MALAT1 Is Associated with Poor Response to Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients and Promotes Chemoresistance through EZH2

• Published in: Molecular cancer therapeutics Vol. 16; no. 4; pp. 739 - 751
• Main Authors: Li, Peilong, Zhang, Xin, Wang, Haiyan, Wang, Lili, Liu, Tong, Du, Lutao, Yang, Yongmei, Wang, Chuanxin
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.04.2017
• Subjects: 3' Untranslated Regions; 5-Fluorouracil; Cancer; Cancer therapies; Cell Line, Tumor; Chemoresistance; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Drug Resistance, Neoplasm; E-cadherin; Enhancer of Zeste Homolog 2 Protein - genetics; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Gene regulation; HT29 Cells; Humans; Mesenchyme; Metastases; Metastasis; MicroRNAs - genetics; Non-coding RNA; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - pharmacology; Oxaliplatin; Patients; Prognosis; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Survival Analysis; Transcription
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0591

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.