Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 211166, China.
Department of Gastroenterology, Dongtai People's Hospital, Yan Chen, 224000, Jiangsu, China.
Cell Oncol (Dordr). 2021 Aug;44(4):907-916. doi: 10.1007/s13402-021-00610-3. Epub 2021 Jun 25.
Cholangiocarcinoma (CCA) is the second most malignant tumor of the hepatobiliary system. Due to its cumbersome early diagnosis and rapid progression, chemotherapy has become the main treatment option. Primary drug resistance is a major cause of the poor efficacy of chemotherapeutic drugs. Therefore, it is considered urgent to explore new drugs to overcome primary drug resistance of CCA.
Western blot and qRT-PCR assays were used to assess the expression of myotrophin (MTPN) and microRNA-885-5p (miR-885-5p) in CCA tissues and cells. The viability of CCA cells treated with arsenic trioxide (ATO), 5-fluorouracil (5-Fu) and cisplatin (CDDP) was analyzed using a CCK-8 assay. A luciferase reporter assay was used to assess the interaction between miR-885-5p and MTPN. Kaplan-Meier analyses were used for survival assessments.
We found that ATO can reduce the resistance of CCA cells to 5-Fu and CDDP and promote the killing effect of 5-Fu and CDDP. Low-dose ATO showed an anti-drug-resistance effect through up-regulation of the expression of miR-885-5p. Combined with sequencing results and database predictions, we found that MTPN may serve as a direct target of miR-885-5p. After MTPN knockdown, the sensitivity of CCA cells to 5-FU and CDDP was increased. Finally, we found that ATO can reverse chemotherapy resistance induced by overexpression of MTPN.
Our data indicate that the ATO/miR-885-5p/MTPN axis may serve as a target for improving the sensitivity of CCA cells to chemotherapy.
胆管癌（CCA）是肝胆系统第二大恶性肿瘤。由于其早期诊断困难且进展迅速，化疗已成为主要治疗选择。原发性耐药是化疗药物疗效不佳的主要原因。因此，探索新的药物来克服 CCA 的原发性耐药性被认为是当务之急。
采用 Western blot 和 qRT-PCR 检测 CCA 组织和细胞中肌萎缩蛋白（MTPN）和微小 RNA-885-5p（miR-885-5p）的表达。用 CCK-8 法分析三氧化二砷（ATO）、5-氟尿嘧啶（5-Fu）和顺铂（CDDP）处理的 CCA 细胞的活力。采用荧光素酶报告基因检测评估 miR-885-5p 与 MTPN 之间的相互作用。采用 Kaplan-Meier 分析进行生存评估。
我们发现 ATO 可以降低 CCA 细胞对 5-Fu 和 CDDP 的耐药性，并增强 5-Fu 和 CDDP 的杀伤作用。低剂量 ATO 通过上调 miR-885-5p 的表达发挥抗耐药作用。结合测序结果和数据库预测，我们发现 MTPN 可能是 miR-885-5p 的直接靶标。敲低 MTPN 后，CCA 细胞对 5-Fu 和 CDDP 的敏感性增加。最后，我们发现 ATO 可以逆转 MTPN 过表达诱导的化疗耐药。
我们的数据表明，ATO/miR-885-5p/MTPN 轴可能成为提高 CCA 细胞对化疗敏感性的靶点。
