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.
引言：SOX4在肿瘤发生和癌症进展中扮演重要角色。SOX4在泛癌中的作用及其在肝细胞癌（LIHC）中的潜在分子机制尚未完全阐明。本研究通过综合分析及实验验证，探讨了SOX4在不同肿瘤类型中的功能。方法：从TCGA和GTEx数据库下载恶性肿瘤中SOX4表达相关原始数据。通过系统生物信息学分析，探究SOX4在不同肿瘤类型中的表达水平、预后价值、基因突变及DNA启动子甲基化状态。在LIHC中分析了ceRNA调控网络、免疫特征及预后模型。最后通过蛋白质印迹、细胞增殖实验、台盼蓝染色及荧光显微镜等体外实验，进一步探索SOX4在LIHC中的功能。结果：SOX4在24种肿瘤类型中表达显著上调。其表达水平与不良预后、基因突变及DNA甲基化程度在不同肿瘤类型中均呈现强相关性。尤其在LIHC中，LINC00152/hsa-miR-139-3p/SOX4被确认为关键ceRNA网络。本研究还揭示了SOX4表达在LIHC中对免疫细胞浸润、巨噬细胞极化、免疫亚型、分子亚型、免疫调节因子以及肿瘤免疫微环境（TIME）相关预后的影响。基于SOX4相关基因构建了六个具有良好预测效能的LIHC预后模型。最后发现仑伐替尼治疗可上调肝细胞癌细胞中SOX4表达并诱导耐药，沉默SOX4能有效消除仑伐替尼引发的耐药性并抑制癌细胞增殖。结论：本研究提示SOX4可能成为肿瘤治疗中具有潜力的治疗靶点。
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