HNF1A inhibition induces the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1
HNF1A inhibition induces the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1
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HNF1A抑制通过靶向ABCB1诱导胰腺癌细胞对吉西他滨产生耐药性
DOI：
10.1016/j.ebiom.2019.05.013
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发表时间：
2019-06-01
期刊：
影响因子：
11.1
通讯作者：
Wang, Zhi
中科院分区：
文献类型：
--
作者：
Lu, Yanan;Xu, Dongni;Wang, Zhi
背景：胰腺导管腺癌（PDAC）是一种预后不良的侵袭性疾病，基于吉西他滨的化疗仍然是大多数 PDAC 患者的有效选择。肝细胞核因子1α（HNF1A）是PDAC中的抑癌因子，但其在PDAC吉西他滨化疗耐药中的作用尚未阐明。方法：通过体外和体外过表达和敲低HNF1A检测HNF1A在吉西他滨中的功能。通过荧光素酶测定、缺失/突变报告基因构建测定和 CHIP 测定进一步证明了 HNF1A 和 ABCB1 之间的调控网络。研究结果：在这里，我们发现 HNF1A 表达与 PDAC 细胞系中的吉西他滨敏感性显着相关。此外，我们发现HNF1A过表达增强了PDAC的体外和体外吉西他滨敏感性，而HNF1A的抑制则具有相反的效果。此外，通过抑制和过表达 HNF1A，我们发现 HNF1A 调节 PDAC 细胞中 MDR 基因（ABCB1 和 ABCC1）的表达。从机制上讲，我们证明 HNF1A 通过与其特定启动子区域结合并抑制其转录水平来调节 ABCB1 的表达。最后，生存分析揭示了 HNF1A 在吉西他滨敏感胰腺癌患者分层中的临床价值。 解释：我们的研究为寻找使用常规细胞毒药物恢复 HNF1A 蛋白功能的新型治疗组合、通过 HNF1A 染色进行个体化治疗以及改善 PDAC 患者预后铺平了道路。 (C) 2019 年由 Elsevier B.V. 出版
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis, and gemcitabine-based chemotherapy remains an effective option for the majority of PDAC patients. Hepatocyte nuclear factor 1 alpha (HNF1A) is a tumor-suppressor in PDAC, but its role in gemcitabine chemoresistance of PDAC has not been clarified.Methods: The function of HNF1A in gemcitabine was detected by overexpression and knockdown of HNF1A in vitro and in vitro. The regulatory network between HNF1A and ABCB1 was further demonstrated by luciferase assays, deletion/mutation reporter construct assays and CHIP assays.Findings: Here, we found that HNF1A expression is significantly associated with gemcitabine sensitivity in PDAC cell lines. Moreover, we identified that HNFlA overexpression enhanced gemcitabine sensitivity of PDAC both in vitro and in vitro, while inhibition of HNF1A had the opposite effect. Furthermore, by inhibiting and overexpressing HNF1A, we revealed that HNF1A regulates the expression of MDR genes (ABCB1 and ABCC1) in PDAC cells. Mechanistically, we demonstrated that HNF1A regulates ABCB1 expression through binding to its specific promoter region and suppressing its transcription levels. Finally, the survival analyses revealed the clinical value of HNF1A in stratification of gemcitabine sensitive pancreatic cancer patients.Interpretation: Our study paved the road for finding novel treatment combinations using conventional cytotoxic agents with functional restoration of the HNF1A protein, individualized treatment through HNF1A staining and improvement of the prognosis of PDAC patients. (C) 2019 Published by Elsevier B.V.