Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma
Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma
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DOI：
10.1097/meg.0b013e3283378405
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发表时间：
2010-09-01
影响因子：
2.1
通讯作者：
Wyld, Lynda
中科院分区：
文献类型：
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作者：
Al-Rawashdeh, Feras Y.;Scriven, Peter;Wyld, Lynda
目的肝细胞癌在全球范围内的年发病率为62.6万例，每年导致55万人死亡。虽然治疗的主要方法是手术切除，但对于不能手术或转移的疾病，也可以提供化疗。使用的主要药物是阿霉素，但应答率很低(<；20%)。未折叠蛋白反应(UPR)是一种细胞保护性应激反应，使细胞能够在缺氧和营养缺乏的时期存活。UPR可能会对抗癌药物产生耐药性，并导致治疗失败。本研究探讨UPR在肝细胞癌中是否被激活，以及这是否与阿霉素耐药有关。方法采用免疫组织化学方法检测86例人肝癌细胞中UPR激活的关键标志物葡萄糖调节蛋白78的表达。采用去糖培养法建立了人肝癌细胞系HepG2中UPR活化的体外模型。蛋白质印迹和聚合酶链式反应证实UPR激活，显示葡萄糖调节蛋白78的高表达。用四唑蓝比色法比较阿霉素化疗对UPR激活的HepG2细胞和正常细胞的相对疗效。结果葡萄糖调节蛋白78在100%的肝癌组织中表达，其中66%呈强阳性表达。UPR的体外激活是在去糖的情况下实现的。UPR激活诱导肝癌细胞对阿霉素产生明显的耐药性：标准培养条件下UPR激活的细胞存活率为34%，而在0.5和1 mmol葡萄糖中UPR激活的细胞存活率分别为58%和63%(P=0.00928)。结论UPR在肝癌细胞中被激活，并在体外诱导化疗耐药。UPR激活可能参与了肝细胞癌的化疗耐药。EURJ胃肠病肝素22：1099-1105(C)2010沃尔特斯·克鲁沃健康|Lippincott Williams&Wilkins。
Objective Hepatocellular carcinoma (HCC) has an annual worldwide incidence of 626 000 cases and causes 550 000 deaths per year. Although the mainstay of treatment is surgical resection, for inoperable or metastatic disease, chemotherapy may be offered. The primary agent used is doxorubicin, but response rates are poor ( < 20%). The unfolded protein response (UPR) is a cytoprotective cellular stress response that enables cells to survive periods of hypoxia and nutrient deprivation. The UPR may confer resistance to anticancer agents and contribute to treatment failure. This study has investigated whether the UPR is activated in HCC and whether this may contribute to doxorubicin resistance.Methods Eighty-six human HCCs were immunohistochemically stained for glucose regulated protein 78, the key marker of UPR activation. An in-vitro model of UPR activation in HepG2 HCC cells was developed by glucose deprived culture. UPR activation was confirmed with western blotting and PCR to show overexpression of glucose regulated protein 78. The relative efficacy of doxorubicin chemotherapy on UPR-activated HepG2 cells was compared with normal HepG2 cells by use of an thiazolyl blue tetrazolium bromide colorimetric assay.Results Expression of glucose regulated protein 78 was shown in 100% of the HCC samples with 66% showing strong staining. In-vitro UPR activation was achieved with glucose deprivation. UPR activation induced significant resistance to doxorubicin: 34% survival under standard culture conditions versus 58% and 63% for UPR- activated cells in 0.5 and 1 mmol glucose respectively (P = 0.00928).Conclusion The UPR is activated in HCCs and confers resistance to chemotherapy in vitro. UPR activation may contribute to HCC chemoresistance. Eur J Gastroenterol Hepatol 22: 1099-1105 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.