Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.
Chaperone-mediated autophagy compensates for impaired macroautophagy in the cirrhotic liver to promote hepatocellular carcinoma.
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DOI：
10.18632/oncotarget.16685
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发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Dash S
中科院分区：
文献类型：
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作者：
Chava S;Lee C;Aydin Y;Chandra PK;Dash A;Chedid M;Thung SN;Moroz K;Wu T;Nayak NC;Dash S
大自噬和分子伴侣介导的自噬（CMA）代表了两个主要的溶酶体降解过程，并且通常相互补偿以促进细胞存活。本研究的目的是确定这些自噬途径是否可以相互补偿，以促进HCC细胞在坏死肝脏中的存活。对正常肝组织的分析显示磷脂酰肌醇蛋白聚糖-3或p62蛋白没有表达，这表明在非病理条件下大自噬是自噬通量的主要贡献者。在46例HCC患者中，39例（84%）HCC显示p62表达增加，36例（78%）显示glypican-3表达增加，而邻近非肿瘤肝细胞p62和glypican-3表达阴性，与正常肝组织相似。这些结果表明，巨自噬通量在HCC中受损。此外，超过95%的HCC显示与周围非肿瘤性肝硬化肝相比改变的LAMP-2A表达，这与HCC中CMA的诱导一致。在100%的HCC和邻近的非肿瘤性肝硬化肝脏中检测到葡萄糖调节蛋白78（GRP 78）和热休克同源蛋白（Hsc 70）的表达升高，这表明未解决的ER应激与肝硬化中HCC的风险相关。有趣的是，使用羟氯喹（HCQ）抑制溶酶体降解诱导肿瘤抑制因子p53的表达，促进细胞凋亡，并抑制HCC生长，而使用mTOR抑制剂（Torin 1）激活自噬促进HCC生长。这项研究的结果表明，CMA的诱导补偿了巨自噬的损害，以促进HCC在坏死肝脏中的存活。
Macroautophagy and chaperone-mediated autophagy (CMA) represent two major lysosomal degradation processes and often compensate for one another to facilitate cell survival. The aim of this study was to determine whether these autophagy pathways could compensate for one another to promote HCC cell survival in the cirrhotic liver. Analysis of normal liver tissue showed no expression of glypican-3 or p62 proteins, suggesting that macroautophagy is the major contributor to autophagic flux under non-pathological conditions. Of 46 cirrhotic livers with HCC examined, 39 (84%) of HCCs showed increased expression of p62, and 36 (78%) showed increased expression of glypican-3, while adjacent non-tumorous hepatocytes were negative for expression of p62 and glypican-3, similar to normal liver tissue. These results suggest that macroautophagy flux is impaired in HCC. Furthermore, more than 95% of HCCs showed altered expression of LAMP-2A compared to the surrounding non-tumorous cirrhotic liver, consistent with induction of CMA in HCC. Elevated expression of glucose-regulated protein 78 (GRP78) and heat shock cognate protein (Hsc70) were detected in 100% of HCC and adjacent non-tumorous cirrhotic livers, suggesting that unresolved ER-stress is associated with HCC risk in liver cirrhosis. Interestingly, inhibition of lysosomal degradation using hydroxychloroquine (HCQ) induced expression of the tumor suppressor p53, promoted apoptosis, and inhibited HCC growth, whereas activation of autophagy using an mTOR inhibitor (Torin1) promoted HCC growth. Results of this study suggest that induction of CMA compensates for the impairment of macroautophagy to promote HCC survival in the cirrhotic liver.