Abstract 2235: miR-200c reduces P-gp mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colon cancer

Abstract MicroRNA-200c (miR-200c) 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 miR-200c in recurred and metastatic colorectal cancers (CRC) were significantly lower, while the JNK2 expression was higher compared to primary tumors. We showed that in MDR CRC cells, miR-200c targeted the 3′UTR of JNK2 gene. Over-expression of miR-200c attenuated the levels of p-JNK, p-c-Jun, P-gp and MMP-2/-9, the downstream factors of 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 CRC mouse model, we demonstrated that over-expression of miR-200c effectively inhibited the tumor growth and metastasis. At last, in the tumor samples from locally advanced CRC patients with routine post-surgical chemotherapy, we observed an inverse correlation between the levels of mRNA expression of miR-200c and JNK2, ABCB1, MMP-9 thus predicting patient therapeutic outcomes. In summary, we found that miR-200c negatively regulated the expression of JNK2 gene and increased the sensitivity of MDR CRC cells to chemotherapeutic drugs, via inhibiting the JNK2/p-JNK/p-c-Jun/ABCB1 signaling. Restoration of miR-200c expression in MDR CRC may serve as a promising therapeutic approach in MDR induced metastasis. Citation Format: Qi Li. miR-200c reduces P-gp mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2235. doi:10.1158/1538-7445.AM2015-2235