Yan Xiaofei, Zhao Jian, Zhang Rui
Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, People's Republic of China.
Cancer Chemother Pharmacol. 2017 Aug;80(2):395-403. doi: 10.1007/s00280-017-3365-y. Epub 2017 Jun 30.
Colorectal cancer (CRC) is one of the prevalent and deadly cancers worldwide. Chemotherapy resistance is one of the most challenging problems for CRC and other cancer treatments. Recent studies indicated that increasing levels of visfatin are correlated with worse clinical prognosis of CRC patients, while the effects and mechanisms of visfatin on progression of CRC remain unclear. Our present study established doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (named HCT-116 Dox/R and SW480 Dox/R). The expression of visfatin, while not IL-6, IL-8, or TGF-β, in CRC Dox-resistant cells was significantly greater than that in their parental cells, while knockdown of visfatin by its specific siRNAs can elevate Dox sensitivity of CRC-resistant cells. In addition, si-visfatin can significantly down regulate the expression of multidrug resistance 1 (MDR1), while not multidrug resistance-associated protein 1 or lung resistance-related protein, in both HCT-116 Dox/R and SW480 Dox/R cells. Visfatin can regulate the transcription of MDR1 via modulating its promoter activities. Si-visfatin can also decrease the activation and nuclear localization of p65, one of the most important transcription factors for the expression of MDR1. Chromatin immunoprecipitation (ChIP) indicated that si-visfatin can suppress the binding between p65 and MDR1 promoter. Collectively, our present study revealed that visfatin mediates the Dox resistance of CRC cells via up regulation of MDR1. It indicated that targeted inhibition of visfatin might be helpful for overcoming Dox resistance of CRC therapy.
结直肠癌（CRC）是全球范围内常见且致命的癌症之一。化疗耐药性是CRC及其他癌症治疗中最具挑战性的问题之一。最近的研究表明，内脂素水平升高与CRC患者较差的临床预后相关，而内脂素对CRC进展的影响和机制仍不清楚。我们目前的研究建立了阿霉素（Dox）耐药的CRC HCT-116和SW480细胞（命名为HCT-116 Dox/R和SW480 Dox/R）。CRC耐药细胞中内脂素的表达显著高于其亲代细胞，而白细胞介素-6、白细胞介素-8或转化生长因子-β则不然，而通过其特异性小干扰RNA（siRNA）敲低内脂素可提高CRC耐药细胞对Dox的敏感性。此外，si-内脂素可显著下调HCT-116 Dox/R和SW480 Dox/R细胞中多药耐药蛋白1（MDR1）的表达，而对多药耐药相关蛋白1或肺耐药相关蛋白则无影响。内脂素可通过调节MDR1的启动子活性来调控其转录。Si-内脂素还可降低p65的激活和核定位，p65是MDR1表达最重要的转录因子之一。染色质免疫沉淀（ChIP）表明，si-内脂素可抑制p65与MDR1启动子之间的结合。总的来说，我们目前的研究表明，内脂素通过上调MDR1介导CRC细胞的Dox耐药性。这表明靶向抑制内脂素可能有助于克服CRC治疗中的Dox耐药性。
