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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 23  |  Page : 2827-2835

Effect of Upregulated DNA Replication and Sister Chromatid Cohesion 1 Expression on Proliferation and Prognosis in Hepatocellular Carcinoma


1 Chinese Center for Disease Control and Prevention, Beijing 102206, China
2 Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Beijing 100044, China
3 Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China

Correspondence Address:
Prof. Yu Wang
Chinese Center for Disease Control and Prevention, 155 Changbai Road, Changping District, Beijing 102206
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.246076

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Background: DNA replication and sister chromatid cohesion 1 (DSCC1) (also called DCC1) is a component of an alternative replication factor C complex that loads proliferating cell nuclear antigen onto DNA during S phase of the cell cycle. It is located at 8q24 and frequently amplified in hepatocellular carcinoma (HCC). However, the role of DSCC1 in the carcinogenesis and progress of HCC has not been fully investigated. Here, we aimed to assert the importance of DSCC1 in the HCC. Methods: In this study, copy number variation data and RNA sequencing data were used to calculate the DNA copy number and mRNA expression of DSCC1 in HCC. Quantitative polymerase chain reaction, Western blotting, and immunohistochemistry analysis were used to determine the mRNA and protein level of DSCC1 in HCC. The Kaplan–Meier analysis and univariate and multivariate Cox regression analysis were used to assess the association of DSCC1 with the overall survival (OS) of HCC patients. Moreover, lentiviral shRNA was used to knockdown DSCC1, and then, colony-forming assay, cell cycle assay, and cell proliferation assay were performed to evaluate the impact of DSCC1 silencing on HCC cell lines. Results: We found that DSCC1 was amplified and highly expressed in HCC tumor tissues than in nontumor tissues. We then found that the overexpression of both mRNA and protein of DSCC1 was linked to the bad prognosis of HCC patients. Astonishingly, the protein level of DSCC1 was an independent prognostic factor for OS (hazard ratio, 1.79; 95% confidence interval, 1.17–2.74; P = 0.007). Furthermore, the clonogenic capacity of DSCC1-amplified HCC cell lines (MHCC-97H, MHCC-97L, and Hep3B) was significantly inhibited by transduction of a lentiviral shRNA that targets DSCC1. We also showed that knockdown of DSCC1 induced G0–G1 cell cycle arrest (increased from 60% to more than 80%) and greatly inhibited the proliferation of HCC cell lines. Conclusion: These results suggest that DSCC1 is a putative HCC driver gene that promotes proliferation and is associated with poor prognosis in HCC.

 

 Abstract in Chinese

原发性肝细胞癌中过表达DSCC1促进增殖并与不良预后相关

摘要

背景:DSCC1(也称为DCC1)是在细胞周期S期负载增殖细胞核抗原(PCNA)到DNA的替代复制因子C(RFC)的组成部分。它所在的染色体8q24区段在原发性肝细胞癌(HCC)中存在高频率的扩增,但是DSCC1在HCC发生发展中的作用尚不清楚。

方法:利用HCC患者的DNA拷贝数变异数据(CNV)和转录组测序数据(RNA-Seq),分析DSCC1的拷贝数变异和mRNA转录水平;使用荧光定量PCR和Western Blot分析该基因mRNA和编码蛋白的表达水平。进一步使用慢病毒shRNA敲减DSCC1进行功能学验证,分析敲减DSCC1对HCC细胞系增殖和克隆形成能力的影响。

结果:我们发现HCC中DSCC1的拷贝数显著扩增、mRNA转录水平显著升高;并且其mRNA和蛋白的表达水平与患者的不良预后显著相关。更重要的是,我们发现使用shRNA敲减部分HCC细胞系(Hep3B,MHCC97H和MHCC97L)的DSCC1能显著抑制其克隆形成能力和增殖能力部分,且这些细胞系均存在DSCC1基因区段的扩增。最后,我们还发现敲减DSCC1能够使HCC细胞停滞于G0/G1期和并显著地抑制细胞增殖。

结论: DSCC1是一个潜在的原发性肝细胞癌驱动基因,其过表达能促进增殖并与HCC患者的不良预后相关。



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