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.

Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

“…miR-124 is a well-recognized tumor suppressor and is epigenetically silenced in various types of cancer including CRC [16,32]. Additionally, it was reported that restoration of miR-124 repressed Frizzled (FZD) 5 to overcome P-gp-mediated multidrug resistance in renal cell carcinoma [33]. Moreover, miR-124 was found to be downregulated in gefitinib-resistant non-small cell lung cancer (NSCLC) cells, and overexpression of miR-124 sensitized gefitinib-resistant cells to gefitinib [34].…”

let-7d-3p is associated with apoptosis and response to neoadjuvant chemotherapy in ovarian cancer

“…Markedly, several studies have shown that miRNAs, such as miR-200c and others, can attenuate the effects of these drug-resistance components (21,22). In addition, miRNAs play a critical role in the drug-resistance of tumor cells and the clinical response to cytotoxic chemotherapy in cancer (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). The inhibition of ABC transporters by miRNAs has been reported in several studies.…”

Paeonol reverses promoting effect of the HOTAIR/miR‐124/Notch1 axis on renal interstitial fibrosis in a rat model

“…It has been elucidated that miR-124 has a decisive and regulatory role in the epithelial phenotype and epithelial to mesenchymal transition (EMT) of breast cancer cells (Liang et al, 2013). In addition, a study revealed that miR-124 was downregulated in RCC (Long, Du, Liu, Li, & He, 2015). Also, another study demonstrated that miR-124 overexpression alleviated renal injury of septic rats (Li, Zhang, Xu, Li, & Li, 2018).…”