An integrated bioinformatics analysis repurposes an antihelminthic drug niclosamide for treating hmga2-overexpressing human colorectal cancer

Stephen Wan Leung, Chia Jung Chou, Tsui Chin Huang, Pei Ming Yang

研究成果: 雜誌貢獻文章同行評審

9 引文 斯高帕斯(Scopus)

摘要

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pancancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cellcycle- related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.
原文英語
文章編號1482
期刊Cancers
11
發行號10
DOIs
出版狀態已發佈 - 十月 2019

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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