Chao Ye1,2, Xiaoqian Zhang1, Xinyu Chen1, Qingyi Cao1, Xiaobing Zhang1, Yanwen Zhou1,3, Wenxin Li1,4, Liangjie Hong5,6, Haiyang Xie5,6, Xiaoli Liu1, Hongcui Cao1, Ying-Jie Wang7, Bo Kang8. 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China. 2. The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China. 3. Department of Infectious Diseases, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. 4. Department of Respiratory Medicine, Institute of Respiratory Disease, The First College of Clinical Medical Sciences, Yichang Central People's Hospital, China Three Gorges University, Yichang, 443003, Hubei, China. 5. NHFPC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. 6. Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. 7. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China. yingjiewang@zju.edu.cn. 8. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310003, Hangzhou, China. kangbo@zju.edu.cn.
Abstract
BACKGROUND: Worldwide, 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. METHODS: Total 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. RESULTS: We 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. CONCLUSIONS: Using 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.
BACKGROUND: Worldwide, 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 HCCpatients are lacking. Therefore, the identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need. METHODS: Total 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. RESULTS: We 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. CONCLUSIONS: Using 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.
Authors: Mingyue Zhu; Wei Li; Yan Lu; Xu Dong; Bo Lin; Yi Chen; Xueer Zhang; Junli Guo; Mengsen Li Journal: Int J Cancer Date: 2017-03-15 Impact factor: 7.396
Authors: S E T Larkin; S Holmes; I A Cree; T Walker; V Basketter; B Bickers; S Harris; S D Garbis; P A Townsend; C Aukim-Hastie Journal: Br J Cancer Date: 2011-11-10 Impact factor: 7.640