title: 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' 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.
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sui
authors.affiliation: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Cai
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Pan
authors.affiliation: Oncology Department I, Traditional Chinese Medical Hospital, Xinjiang Medical University, Xinjiang, China.
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Deng
authors.affiliation: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York.
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.affiliation: Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: San-Jun
authors.initials: SJ
authors.lastname: Cai
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Hui-Rong
authors.initials: HR
authors.lastname: Zhu
authors.affiliation: Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Lzwf@hotmail.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D048056:Mitogen-Activated Protein Kinase 9 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D048056:Mitogen-Activated Protein Kinase 9; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9