Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression

Abstract

Background Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. Methods The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. Results The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. Conclusions MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

A novel risk model based on cuproptosis-related lncRNAs predicted prognosis and indicated immune microenvironment landscape of patients with cutaneous melanoma

“…Interestingly, elevated lncRNAs in the low-risk group are generally considered oncogenic agents in other tumor types. MIR100HG promotes EMT, tumor invasion and metastasis of colorectal cancer cells (Liu et al, 2022). LINC00339, a highly expressed lncRNA in a Frontiers in Genetics frontiersin.org variety of malignant diseases, such as digestive system tumors, respiratory system tumors and nervous system tumors, is associated with the proliferation, motility and invasion of tumor cells (Wu Z. et al, 2022).…”

Role of m6A writers, erasers and readers in cancer

“…A large number of studies showed that hnRNPs were closely related to the occurrence and development of tumors. Recent studies showed that the interaction of the lncRNA MIR100HG with hnRNPA2B1 promoted m6A-dependent TCF7L2 mRNA stabilization and colorectal cancer progression [ 174 ]. HNRNPA2B1 recognizes the m6A site on ILF3 mRNA to stabilize ILF3 mRNA, leading to increased ILF3 expression and promoting the malignant progression of lymphoma [ 175 ].…”

Role of N6-Methyladenosine Methylation Regulators in the Drug Therapy of Digestive System Tumours

“…Furthermore, hnRNPA2B1 binds with MIR100HG and maintains the mRNA stability of TCF7L2. hnRNPA2B1 identifies the TCF7L2 mRNA m6A site via the MIR100HG hnRNPA2B1/TCF7L2 axis and enhances CRC resistance to cetuximab ( Liu et al, 2022b ). Therefore, targeted therapy combined with MIR100HG and immune checkpoint blockade could be a potential therapeutic strategy to improve the immunotherapy response of patients with CRC.…”