Multiple Novel Hepatocellular Carcinoma Signature Genes Are Transcriptionally Controlled in Common by the Master Pluripotency Factor OCT4

Background: Hepatocellular carcinoma (HCC) is a common solid tumor worldwide with a very poor prognosis. Identifying more specific and sensitive HCC biomarkers remains an urgent need for its early diagnosis and treatment. Methods: Total RNAs from paired HBV-derived HCC tumors and adjacent peritumor tissues (APTs) were amplified and subjected to RNA sequencing analysis, and differentially expressed genes (DEGs) between tumors and APTs were selected and verified. Findings: 166 DEGs were identified, and remarkably, eight top-ranked and verified DEGs (TK1, CTTN, CEP72, TRIP13, FTH1, FLAD1, CHRM2, AMBP) all contained putative OCT4 binding motifs at their promoter regions. TK1, TRIP13 and OCT4 were exemplified to have concurrent higher expression in HCC tumors than in APTs, and OCT4 proteins were bound to the promoters of both genes in vitro and in vivo. Knocking out OCT4 gene in hepatoma cell lines reduced the expression of TK1 and TRIP13 and significantly dampened their tumorigenicity. Interpretation: We identified multiple novel HCC signature genes that may serve as promising biomarkers for HCC diagnosis and prognosis. Their common transcriptional regulation by OCT4 implicates its key roles in the occurrence and development of HCC, and thus positions OCT4 as a potential therapeutic target for treating HCC. Funding Statement: This work was supported by grants from the National Key Research and Development Program of China (grant numbers 2016YFA0101201, 2016YFA0100303), the National Natural Science Foundation of China (grant number 31601103), the National High Technology Research and Development Program of China (grant number 2012AA020204) and the Fundamental Research Funds for the Central Universities (grant number WK9110000023). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All studies on mice were conducted in accordance with the National Institute Guide for the Care and Use of Laboratory Animal. The animal protocol has been approved by the Committee of the Ethics of Animal Experiments, Zhejiang University.