Journal Article

lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling

Fan, Daiming, Yeatman, Timothy J, Saito-Diaz, Kenyi, Zhao, Xiaodi, Klusmann, Jan-Henning, Singh, Bhuminder, Franklin, Jeffrey L, Wang, Jing, Liu, Qi, Wei, Tianying, Cao, Zheng, Lu, Yuanyuan, Coffey, Robert J, Lee, Ethan, Graves-Deal, Ramona, Emmrich, Stephan, Chung, Christine H, Yang, Mingli, Patton, James G, Li, Cunxi, Hu, Huaying, Hinger, Scott

2017

Overview

Concomitant overexpression of microRNAs miR-100 and miR-125b-1 within the host long non-coding RNA MIR100HG induces cetuximab resistance in cancer in the absence of previously associated genetic alterations. miR-100 and miR-125b target negative regulators of Wnt/β-catenin signaling and sustain drug resistance through feedback inhibition of GATA6 expression and this resistance can be overcome by pharmacological inhibition of Wnt activity. These findings, together with those by Tan et al . in the previous issue, highlight the emerging functional role of non-coding RNAs in modulating the response to anti-cancer therapies. De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.

• Publisher: Nature Publishing Group US
• Subject: 38/109 / 38/15 / 38/23 / 38/32 / 38/35 / 38/39 / 38/77 / 38/90 / 38/91 / 631/337/384/2568 / 631/67/1059/602 / 631/67/1504/1885/1393 / 631/80/86 / Antineoplastic Agents, Immunological - pharmacology / beta Catenin - metabolism / Biomedicine / Cancer Research / Cell Line, Tumor / Cetuximab - pharmacology / Disease Progression / Drug Resistance, Neoplasm - genetics / Epigenesis, Genetic / GATA6 Transcription Factor - metabolism / Humans / Infectious Diseases / Metabolic Diseases / MicroRNAs - genetics / Molecular Medicine / Neurosciences / RNA, Long Noncoding - genetics / Signal Transduction / Wnt Proteins - metabolism