Identification of NOX4 as a New Biomarker in Hepatocellular Carcinoma and Its Effect on Sorafenib Therapy

To improve the survival of patients with hepatocellular carcinoma (HCC), new biomarkers and therapeutic targets are urgently needed. In this study, the GEO and TCGA dataset were used to explore the differential co-expressed genes and their prognostic correlation between HCC and normal samples. The mRNA levels of these genes were validated by qRT-PCR in 20 paired fresh HCC samples. The results demonstrated that the eight-gene model was effective in predicting the prognosis of HCC patients in the validation cohorts. Based on qRT-PCR results, NOX4 was selected to further explore biological functions within the model and 150 cases of paraffin-embedded HCC tissues were scored for NOX4 immunohistochemical staining. We found that the NOX4 expression was significantly upregulated in HCC and was associated with poor survival. In terms of function, the knockdown of NOX4 markedly inhibited the progression of HCC in vivo and in vitro. Mechanistic studies suggested that NOX4 promotes HCC progression through the activation of the epithelial–mesenchymal transition. In addition, the sensitivity of HCC cells to sorafenib treatment was obviously decreased after NOX4 overexpression. Taken together, this study reveals NOX4 as a potential therapeutic target for HCC and a biomarker for predicting the sorafenib treatment response.