Pan-Cancer Analysis and Experimental Validation of SOX4 as a Potential Diagnosis, Prognosis, and Immunotherapy Biomarker

SIMPLE SUMMARY: Data show that the global cancer burden continues to grow. It is estimated that there were 19.3 million new cancer cases and nearly 10 million cancer deaths worldwide in 2020. Therefore, a comprehensive analysis is of great significance for the accurate diagnosis and effective treatment of tumors. This study aims to visualize the expression, survival, mutation, methylation, ceRNA network, and immune and prognostic models, as well as to explore the potential role of SOX4 in different tumor types and specific LIHCs using different online tools. In addition, we also confirm that SOX4 may be related to lenvatinib resistance in HCC patients through in vitro experiments. Knockdown of SOX4 can significantly inhibit the proliferation of HCC cells. Finally, this study highlights the key roles of SOX4 in the diagnosis and prognosis of tumors, especially in LIHC, and its potential as a promising therapeutic target for tumors. ABSTRACT: Introduction: SOX4 plays an important role in tumorigenesis and cancer progression. The role of SOX4 in pan-cancer and its underlying molecular mechanism in liver hepatocellular carcinoma (LIHC) are not fully understood. In this study, a comprehensive analysis and experimental validation were performed to explore the function of SOX4 across tumor types. Methods: Raw data in regard to SOX4 expression in malignant tumors were downloaded from the TCGA and GTEx databases. The expression levels, prognostic values, genetic mutation, and DNA promoter methylation of SOX4 across tumor types were explored via systematic bioinformatics analysis. The ceRNA regulatory network, immune characteristics, and prognostic models were analyzed in LIHC. Finally, we conducted in vitro experiments including Western blotting, cell proliferative assay, trypan blue staining, and fluorescence microscopy to further explore the function of SOX4 in LIHC. Results: SOX4 expression was significantly upregulated in 24 tumor types. SOX4 expression level was strongly associated with unfavorable prognoses, genetic mutations, and DNA methylation levels across different tumor types. Especially in LIHC, LINC00152/hsa-miR-139-3p/SOX4 was identified as a crucial ceRNA network. Moreover, this study also provides insight into the roles of SOX4 expression in immune cell infiltration, macrophage polarization, immune subtype, molecular subtype, and immunomodulators, as well as the tumor immune microenvironment (TIME)-related prognosis, in LIHC. The study established six favorable prognostic models to predict LIHC prognosis based on the SOX4-associated genes. Finally, lenvatinib treatment can increase the expression of SOX4 in hepatocellular carcinoma cells and lead to drug resistance. Silencing SOX4 can effectively eliminate the drug resistance caused by lenvatinib treatment and inhibit the proliferation of cancer cells.Conclusions: This study highlights that SOX4 may serve as a promising therapeutic target for tumor treatment.