lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling
| Autor: | Xiaodi Zhao, Christine H. Chung, Cunxi Li, James G. Patton, Mingli Yang, Robert J. Coffey, Daiming Fan, Bhuminder Singh, Zheng Cao, Timothy J. Yeatman, Qi Liu, Scott Hinger, Tian-Ying Wei, Jan-Henning Klusmann, Jeffrey L. Franklin, Yuanyuan Lu, Ethan Lee, Huaying Hu, Stephan Emmrich, Jing Wang, Kenyi Saito-Diaz, Ramona Graves-Deal |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Colorectal cancer Cetuximab Biology General Biochemistry Genetics and Molecular Biology Article Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Antineoplastic Agents Immunological Cell Line Tumor GATA6 Transcription Factor microRNA medicine Humans Epigenetics Transcription factor neoplasms beta Catenin GATA6 Wnt signaling pathway General Medicine medicine.disease digestive system diseases 3. Good health Wnt Proteins MicroRNAs 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Disease Progression RNA Long Noncoding Signal transduction Colorectal Neoplasms medicine.drug Signal Transduction |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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