title: MALAT1 Is Associated with Poor Response to Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients and Promotes Chemoresistance through EZH2.
abstract: A major reason for oxaliplatin chemoresistance in colorectal cancer is the acquisition of epithelial-mesenchymal transition (EMT) in cancer cells. The long noncoding RNA (lncRNA), MALAT1, is a highly conserved nuclear ncRNA and a key regulator of metastasis development in several cancers. However, its role in oxaliplatin-induced metastasis and chemoresistance is not well known. In this study, we aim to investigate the prognostic and therapeutic role of lncRNA MALAT1 in colorectal cancer patients receiving oxaliplatin-based therapy and further explore the potential transcriptional regulation through interaction with EZH2 based on the established HT29 oxaliplatin-resistant cells. Our results showed that high MALAT1 expression was associated with reduced patient survival and poor response to oxaliplatin-based chemotherapy in advanced colorectal cancer patients. Oxaliplatin-resistant colorectal cancer cells exhibited high MALAT1 expression and EMT. LncRNA MALAT1 knockdown enhances E-cadherin expression and inhibits oxaliplatin-induced EMT in colorectal cancer cells. EZH2 is highly expressed and associated with the 3' end region of lncRNA MALAT1 in colorectal cancer, and this association suppressed the expression of E-cadherin. Furthermore, targeted inhibition of MALAT1 or EZH2 reversed EMT and chemoresistance induced by oxaliplatin. Finally, the interaction between lncRNA MALAT1 and miR-218 was observed, which further indicated its prognostic value in patients who received standard FOLFOX (oxaliplatin combine with 5-fluorouracil and leucovorin) treatment. In conclusion, this study illuminates the prognostic role of lncRNA MALAT1 in colorectal cancer patients receiving oxaliplatin-based treatment and further demonstrates how lncRNA MALAT1 confers a chemoresistant function in colorectal cancer. Thus, lncRNA MALAT1 may serve as a promising prognostic and therapeutic target for colorectal cancer patients.Mol Cancer Ther; 16(4); 739-51. ©2017 AACR.
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Peilong
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, Women & Children's Hospital of Linyi, Linyi, Shandong Province, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Lutao
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong Province, China. cxwang@sdu.edu.cn.
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D000077150:Oxaliplatin; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D020413:3' Untranslated Regions; C557041:MALAT1 long non-coding RNA, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D062085:RNA, Long Noncoding; D000077150:Oxaliplatin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein