title: miR-124 represses FZD5 to attenuate P-glycoprotein-mediated chemo-resistance in renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) is one of most malignant neoplasms, exhibiting poor responsiveness to the conventional chemo-regime. Abnormal expression of P-glycoprotein (P-gp) has been implicated in the emergence of multiple-drug resistance (MDR) by reducing the accumulation of intracellular chemotherapy drugs. Wnt signaling plays critical roles in renal cancer and is triggered by binding of Wnt ligands to Frizzled (FZD) receptor proteins. miR-124 is a tumor suppressor associated with cancer relapse and MDR, whereas its role in P-gp-mediated MDR in refractory RCC is as yet unrevealed. Our study aimed to investigate the roles of miR-124 in chemo-resistant RCC cells and the potential targeted signaling paths in inducing P-gp expression. Doxorubicin (DOX)- and vinblastine (VBL)-resistant Caki-2 cells were developed by exposure of parental Caki-2 cells to the agents over a long period of time. In comparison with their parental cells, miR-124 was downregulated in Caki-2/DOX and Caki-2/VBL cells, accompanied by increased FZD5 and P-gp. IC50 values were reduced significantly after miR-124 mimics were introduced into Caki-2/DOX cells. In addition, miR-124 mimics significantly promoted apoptosis of Caki-2/DOX cells. miR-124 targeted to FZD5 and miR-124 mimics as well as FZD5 siRNA showed significant inhibitory effects on P-gp expression in Caki-2/DOX cells. Furthermore, Wnt-5a dose-dependently stimulated the presentation of p-PKCα/βII and p-CamKII via activating FZD5, which was reversed by FZD5 silencing. Moreover, FZD5/protein kinase C (PKC) signaling is responsible for the elevation of P-gp and cancer cell survival. In conclusion, restoring miR-124 may function as a promising strategy to overcome P-gp-mediated MDR by inhibiting FZD5/PKC signaling.
authors: Department of Urology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
authors: Qing-Zhi
authors: QZ
authors: Long
authors: Department of Urology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
authors: Yue-Feng
authors: YF
authors: Du
authors: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors: Xiao-Gang
authors: XG
authors: Liu
authors: Department of Urology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
authors: Xiang
authors: X
authors: Li
authors: Department of Urology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China. dalinhe126@163.com.
authors: Da-Lin
authors: DL
authors: He
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D051157:Frizzled Receptors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009364:Neoplasm Recurrence, Local; D011493:Protein Kinase C / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D014747:Vinblastine / Q000008:administration & dosage; D051153:Wnt Proteins / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000071818:Wnt-5a Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C498589:FZD5 protein, human; D051157:Frizzled Receptors; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D014747:Vinblastine; D004317:Doxorubicin; D011493:Protein Kinase C
keywords: Chemo-resistance; FZD5; P-gp; PKC; Renal cell carcinoma; miR-124