title: H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/β-catenin pathway.
abstract: Colorectal cancer (CRC) is a common malignancy, most of which remain unresponsive to chemotherapy. As one of the earliest cytotoxic drugs, methotrexate (MTX) serves as an anti-metabolite and anti-folate chemotherapy for various cancers. Unfortunately, MTX resistance prevents its clinical application in cancer therapy. Thereby, overcoming the drug resistance is an alternative strategy to maximize the therapeutic efficacy of MTX in clinics. Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years. More and more emerging evidences have demonstrated that they play important regulatory roles in various biological activities and disease progression including drug resistance. In the present study, a MTX-resistant colorectal cell line HT-29 (HT-29-R) was developed, which displayed the active proliferation and shortened cell cycle. LncRNA H19 was found to be significantly upregulated in this resistant cell line. Further investigation showed that H19 knockdown sensitized the MTX resistance in HT-29-R cells while its overexpression improved the MTX resistance in the parental cells, suggesting that H19 mediate MTX resistance. The Wnt/β-catenin signaling was activated in HT-29-R cells, and H19 knockdown suppressed this signaling in the parental cells. In conclusion, H19 mediated MTX resistance via activating Wnt/β-catenin signaling, which help to develop H19 as a promising therapeutic target for MTX resistant CRC.
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, PR China.
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Wu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Liang
authors.affiliation: Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Feng
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Pang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Mary Miu-Yee
authors.initials: MM
authors.lastname: Waye
authors.affiliation: Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.
authors.forename: Jin-Fang
authors.initials: JF
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Electronic address: fuweiming76@smu.edu.cn.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Fu
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019073:HT29 Cells; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D062085:RNA, Long Noncoding / Q000235:genetics*; D060449:Wnt Signaling Pathway
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D008727:Methotrexate
keywords: Colorectal cancer; H19; Methotrexate; Wnt/β-catenin signaling