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中期因子对胆管癌中吉西他滨耐药的影响。

Effect of midkine on gemcitabine resistance in biliary tract cancer.

机构信息

Department of Medicine, Huzhou University, Huzhou, Zhejiang 313000, P.R. China.

Department of Pharmacy, The First Affiliated Hospital of Huzhou University, The First People's Hospital of Huzhou, Huzhou, Zhejiang 313000, P.R. China.

出版信息

Int J Mol Med. 2018 Apr;41(4):2003-2011. doi: 10.3892/ijmm.2018.3399. Epub 2018 Jan 18.

DOI:10.3892/ijmm.2018.3399
PMID:29344648
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5810218/
Abstract

Gemcitabine‑based chemotherapy is one of the most effective and commonly used chemotherapeutic regimens for biliary tract cancer (BTC). However, development of resistance to this drug limits its efficacy. The present study aimed to explore the effects of midkine (MDK) on the resistance of BTC cells to gemcitabine. Cell viability and proliferation were measured by a Cell Counting Kit‑8 assay and 5‑ethynyl‑2'‑deoxyuridine staining, respectively. Western blot analysis was used to detect the expression of E‑cadherin and vimentin. The results indicated that BTC cell lines were more resistant to gemcitabine plus MDK compared with gemcitabine alone. In terms of the underlying mechanism, MDK promoted the epithelial to mesenchymal transition (EMT) of BTC cells and the enhancing effect of MDK on gemcitabine resistance was abrogated when the EMT was blocked with small interfering (si)RNA targeting Twist. In addition, MDK promoted the expression of Notch‑1, while knockdown of Notch‑1 by siRNA blocked the EMT process in the BTC cell lines. Taken together, these results indicated that MDK promoted gemcitabine resistance of BTC through inducing EMT via upregulating Notch‑1. It was suggested that inhibition of the EMT is a promising strategy to overcome MDK‑induced drug resistance.

摘要

基于吉西他滨的化疗是胆管癌 (BTC) 最有效和最常用的化疗方案之一。然而，对这种药物的耐药性的发展限制了它的疗效。本研究旨在探讨中期因子 (MDK) 对 BTC 细胞对吉西他滨耐药性的影响。通过细胞计数试剂盒-8 检测和 5-乙炔基-2'-脱氧尿苷染色分别测量细胞活力和增殖。Western blot 分析用于检测 E-钙粘蛋白和波形蛋白的表达。结果表明，与单独使用吉西他滨相比，BTC 细胞系对吉西他滨加 MDK 的耐药性更高。就潜在机制而言，MDK 促进了 BTC 细胞的上皮间质转化 (EMT)，并且当用针对 Twist 的小干扰 (si)RNA 阻断 EMT 时，MDK 增强吉西他滨耐药性的作用被消除。此外，MDK 促进了 Notch-1 的表达，而 Notch-1 的 siRNA 敲低阻断了 BTC 细胞系中的 EMT 过程。总之，这些结果表明，MDK 通过上调 Notch-1 诱导 EMT 促进了 BTC 对吉西他滨的耐药性。抑制 EMT 是克服 MDK 诱导的耐药性的一种有前途的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/743ffeede691/IJMM-41-04-2003-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/13edb2095b6d/IJMM-41-04-2003-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/05b9c1bc7170/IJMM-41-04-2003-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/e01b8833a3e5/IJMM-41-04-2003-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/b891f1cfc00d/IJMM-41-04-2003-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/1c58d469f6f2/IJMM-41-04-2003-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/743ffeede691/IJMM-41-04-2003-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/13edb2095b6d/IJMM-41-04-2003-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/05b9c1bc7170/IJMM-41-04-2003-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/e01b8833a3e5/IJMM-41-04-2003-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/b891f1cfc00d/IJMM-41-04-2003-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/1c58d469f6f2/IJMM-41-04-2003-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d9/5810218/743ffeede691/IJMM-41-04-2003-g05.jpg

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