Cytoplasmic fragment of CD147 generated by regulated intramembrane proteolysis contributes to HCC by promoting autophagy.
Cytoplasmic fragment of CD147 generated by regulated intramembrane proteolysis contributes to HCC by promoting autophagy.
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调节膜内蛋白水解产生的 CD147 细胞质片段通过促进自噬促进 HCC
DOI：
10.1038/cddis.2017.251
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发表时间：
2017-07-13
影响因子：
9
通讯作者：
Chen ZN
中科院分区：
文献类型：
--
作者：
Wu B;Cui J;Yang XM;Liu ZY;Song F;Li L;Jiang JL;Chen ZN
肝细胞癌（HCC）是全世界最致命和最常见的癌症之一。 CD147（EMMPRIN或basigin）是与肝癌发生和转移相关的先导基因，在HCC患者中以跨膜、外泌体或循环形式检测到。从动态角度来看，CD147的内体循环进一步增强了这种癌蛋白的功能。然而，以往关于CD147的研究主要集中在一种单独的形式，而很少关注肿瘤来源的CD147的不同形式如何变化。此外，为了充分了解 CD147 促进肿瘤进展，揭示 CD147 脱落后残留的 C 端部分的作用是不可避免的。在本研究中，我们发现在低胆固醇条件下，CD147的内吞作用受到抑制，但ADAM10介导的CD147的脱落增强。残留的CD147在溶酶体中进一步加工产生核定位的CD147-ICD（CD147的细胞内结构域），其通过NF-κB-TRAIL-caspase8-ATG3轴促进自噬。由于自噬赋予癌细胞对化疗的适应性增强，而HAb 18（一种针对CD147的特异性抗体）抑制CD147脱落以及连续的CD147-ICD增强自噬，我们发现HAb 18和顺铂的组合表现出显着的抗肿瘤效率。
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers worldwide. CD147 (EMMPRIN or basigin) is a leading gene relating to hepatocarcinogenesis and metastasis, and is detected in transmembrane, exosome or circulating forms in HCC patients. The endosome recycling of CD147 further enhances the function of this oncoprotein from a dynamic perspective. However, previous studies about CD147 mainly focused on one separate form, and little attention has been paid to how the different forms of tumor-derived CD147 changes. Moreover, uncovering the roles of the residual C-terminal portion of CD147 after shedding is inevitable to fully understand CD147 promoting tumor progression. In this study, we discovered that under low-cholesterol condition, CD147 endocytosis is inhibited but its shedding mediated by ADAM10 is enhanced. Further procession of residual CD147 in the lysosome produces nuclear-localized CD147-ICD (intracellular domain of CD147), which contributes to autophagy through NF-κB–TRAIL–caspase8–ATG3 axis. As autophagy endows cancer cells with increased adaptability to chemotherapy, and HAb 18 (a specific antibody targeting CD147) inhibits CD147 shedding and sequential CD147-ICD enhances autophagy, we found the combination of HAb 18 and cisplatin exhibited marked antitumor efficiency.
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通讯作者：
Toole BP
影响因子：
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作者：
Eyster CA;Cole NB;Petersen S;Viswanathan K;Früh K;Donaldson JG
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