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.
Highlights
Colorectal cancer is a leading cause of cancer-related deaths in the world
We investigated the association of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression with clinical parameters, including age, gender, differentiation, pathologic tumor classification, pathologic lymph node status, pathologic metastatic status, and stage
The expression of MALAT1 was significantly higher in pathologic tumor classification (pT), pathologic lymph node status (pN) (þ), pathologic metastatic status (pM) (þ), and high stage (3þ4) patients compared with lower stage (1þ2) patients (Supplementary Table S2), which indicated that MALAT1 may play its oncogenic role primarily in colorectal cancer with advancing progression, but not in the initial phase
Summary
Colorectal cancer is a leading cause of cancer-related deaths in the world. It is the second- and third-most commonly diagnosed cancer in females and males, respectively, and more than 1.2 million patients are diagnosed with colorectal cancer every year [1, 2]. Oxaliplatin-based chemotherapy after surgical resection is one of the most frequently used therapeutic strategies [3]. Its use in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) has led to response rates >50% and median survival approaching 2 years for metastatic colorectal cancer [4]. A large proportion of patients receiving chemotherapy. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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