High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti-apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients.
High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti-apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients.
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PGAM5 高表达通过增强 Bcl-xL 介导的抗凋亡信号传导诱导化疗耐药，并预测肝细胞癌患者的不良预后。
DOI：
10.1038/s41419-018-1017-8
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发表时间：
2018-09-24
影响因子：
9
通讯作者：
Yuan Z
中科院分区：
文献类型：
--
作者：
Cheng J;Qian D;Ding X;Song T;Cai M;Dan Xie;Wang Y;Zhao J;Liu Z;Wu Z;Pang Q;Zhu L;Wang P;Hao X;Yuan Z
肝细胞癌（HCC）是最常见和最致命的癌症之一，并且对常规化疗具有高度耐药性。线粒体磷酸甘油酸突变酶/蛋白磷酸酶（PGAM5）调节线粒体稳态和细胞死亡，然而，其在癌症中的作用知之甚少。本研究旨在探讨PGAM5在肝细胞癌中的临床意义及潜在的生物学功能。我们的研究结果首次表明，与相应的邻近非癌性肝组织相比，PGAM5在HCC中的表达显著上调，在单因素和多因素分析中，PGAM5的高表达是生存时间缩短的独立预测因子。此外，体内和体外研究表明，减少PGAM5表达可抑制肿瘤生长，增加HCC细胞对5-氟尿嘧啶的敏感性。相反，在PGAM5敲低的细胞中恢复PGAM5的表达可显著增强HCC细胞对5-氟尿嘧啶的耐药性。重要的是，我们证明了PGAM5赋予HCC细胞5-氟尿嘧啶耐药的机制是通过相互作用和稳定Bcl-xL来抑制BAX-和细胞色素c介导的凋亡信号传导。同样，在HCC患者组织的相同队列中，Bcl-xL表达与PGAM5呈正相关，并共同预测预后不良。总之，我们的数据强调了PGAM5在HCC中的分子病因学和临床意义。靶向PGAM5/Bcl-xL介导的新型信号通路可能是改善HCC患者生存结局的一种新的治疗策略。
Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.
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影响因子：
9
作者：
Kim JH;Lee DK;Kim J;Choi S;Park W;Ha KS;Kim TH;Choe J;Won MH;Kwon YG;Kim YM
通讯作者：
Kim YM
影响因子：
44.1
作者：
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影响因子：
6.1
作者：
Hong, Jeong-Min;Lee, Sun-Mee
通讯作者：
Lee, Sun-Mee
包含 PGAM5 磷酸酶和 CK2 的调节信号环路控制受体介导的线粒体自噬
影响因子：
16
作者：
Chen, Guo;Han, Zhe;Chen, Quan
通讯作者：
Chen, Quan
影响因子：
12.4
作者：
Liu, Y.;Clegg, H. V.;Zhang, Y.
通讯作者：
Zhang, Y.