J Cancer 2021; 12(12):3486-3500. doi:10.7150/jca.46579

Research Paper

SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma

Jian-Lv Huang1, Xiang-Kun Wang1, Xi-Wen Liao1, Chuang-Ye Han1, Ting-Dong Yu1, Ke-Tuan Huang1, Cheng-Kun Yang1, Xiao-Guang Liu1,2, Long Yu1,3, Guang-Zhi Zhu1, Hao Su1, Wei Qin1, Quan-Fa Han1, Zheng-Qian Liu1, Xin Zhou1, Jun-Qi Liu1, Xin-Ping Ye1, Tao Peng1✉

1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
2. Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong Province, China.
3. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan Province, China.

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Citation:
Huang JL, Wang XK, Liao XW, Han CY, Yu TD, Huang KT, Yang CK, Liu XG, Yu L, Zhu GZ, Su H, Qin W, Han QF, Liu ZQ, Zhou X, Liu JQ, Ye XP, Peng T. SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma. J Cancer 2021; 12(12):3486-3500. doi:10.7150/jca.46579. Available from https://www.jcancer.org/v12p3486.htm

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Abstract

Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC).

Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC.

Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival.

Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.

Keywords: SOX4, hepatocellular carcinoma, hepatitis B virus, mRNA expression