lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling.
Yuanyuan LuXiao-Di ZhaoQi LiuCunxi LiRamona Graves-DealZheng CaoBhuminder SinghJeffrey L FranklinJing WangHuaying HuTianying WeiMingli YangTimothy J YeatmanEthan LeeKenyi Saito-DiazScott HingerJames G PattonChristine H ChungStephan EmmrichJan-Henning KlusmannDaiming FanD Borden LacyPublished in: Nature medicine (2017)
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.
Keyphrases
- long non coding rna
- cell proliferation
- transcription factor
- poor prognosis
- long noncoding rna
- metastatic colorectal cancer
- epidermal growth factor receptor
- locally advanced
- wild type
- squamous cell
- induced apoptosis
- small cell lung cancer
- stem cells
- gene expression
- squamous cell carcinoma
- genome wide
- tyrosine kinase
- dna methylation
- radiation therapy
- mesenchymal stem cells
- signaling pathway
- lymph node metastasis
- oxidative stress
- rectal cancer
- dna binding
- pi k akt
- heat shock
- aqueous solution
- cancer therapy