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Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4
Cellular Oncology ( IF 6.6 ) Pub Date : 2019-12-17 , DOI: 10.1007/s13402-019-00487-3
Chao Ye 1, 2 , Xiaoqian Zhang 1 , Xinyu Chen 1 , Qingyi Cao 1 , Xiaobing Zhang 1 , Yanwen Zhou 1, 3 , Wenxin Li 1, 4 , Liangjie Hong 5, 6 , Haiyang Xie 5, 6 , Xiaoli Liu 1 , Hongcui Cao 1 , Ying-Jie Wang 1 , Bo Kang 1
Affiliation  

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.


中文翻译:

多个新的肝细胞癌特征基因通常由多能性主因子OCT4控制

摘要

背景

在世界范围内,肝细胞癌(HCC)是一种预后较差的常见实体瘤。肝癌通常归因于乙型肝炎病毒(HBV)感染。迄今为止,尚缺乏针对晚期HCC患者的有效HCC治疗方案。因此,鉴定更特异性和敏感性的生物标志物以用于其早期诊断和治疗仍然是迫切需要。

方法

对来自成对的HBV的HCC肿瘤和邻近的癌旁组织(APT)的总RNA进行RNA测序(RNA-seq),并选择和验证HCC肿瘤和APT之间的差异表达基因(DEG)。

结果

我们确定了166度的视角,并发现8排名第一和验证度的视角(TK1CTTNCEP72TRIP13FTH1FLAD1CHRM2AMBP)均在其启动子区域包含推定的OCT4结合基序。发现TK1,TRIP13和OCT4在HCC肿瘤中同时表现出比APT高的表达水平。在TCGA数据库的384份HCC样本队列中,TK1,TRIP13和OCT4的mRNA水平均与患者总体生存,无复发生存和无进展生存负相关,这突出了TK1和HCC的HCC生物标志物状态一方面是TRIP13,另一方面是它们与OCT4的关联。此外,发现OCT4蛋白在体外和体内均与两个基因的启动子结合。在HCC衍生的细胞系中剔除OCT4可降低TK1TRIP13的表达,并显着降低其致瘤性。

结论

使用RNA序列,我们确定了几个新的HCC签名基因,可作为其诊断和预后的生物标记。它们由OCT4共同的转录调控提示在HCC的发生中起关键作用,并表明OCT4可以作为潜在的治疗靶标。
更新日期:2019-12-17
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