Clinical significance of mitogen-activated protein kinase kinase kinases in hepatitis B virus -related hepatocellular carcinoma and underlying mechanism exploration

The purpose of this research was to explore the diagnostic/prognostic significance and prospective molecular mechanisms of mitogen-activated protein kinase kinase kinases (MAP3Ks) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Diagnostic/prognostic significance of MAP3Ks was screened in the GSE1450 data set and validated in the Guangxi cohort. Various bioinformatics tools were used to explore the biological functions of prognosis-related genes. Subsequently, molecular biology assays were used to verify the biological functions and molecular mechanisms of specific gene. MAP3K9 was observed to be differentially expressed in HCC and adjacent tissues with satisfactory diagnostic value. It was discovered in survival analysis that MAP3K13 and MAP3K15 were associated with overall survival (OS) of patients with HBV-related HCC in the GSE1450 data set and the Guangxi cohort. Nomograms were established based on prognosis-related genes and clinical factors for individualized risk assessment. The assays on HCC cells demonstrated that MAP3K13 regulated the death and proliferation of HCC cells by activating the JNK pathway and inducing the expression of apoptosis-related factors. In conclusion, our results suggested that MAP3K9 might serve as a diagnostic biomarker in HBV-related HCC and MAP3K13 and MAP3K15 might serve as useful prognostic biomarkers. Besides, cytological assays prompted that MAP3K13 might impact the prognosis of HCC by regulating the JNK pathway and inducing apoptosis.