Format

Send to

Choose Destination
Nat Med. 2017 Nov;23(11):1331-1341. doi: 10.1038/nm.4424. Epub 2017 Oct 16.

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

Author information

1
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
2
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
3
Department of Biomedical Informatics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4
Jiaen Genetics Laboratory, Beijing Jiaen Hospital, Beijing, China, and Molecular Pathology, Cancer Research Center, Medical College of Xiamen University, Xiamen, China.
5
Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina, USA.
6
Department of Cell and Developmental Biology and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
7
Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
8
Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
9
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
10
Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA.

Abstract

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.

PMID:
29035371
PMCID:
PMC5961502
DOI:
10.1038/nm.4424
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center