer and radiotherapy-induced cell death via autophagy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mammalian ste20-like kinase 4 (MST4) and autophagy are implicated in inflammatory diseases and cancers.
- Understanding the role of MST4 in cancer progression is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the expression patterns and prognostic significance of MST4 in gastric cancer.
- To explore the relationship between MST4, immune cell infiltration, methylation, and autophagy in gastric cancer.
- To determine the effect of MST4 on irradiation-induced cell death in gastric cancer.
Main Methods:
- MST4 expression data analyzed from TCGA, GTEx, and GEPIA databases.
- Immune cell infiltration and methylation levels assessed using GEPIA 2021, TISIDB, UALCAN, EWAS, MethSurv, and MEXPRESS.
- Protein expression (MST4, P62, LC3) evaluated by immunohistochemistry in gastric cancer tissues.
- In vitro assays and western blotting used to study MST4's effect on autophagy and irradiation-induced cell death.
Main Results:
- MST4 exhibited high transcription but decreased protein levels in tumors.
- MST4 identified as an independent prognostic marker for gastric cancer, correlating with tumor grade and treatment.
- Lower MST4 promoter methylation in tumors explained high transcription; MST4 inversely correlated with immune cell infiltration.
- MST4 up-regulation positively associated with autophagy, validated across datasets.
Conclusions:
- MST4, an autophagy-associated protein, shows potential in inducing cell death during radiotherapy.
- MST4 may serve as a valuable prognostic biomarker and therapeutic target in gastric cancer.
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