Novel crosstalk between KLF4 and ZEB1 regulates gemcitabine resistance in pancreatic ductal adenocarcinoma
作者
Wang, ZY;Chen, Y;Lin, YL;Wang, XX;Cui, XP;Zhang, ZH;Xian, GZ;Qin, CK
作者单位
[Wang, Zhiyi; Wang, Xinxing; Cui, Xianping; Zhang, Zhenhai; Xian, Guozhe; Qin, Chengkun] Shandong Univ, Shandong Prov Hosp, Dept Hepatobiliary Surg, Jinan 250021, Shandong, Peoples R China.;-;[Chen, Yuan] Shandong Univ, Shandong Prov Hosp, Dept Paediat, Jinan 250021, Shandong, Peoples R China.;-;[Lin, Yanliang] Shandong Univ, Shandong Prov Hosp, Ctr Lab, Jinan 250021, Shandong, Peoples R China.
摘要
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with broad resistance to chemotherapeutic drugs. Kruppel-like factor 4 (KLF4) is a candidate tumor suppressor in PDAC. However, the precise role of KLF4 in gemcitabine resistance of PDAC remains largely unclear. In this study, we demonstrated that gemcitabine inhibited KLF4 expression. Moreover, gemcitabine also reduced the levels of miR-200b and miR-183, but promoted ZEB1 expression in PDAC cells. KLF4 knockdown blocked the expression of miR-200b and miR-183, and inversely, KLF4 overexpression promoted the expression of miR-200b and miR-183, suggesting that KLF4 positively regulated the expression of miR-200b and miR-183. Moreover, KLF4 knockdown enhanced ZEB1 expression and gemcitabine resistance while KLF4 overexpression induced the opposite effect. ChIP assays verified that KLF4 positively regulated the expression of miR-200b and miR-183 by directly binding to their promoters. Then, miR-200b and miR-183 directly inhibited ZEB1 expression by targeting its 3'UTR region. ZEB1 knockdown attenuated gemcitabine resistance in PDAC cells. KLF4 overexpression promoted gemcitabine sensitivity of PDAC in vivo by negatively regulating ZEB1 expression. Our results revealed that novel crosstalk between KLF4 and ZEB1 regulated gemcitabine resistance in PDAC.
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; SIGNALING PATHWAY; CANCER-CELLS; LUNG ADENOCARCINOMA; TUMOR-SUPPRESSOR; DOWN-REGULATION; UP-REGULATION; METASTASIS; PROGRESSION; INHIBITION
基本信息
