Abstract
BackgroundWorldwide, hepatocellular carcinoma (HCC) is a common solid tumor with a poor prognosis. HCC is often due to hepatitis B virus (HBV) infection. As yet, efficacious HCC treatment regimens for late-stage HCC patients are lacking. Therefore, the identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need.MethodsTotal RNAs from paired HBV-derived HCC tumors and adjacent peritumor tissues (APTs) were subjected to RNA sequencing (RNA-seq), and differentially expressed genes (DEGs) between HCC tumors and APTs were selected and verified.ResultsWe identified 166 DEGs and found that eight top-ranked and verified DEGs (TK1, CTTN, CEP72, TRIP13, FTH1, FLAD1, CHRM2, AMBP) all contained putative OCT4 binding motifs in their promoter regions. TK1, TRIP13 and OCT4 were found to exhibit concurrent higher expression levels in HCC tumors than in APTs. The mRNA levels of TK1, TRIP13 and OCT4 in a cohort of 384 HCC samples from the TCGA database were all found to be negatively correlated with patient overall survival, relapse-free survival and progression-free survival, underscoring the HCC biomarker status of TK1 and TRIP13 on one hand, and implicating their association with OCT4 on the other hand. Furthermore, OCT4 proteins were found to bind to the promoters of both genes in vitro and in vivo. Knocking out OCT4 in HCC-derived cell lines reduced the expression of TK1 and TRIP13 and significantly decreased their tumorigenicity.ConclusionsUsing RNA-seq, we identified several novel HCC signature genes that may serve as biomarkers for its diagnosis and prognosis. Their common transcriptional regulation by OCT4 suggests key roles in the development of HCC, and indicates that OCT4 may serve as a potential therapeutic target.
Highlights
Hepatocellular carcinoma (HCC) is a common solid tumor and the third leading cause of cancer-related death worldwide [1]
The mRNA levels of TK1, TRIP13 and OCT4 in a cohort of 384 hepatocellular carcinoma (HCC) samples from the The Cancer Genome Atlas (TCGA) database were all found to be negatively correlated with patient overall survival, relapse-free survival and progression-free survival, underscoring the HCC biomarker status of TK1 and TRIP13 on one hand, and implicating their association with OCT4 on the other hand
Knocking out OCT4 in HCC-derived cell lines reduced the expression of TK1 and TRIP13 and significantly decreased their tumorigenicity
Summary
Hepatocellular carcinoma (HCC) is a common solid tumor and the third leading cause of cancer-related death worldwide (second leading cause of cancer-related death in less developed countries) [1]. Several invasive and non-invasive diagnostic biomarkers [e.g. α-fetoprotein (AFP), AFP-L3, des-γ-carboxyprothrombin (DCP)] have already been identified and evaluated in different clinical settings [6] Those biomarkers display limited sensitivity and specificity, especially with respect to early HCC stages and, combinations with other newly-identified candidate biomarkers are currently being evaluated [6]. Huang et al [10] for the first time conducted genome-wide transcriptome analyses of 10 matched pairs of cancer and noncancerous tissues from HCC patients They found that the 1378 differentially expressed genes (DEGs) identified were mostly enriched in 54 bio-function terms and 41 canonical pathways, thereby providing important clues for our understanding the molecular mechanisms underlying HCC development. The identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need
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