磷脂酰肌醇蛋白聚糖3和泛素D基因在肝细胞癌中的异常表达及其相互作用

谭玉靓; 戴姿薇; 唐标

doi:10.16098/j.issn.0529-1356.2021.05.011

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解剖学报 ›› 2021, Vol. 52 ›› Issue (5) : 744-750. DOI: 10.16098/j.issn.0529-1356.2021.05.011

肿瘤生物学

磷脂酰肌醇蛋白聚糖3和泛素D基因在肝细胞癌中的异常表达及其相互作用

谭玉靓¹ 戴姿薇² 唐标^2*

作者信息 +

Abnormal expression of glypican-3 and ubiquitin D in hepatocellular carcinoma and the associated interaction#br#

TAN Yu-jing¹ DAI Zi-wei² TANG Biao^2*#br#

Author information +

文章历史 +

摘要

目的利用基因组学和表观遗传组学分析工具，分析磷脂酰肌醇蛋白聚糖3（GPC3）和泛素D（UBD）在肝细胞癌（HCC）中的异常表达情况，以及两者对HCC患者预后的影响。方法利用ULCAN（http://ualan.path.uab.edu）和Gene Expression Profiling Interative Analysis(GEPIA)数据库，分析UBD和GPC3在正常肝组织和HCC组织的异常表达情况和甲基化水平，以及对HCC患者生存的影响。利用GeneCards数据库分析UBD和GPC3的定位。利用STRING数据库对UBD和GPC3分别构建蛋白质互相作用（PPI）网络，并对UBD和GPC3进行基因注释。基于皮尔森相关系数，计算UBD和GPC3在HCC发生发展中的关联。结果 UBD和GPC3在HCC组织中表达上调，启动子甲基化水平下降。UBD位于6p22.1，主要表达于细胞核；GPC3位于Xq26.2，主要表达于细胞膜、细胞外基质、内质网、溶酶体和高尔基体。富集分析显示，UBD主要与蛋白酶体活动相关：翻译后蛋白修饰、泛素化和去泛素化；GPC3主要参与黏多糖的生物合成和分解过程，介导的生物通路主要涉及癌症多聚糖、细胞外基质受体相互作用和细胞黏附分子。关联分析显示，UBD和GPC3成线性正相关，共同调控HCC的发生发展。预后分析显示，GPC3对HCC的预后有明显的影响。结论 UBD和GPC3在HCC的表达均上调，甲基化水平均降低，GPC3对HCC的预后影响较大，或许可以作为预后评估的生物标志。

Abstract

Objective To explore the abnormal expression of ubiquitin D(UBD) and glypican-3(GPC3) among patients of hepatocellular carcinoma(HCC) by using analysis tools of genomics and epigenetics, so as to study their prognostic effects. Methods The online tools called ULCAN(http://ualan.path.uab.edu) and Gene Expression Profiling Interative Analysis(GEPIA) were used to perform expression analysis in genomics and epigenetics of UBD and GPC3. Moreover, GEPIA was conducted to evaluate the survival effects on HCC patients. The GeneCards was used to find the localization of UBD and GPC3 in tumor tissue and normal tissue. The STRING was utilized to perform the construction of PPI network and gene annotation. The correlation between UBD and GPC3 in progress of HCC was revealed based on Pearson correlation coefficient. Results UBD and GPC3 were dramatically up-regulated in HCC tissues, with downregulation of methylation level. UBD was located in 6p22.1 with primary expression in the nucleus, while GPC3 was located in Xq26.2 with main expression in the plasma membrane, extracellular matrix, endoplasmic reticulum, lysosome and golgi apparatus. The enrichment analysis showed that, UBD was enriched in activities involving proteasome, such as post-translation protein modification, ubiquitination and deubiquitination. GPC3 was enriched in the biosynthetic and catabolic process of glycosaminoglycan, possessed relationship with proteoglycans in cancer, ECM-receptor interaction, cell adhesion molecules (CAMs). Both of UBD and GPC3 were shown to exhibit a positive linear correlation, which suggested that GPC3 and UBD mediated the pathological process of HCC in cooperation. The survival analysis showed that, GPC3 exhibited a critical effect on survival of HCC patients. Conclusion UBD and GPC3 represent up-regulation in tumor tissue, in which GPC3 possesses a greater impact on the prognosis of HCC. GPC3 could be potential to serve as a practical biomarker for early diagnosis and medical intervention.

导出引用

谭玉靓戴姿薇唐标. 磷脂酰肌醇蛋白聚糖3和泛素D基因在肝细胞癌中的异常表达及其相互作用[J]. 解剖学报. 2021, 52(5): 744-750 https://doi.org/10.16098/j.issn.0529-1356.2021.05.011

TAN Yu-jing DAI Zi-wei TANG Biao. Abnormal expression of glypican-3 and ubiquitin D in hepatocellular carcinoma and the associated interaction#br#[J]. Acta Anatomica Sinica. 2021, 52(5): 744-750 https://doi.org/10.16098/j.issn.0529-1356.2021.05.011

中图分类号： R378.3

参考文献

［1］ Tang A, Hallouch O, Chernyak Ⅴ, et al. Epidemiology of hepatocellular carcinoma: target population for surveillance and diagnosis［J］. Abdom Radiol (NY), 2018, 43(1):13-25. 
［2］ Akk?z H. Hepatocellular carcinoma: from molecular basis to novel treatment approaches［J］. Can J Gastroenterol Hepatol, 2019, 2019:4970731. 
［3］ Lin DC, Mayakonda A, Dinh HQ, et al. Genomic and epigenomic heterogeneity of hepatocellular carcinoma［J］. Cancer Res, 2017, 77(9):2255-2265. 
［4］ Lee SM, Kim-Ha J, Choi WY, et al. Interplay of genetic and epigenetic alterations in hepatocellular carcinoma［J］. Epigenomics, 2016, 8(7):993-1005. 
［5］ Rongrui L, Na H, Zongfang L, et al. Epigenetic mechanism involved in the HBV/HCV-related hepatocellular carcinoma tumorigenesis［J］. Curr Pharm Des, 2014, 20(11):1715-1725. 
［6］ Yu M, Luo H, Fan M, et al. Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma［J］. Mol Ther, 2018, 26(2):366-378.
［7］ Cartier F, Indersie E, Lesjean S, et al. New tumor suppressor microRNAs target glypican-3 in human liver cancer［J］. Oncotarget, 2017, 8(25):41211-41226. 
［8］ Shimizu Y, Suzuki T, Yoshikawa T, et al. Nextgeneration cancer immunotherapy targeting glypican-3［J］. Front Oncol, 2019, 9:248. 
［9］ Nishida T, Kataoka H. Glypican 3-targeted therapy in hepatocellular carcinoma［J］. Cancers (Basel), 2019, 11(9):1339. 
［10］ Arendt BM, Teterina A, Pettinelli P, et al. Cancer-related gene expression is associated with disease severity and modifiable lifestyle factors in non-alcoholic fatty liver disease［J］. Nutrition, 2019, 62:100-107. 
［11］ Aichem A, Groettrup M. The ubiquitin-like modifier FAT10 in cancer development［J］. Int J Biochem Cell Biol, 2016, 79:451-461. 
［12］ Hernández M, Quijada NM, Rodríguez-Lázaro D, et al. Bioinformatics of next generation sequencing in clinical microbiology diagnosis ［J］. Rev Argent Microbiol, 2020, 52(2):150-161.
［13］ Keerthikumar S. An introduction to proteome bioinformatics ［J］. Methods Mol Biol, 2017, 1549: 1-3.
［14］ Li N, Gao W, Zhang YF, et al. Glypicans as cancer therapeutic targets［J］. Trends Cancer, 2018, 4(11):741-754.
［15］ French SW, Bardag-Gorce F, French BA, et al. The role of innate immunity in the pathogenesis of preneoplasia in drug-induced chronic hepatitis based on a mouse model［J］. Exp Mol Pathol, 2011, 91(3):653-659.
［16］ Filmus J, Capurro M, Rast J. Glypicans［J］. Genome Biol, 2008, 9(5):224. 
［17］ Wu M, Liu Z, Zhang A, et al. Associated measurement of fucosylated levels of AFP, DCP, and GPC3 for early diagnosis in hepatocellular carcinoma［J］. Int J Biol Markers, 2019, 34(1):20-26.
［18］ Sun B, Huang Z, Wang B, et al. Significance of glypican-3 (GPC3) expression in hepatocellular cancer diagnosis［J］. Med Sci Monit, 2017, 23:850-855. 
［19］ Oliva J, Bardag-Gorce F, French BA, et al. Independent phenotype of binuclear hepatocytes and cellular localization of UbD［J］. Exp Mol Pathol, 2010, 89(2):103-108.
［20］ Cui J, Chen Y, Wang HY, et al. Mechanisms and pathways of innate immune activation and regulation in health and cancer［J］. Hum Vaccin Immunother, 2014, 10(11):3270-3285.