Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker.
Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker.
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利用蛋白质组学鉴定具有 CYP2D610 多态性的肝细胞癌机制，并将 ANGPTL6 鉴定为新的诊断和预后生物标志物
DOI：
10.1186/s12967-021-03038-3
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发表时间：
2021-08-19
影响因子：
7.4
通讯作者：
Qiao H
中科院分区：
文献类型：
--
作者：
Hu G;Gao F;Wang G;Fang Y;Guo Y;Zhou J;Gu Y;Zhang C;Gao N;Wen Q;Qiao H
尽管细胞色素P4502D6(CYP2D6)*10(100C>；T)基因多态性与肝细胞癌的关系已知，但其机制尚不清楚。本研究旨在探讨CYP2D6*10(100C&gT；T)基因多态性与肝细胞癌的发病机制，筛选肝细胞癌的标志物。对61例肝癌患者的34个正常肝脏和癌旁组织进行了无标记的整体蛋白质组分析，并在2个肝脏样本验证队列和2个血液样本验证队列中评估了血管生成素样蛋白-6(ANGPTL6)。我们发现在肝细胞癌患者中TT频率显著降低，这降低了69.2%的肝癌易感性，并伴随着CYP2D6酶活性的降低。蛋白质组学分析发现1342个差异表达蛋白(DEP)与肝癌相关，88个DEP被鉴定为100个TT相关蛋白，可能与肝癌的易感性有关。22个上调的DEPS和66个下调的DEPS分别主要与脂质代谢和细胞外基质有关。ANGPTL6水平高的患者发生肝癌的风险较高，预后较差。ANGPTL6既是一个独立的危险因素，也是一个独立的预后因素，与甲胎蛋白相比，AUC值相当，敏感性更高，具有很强的预测肝癌发生的潜力。TT型相关的肝癌风险降低可能与肿瘤微环境中细胞色素P450 2 D6活性降低和蛋白表达改变有关，ANGPTL6是一种有希望的新的肝癌诊断和预后生物标志物。我们的发现揭示了与肝癌风险相关的基因多态的新的机制洞察力，并为肝癌的筛查提供了途径。网上版载有补充材料，可在10.1186/s12967-021-03038-3查阅。
Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC. The online version contains supplementary material available at 10.1186/s12967-021-03038-3.
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DOI：
10.1038/nrg.2018.4
发表时间：
2018-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Karczewski KJ;Snyder MP
通讯作者：
Snyder MP
影响因子：
64.8
作者：
BRESSAC, B;KEW, M;OZTURK, M
通讯作者：
OZTURK, M
影响因子：
6.4
作者：
Silvestri, L;Sonzogni, L;Silini, EM
通讯作者：
Silini, EM
影响因子：
3.9
作者：
Cui, J. G.;Zhao, Y.;Lukiw, W. J.
通讯作者：
Lukiw, W. J.
从肝纤维化到肝癌：较高的细胞色素 P450 2E1 活性是潜在的危险因素
影响因子：
4.6
作者：
Gao, Jie;Wang, Zhao;Qiao, Hai-Ling
通讯作者：
Qiao, Hai-Ling