MALAT1 is associated with poor response to oxaliplatin-based chemotherapy in colorectal cancer patients and promotes chemoresistance through EZH2
Menée à l'aide de lignées cellulaires de cancer colorectal, de 228 échantillons sériques et de 94 échantillons tissulaires prélevés sur des patients atteints d'un cancer colorectal et ayant reçu une chimiothérapie par oxaliplatine ou une chimiothérapie de type FOLFOX entre 2008 et 2014, cette étude montre que l'expression de MALAT1, un long ARN non codant, est associée à une faible réponse thérapeutique à l'oxaliplatine et favorise la chimiorésistance des cellules tumorales via un mécanisme impliquant l'enzyme EZH2
A major reason for oxaliplatin chemoresistance in colorectal cancer (CRC) is the acquisition of epithelial-mesenchymal transition (EMT) in cancer cells. The long non-coding RNA, 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 chemo-resistance is not well known. In this study, we aim to investigate the prognostic and therapeutic role of MALAT1 in CRC 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 CRC patients. Oxaliplatin-resistant CRC cells exhibited high MALAT1 expression and epithelial-mesenchymal transition (EMT). LncRNA MALAT1 knockdown enhances E-cadherin expression and inhibits oxaliplatin-induced EMT in CRC cells. EZH2 is highly expressed and associated with the 3' end region of lncRNA MALAT1 in CRC, and this association suppressed the expression of E-cadhrin. 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 (5-FU) and leucovorin) treatment. In conclusion, this study illuminates the prognostic role of lncRNA MALAT1 in CRC patients receiving oxaliplatin-based treatment and further demonstrates how lncRNA MALAT1 confers a chemoresistant function in CRC. Thus, lncRNA MALAT1 may serve as a promising prognostic and therapeutic target for CRC patients.
Molecular Cancer Therapeutics , résumé, 2016