miR200c Attenuates P-gp–Mediated MDR and Metastasis by Targeting JNK2/c-Jun Signaling Pathway in Colorectal Cancer

Abstract

MicroRNA-200c (miR200c) recently emerged as an important regulator of tumorigenicity and cancer metastasis; however, its role in regulating multidrug resistance (MDR) remains unknown. In the current study, we found that the expression levels of miR200c in recurrent and metastatic colorectal cancers were significantly lower, whereas the JNK2 expression was higher compared with primary tumors. We showed that in MDR colorectal cancer cells, miR200c targeted the 3 0 untranslated region of the JNK2 gene. Overexpression of miR200c attenuated the levels of p-JNK, p-c-Jun, P-gp, and MMP-2/-9, the downstream factors of the JNK signaling pathway, resulting in increased sensitivity to chemotherapeutic drugs, which was accompanied by heightened apoptosis and decreased cell invasion and migration. Moreover, in an orthotopic MDR colorectal cancer mouse model, we demonstrated that overexpression of miR200c effectively inhibited the tumor growth and metastasis. At last, in the tumor samples from patients with locally advanced colorectal cancer with routine postsurgical chemotherapy, we observed an inverse correlation between the levels of mRNA expression of miR200c and JNK2, ABCB1, and MMP-9, thus predicting patient therapeutic outcomes. In summary, we found that miR200c negatively regulated the expression of JNK2 gene and increased the sensitivity of MDR colorectal cancer cells to chemotherapeutic drugs, via inhibiting the JNK2/p-JNK/p-c-Jun/ ABCB1 signaling. Restoration of miR200c expression in MDR colorectal cancer may serve as a promising therapeutic approach in MDR-induced metastasis.

The role of the miR‐200 family in epithelial–mesenchymal transition in colorectal cancer: a systematic review

“…As previously mentioned, methylation of the miR-200 promoter regions results in the repression of epithelial markers. 39 The results of these studies support the hypothesis that reverting to an epithelial phenotype facilitates chemotherapy response and that the miR-200 family may have a therapeutic role in the management of advanced stage CRC. 35,36 However, as previously mentioned, the demethylating agents used are not specific to the promoter regions of the miR-200 family, and other genes may be activated with demethylation and contribute to the phenotypic changes.…”

MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1

“…Several mechanisms have been found correlated with intrinsic and acquired resistance, but each of them only partially accounts for the development of resistance in cancer patients. Several emerging evidences suggest that miRNAs by targeting chemosensitivity-related genes can regulate chemosensitivity through modulation of different mechanisms as regulation of drug efflux transporters [21,22], DNA repair pathways [23], and modulation of apoptosis-related genes [24,25].…”

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

“…In recurrent and metastatic colorectal cancer, miR-200c expression is suppressed, and its overexpression attenuates the JNK signaling pathway resulting in an increased sensitivity of resistant cells to several chemotherapeutic agents and a subsequent decrease in their metastatic potential in both in vitro and in vivo models. Furthermore, miR-200c level is inversely correlated with JNK2, ABCB1, and MMP-9, which are the downstream targets of the JNK pathway, and this negative correlation may be used as a predictive marker of therapeutic outcome in these patients [59]. In two different breast cancer cell lines, resistance against doxorubicin is correlated with marked inhibition of miR-200c where TrkB has been suggested as the key target of miR-200c in regulating this resistance [60].…”