AFP promotes HCC progression by suppressing the HuR-mediated Fas/FADD apoptotic pathway.
AFP promotes HCC progression by suppressing the HuR-mediated Fas/FADD apoptotic pathway.
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AFP 通过抑制 HuR 介导的 Fas/FADD 凋亡途径促进 HCC 进展
DOI：
10.1038/s41419-020-03030-7
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发表时间：
2020-10-02
影响因子：
9
通讯作者：
Lu X
中科院分区：
文献类型：
--
作者：
Chen T;Dai X;Dai J;Ding C;Zhang Z;Lin Z;Hu J;Lu M;Wang Z;Qi Y;Zhang L;Pan R;Zhao Z;Lu L;Liao W;Lu X
肝细胞癌是世界范围内癌症相关死亡的主要原因。甲胎蛋白(AFP)在大多数肝细胞癌(HCC)中被重新激活，并与不良的患者预后相关。虽然越来越多的证据表明AFP可以调节肝癌细胞的生长，但AFP在肝癌发生中的确切功能及其相关的潜在机制仍不完全清楚。在这项研究中，我们证明了去甲胎蛋白显著抑制二乙基亚硝胺(DEN)在甲胎蛋白基因缺陷小鼠模型中诱导的肝肿瘤进展。同样，下调AFP表达可通过诱导细胞凋亡来抑制人肝癌细胞的增殖和肿瘤生长。AFP表达水平与小鼠和人肝细胞癌标本的凋亡率呈负相关。对AFP与细胞凋亡信号之间潜在的相互作用的研究表明，AFP通过抑制Fas/FADD介导的外源性细胞凋亡途径发挥其促生长作用。在机制上，AFP与RNA结合蛋白HUR结合，增加HUR在细胞质中的积聚，从而抑制Fas mRNA的翻译。此外，我们还发现，抑制AFP可通过激活Hur介导的Fas/FADD凋亡信号来增强药物对AFP阳性肝癌细胞的细胞毒作用。结论：我们的研究明确了AFP在肝癌进展中的促癌作用，并发现了一种新的抗凋亡机制，将AFP与Hur介导的Fas翻译联系起来。我们的发现提示AFP参与了肝细胞癌的发病机制和化疗敏感性，阻断AFP可能是治疗晚期肝细胞癌的一种有前途的策略。
Hepatocellular carcinoma (HCC) is a major leading cause of cancer-related death worldwide. Alpha fetoprotein (AFP) is reactivated in a majority of hepatocellular carcinoma (HCC) and associated with poor patient outcomes. Although increasing evidence has shown that AFP can regulate HCC cell growth, the precise functions of AFP in hepatocarcinogenesis and the associated underlying mechanism remain incompletely understood. In this study, we demostrated that depleting AFP significantly suppressed diethylnitrosamine (DEN)-induced liver tumor progression in an AFP gene-deficient mouse model. Similarly, knocking down AFP expression inhibited human HCC cell proliferation and tumor growth by inducing apoptosis. AFP expression level was inversely associated with the apoptotic rate in mouse and human HCC specimens. Investigation of potential cross-talk between AFP and apoptotic signaling revealed that AFP exerted its growth-promoting effect by suppressing the Fas/FADD-mediated extrinsic apoptotic pathway. Mechanistically, AFP bound to the RNA-binding protein HuR, increasing the accumulation of HuR in the cytoplasm and subsequent inhibition of Fas mRNA translation. In addition, we found that inhibiting AFP enhanced the cytotoxicity of therapeutics to AFP-positive HCC cells by activating HuR-mediated Fas/FADD apoptotic signaling. Conclusion: Our study defined the pro-oncogenic role of AFP in HCC progression and uncovered a novel antiapoptotic mechanism connecting AFP to HuR-mediated Fas translation. Our findings suggest that AFP is involved in the pathogenesis and chemosensitivity of HCC and that blockade of AFP may be a promising strategy to treat advanced HCC.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.251667098
发表时间：
2002-02-19
影响因子：
11.1
作者：
Bennett, JA;Mesfin, FB;Jacobson, HI
通讯作者：
Jacobson, HI
影响因子：
5.3
作者：
De Mees, C;Laes, JF;Szpirer, C
通讯作者：
Szpirer, C
影响因子：
--
作者：
Dudich, E;Semenkova, L;Sukhikh, G
通讯作者：
Sukhikh, G
DOI：
10.1046/j.1432-1327.1999.00868.x
发表时间：
1999-12-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Dudich, E;Semenkova, L;Sukhikh, G
通讯作者：
Sukhikh, G