Purpose

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.

Methods

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.

Result

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.

Conclusion

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.

中文翻译：

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ATO/miRNA-885-5p/MTPN 轴诱导胆管癌耐药性逆转

目的

胆管癌（CCA）是肝胆系统第二大恶性肿瘤。由于其早期诊断繁琐且进展迅速，化疗已成为主要的治疗选择。原发性耐药是化疗药物疗效不佳的主要原因。因此，迫切需要探索新的药物来克服CCA的原发性耐药性。

方法

蛋白质印迹和 qRT-PCR 测定用于评估 CCA 组织和细胞中肌营养蛋白 (MTPN) 和 microRNA-885-5p (miR-885-5p) 的表达。使用 CCK-8 测定法分析用三氧化二砷 (ATO)、5-氟尿嘧啶 (5-Fu) 和顺铂 (CDDP) 处理的 CCA 细胞的活力。荧光素酶报告基因检测用于评估 miR-885-5p 和 MTPN 之间的相互作用。Kaplan-Meier 分析用于生存评估。

结果

我们发现ATO可以降低CCA细胞对5-Fu和CDDP的抵抗力，促进5-Fu和CDDP的杀伤作用。低剂量 ATO 通过上调 miR-885-5p 的表达而显示出抗药性作用。结合测序结果和数据库预测，我们发现MTPN可以作为miR-885-5p的直接靶点。MTPN 敲低后，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。

结论

我们的数据表明，ATO/miR-885-5p/MTPN 轴可以作为提高 CCA 细胞对化疗敏感性的靶点。