Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Biochem Biophys Res Commun. 2018 Nov 17;506(1):87-93. doi: 10.1016/j.bbrc.2018.10.071. Epub 2018 Oct 16.
Colorectal cancer (CRC) is a major health problem due to its high mortality rate. The incidence of CRC is increasing in young individuals. Oxaliplatin (OXA) is an approved third-generation drug and is used for first-line chemotherapy in CRC. Although current standard chemotherapy improves the overall survival of CRC patients, an increasing number of reports of OXA resistance in CRC therapy indicates that resistance has become an urgent problem in clinical applications. Dicer is a critical enzyme involved in miRNA maturation. The expression of Dicer has been reported to be involved in the resistance to various drugs in cancer. In the present study, we aimed to investigate the role of Dicer in OXA resistance in CRC. We found that OXA treatment inhibited Dicer expression through decreasing the protein stability. OXA-induced Dicer protein degradation occurred through both proteasomal and lysosomal proteolysis, while the CHIP E3 ligase was involved in OXA-mediated Dicer ubiquitination and degradation. We established stable OXA-resistant clones from CRC cells, and observed that the CHIP E3 ligase was decreased, along with the increased Dicer expression in OXA-resistant cells. Knockdown of Dicer resensitized CRC cells to OXA treatment. In this study, we have revealed the role of miRNA biogenesis factors in OXA resistance in CRC cells.
结直肠癌（CRC）因其高死亡率而成为一个主要的健康问题。CRC 在年轻人中的发病率正在增加。奥沙利铂（OXA）是一种已批准的第三代药物，用于 CRC 的一线化疗。尽管目前的标准化疗提高了 CRC 患者的总生存率，但 CRC 治疗中 OXA 耐药的报道越来越多，表明耐药性已成为临床应用中的一个迫切问题。Dicer 是一种参与 miRNA 成熟的关键酶。据报道，Dicer 的表达参与了癌症对各种药物的耐药性。在本研究中，我们旨在研究 Dicer 在 CRC 中 OXA 耐药性中的作用。我们发现 OXA 通过降低蛋白质稳定性抑制 Dicer 的表达。OXA 诱导的 Dicer 蛋白降解通过蛋白酶体和溶酶体蛋白酶解发生，而 CHIP E3 连接酶参与 OXA 介导的 Dicer 泛素化和降解。我们从 CRC 细胞中建立了稳定的 OXA 耐药克隆，并观察到 OXA 耐药细胞中 CHIP E3 连接酶减少，同时 Dicer 表达增加。Dicer 的敲低使 CRC 细胞对 OXA 治疗重新敏感。在这项研究中，我们揭示了 miRNA 生物发生因子在 CRC 细胞中 OXA 耐药性中的作用。
