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

Abstract

De novo and acquired resistance, largely attributed to genetic alterations, are barriers to effective anti-EGFR therapy. We generated cetuximab-resistant cells following prolonged cetuximab exposure to cetuximab-sensitive colorectal cancer cells in three-dimensional culture. Through whole exome sequencing and transcriptional profiling, we found overexpression of lncRNA MIR100HG and two embedded miRNAs, miR-100 and miR-125b, in the absence of known genetic events linked to cetuximab resistance. MIR100HG and miR-100/125b 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-100/125b coordinately represses five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. We describe a double-negative feedback loop between MIR100HG and GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These studies identify a clinically actionable, epigenetic cause of cetuximab resistance.

LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40‐MDM2‐p53 pathway through binding with UBA52

“…LUCAT1 has also been reported as a liver metastasis‐associated lncRNA through an analysis of CRC tissues from TCGA and Gene Expression Omnibus (GEO) databases; however, the underlying mechanisms are still unclear. Consistent with other studies, in which some lncRNAs including LUCAT1 are associated with chemotherapy resistance, our results revealed that LUCAT1 knockdown enhanced the apoptosis of CRC cells treated with oxaliplatin and 5‐FU.…”

New genetic variations discovered in KRAS wild‐type cetuximab resistant chinese colorectal cancer patients

“…Moreover, we also observed Wnt signaling as a significantly relevant pathway in cetuximab resistance patients, which is in agreement with other studies in which blockade of Wnt signaling, either upstream or downstream of the APC/β‐catenin degradation complex, restores cetuximab responsiveness to cetuximab‐resistant cells 54 . Guinney et al marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor β activation, stromal invasion and angiogenesis 55 …”

A stroma‐related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early‐stage colon cancer

“…MIR100HG is a kind of microRNA host gene, the intron of which encodes three kinds of microRNA, including miR‐100, miR‐125b‐1 and let‐7a‐2. There has only been one study showing that MIR100HG could form a double‐negative feedback loop with GATA6 and activate the Wnt/β‐catenin pathway, causing cetuximab resistance in colon cancer cells . As for MIR31HG, Eide et al found that MIR31HG was an independent prognostic factor for patients with colon cancer .…”