Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China.
Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China.
Mini Rev Med Chem. 2020;20(12):1153-1165. doi: 10.2174/1389557520666200331072122.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Chemoresistance remains the major factor for limited efficacy of the HCC treatment. Thus, exploring the mechanisms underlying drug resistance is of great importance. Secretory clusterin (sCLU), a stressactivated and ATP-independent molecular chaperone, is up-regulated in numerous tumors and correlated with malignant phenotypes. For HCC, the implication of sCLU was previously addressed in tumor growth, metastasis, as well as early diagnosis and poor prognosis. Notably, accumulating studies have emphasized its vital role in drug resistance of HCC. Depletion of sCLU synergistically could enhance the sensitivity of HCC cells to a variety of chemotherapy agents. Herein, we summarized the potential mechanisms accounting for the sCLU-induced chemoresistance, including promoting apoptosis evasion, facilitating epithelial-mesenchymal transition (EMT), maintaining the viability of cancer stem cell (CSC), enhancing drug efflux capacity, and regulating autophagic activities. The current evidence suggest that targeting sCLU might be a promising approach in overcoming chemoresistance of HCC.
肝细胞癌 (HCC) 是全球癌症相关死亡的主要原因。化疗耐药性仍然是 HCC 治疗效果有限的主要因素。因此，探索耐药性的机制非常重要。分泌性簇蛋白 (sCLU) 是一种应激激活的、ATP 非依赖性的分子伴侣，在许多肿瘤中上调，并与恶性表型相关。对于 HCC，sCLU 的作用先前在肿瘤生长、转移以及早期诊断和预后不良中得到了研究。值得注意的是，越来越多的研究强调了它在 HCC 耐药性中的重要作用。sCLU 的耗竭可以协同增强 HCC 细胞对多种化疗药物的敏感性。在此，我们总结了导致 sCLU 诱导的化疗耐药性的潜在机制，包括促进细胞凋亡逃逸、促进上皮-间充质转化 (EMT)、维持癌症干细胞 (CSC) 的活力、增强药物外排能力以及调节自噬活性。目前的证据表明，靶向 sCLU 可能是克服 HCC 化疗耐药性的一种有前途的方法。
