IGF2BP3 promotes the progression of colorectal cancer and mediates cetuximab resistance by stabilizing EGFR mRNA in an m6A-dependent manner

Abstract

Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an RNA-binding protein, is associated with tumorigenesis and progression. However, the exact molecular mechanisms of IGF2BP3 in colorectal cancer (CRC) oncogenesis, progression, and drug resistance remain unclear. This study found that IGF2BP3 was upregulated in CRC tissues. Clinically, the elevated IGF2BP3 level is predictive of a poor prognosis. Functionally, IGF2BP3 enhances CRC tumorigenesis and progression both in vitro and in vivo. Mechanistically, IGF2BP3 promotes epidermal growth factor receptor (EGFR) mRNA stability and translation and further activates the EGFR pathway by serving as a reader in an N6-methyladenosine (m6A)-dependent manner by cooperating with METTL14. Furthermore, IGF2BP3 increases the drug resistance of CRC cells to the EGFR-targeted antibody cetuximab. Taken together, our results demonstrated that IGF2BP3 was a functional and clinical oncogene of CRC. Targeting IGF2BP3 and m6A modification may therefore offer rational therapeutic targets for patients with CRC.

Comprehensive Transcriptomic Profiling of m6A Modification in Age-Related Hearing Loss

“…Previous studies have provided evidence that EGFR was required for the regenerative proliferation of auditory supporting cells in mammals and birds [50], and impaired glycolysis promotes alcohol exposure-induced apoptosis in HEI-OC1 cells by inhibiting EGFR signalling [51]. Interestingly, recent research has found that reader proteins IGF2BP3 or YTHDF2 also can directly bind to the m6A modification site of EGFR mRNA to change its stability [52,53]. However, the m6 A modification of EGFR mRNA in ARHL is still poorly understood and its role in ARHL is the next step in our research plan.…”

Inhibiting the m6A Reader IGF2BP3 Suppresses Ovarian Cancer Cell Growth via Regulating PLAGL2 mRNA Stabilization

“…World J Oncol. 2024;15 (1):100-113 ing to N6-methyladenosine-modified target mRNAs [1]. Meanwhile, IGF2BPs were shown to regulate the mRNA stability and modulate neural stem cell proliferation [6].…”

“…The RNA-binding protein, IGF2BP3, plays a role in the regulation of mRNA stability during carcinogenesis [ 1 ]. There is, however, little information about their paralogue-specific functions in tumor cells [ 5 ].…”

“…There is, however, little information about their paralogue-specific functions in tumor cells [ 5 ]. IGF2BP3 has recently been identified as a reader of m 6 A modification, exhibiting a preference for binding to N6-methyladenosine-modified target mRNAs [ 1 ]. Meanwhile, IGF2BPs were shown to regulate the mRNA stability and modulate neural stem cell proliferation [ 6 ].…”

“…N6-methyladenosine (m 6 A) is the predominant modification found in RNA and plays a crucial role in regulating diverse posttranscriptional processes, including mRNA stability, translocation, and protein translation efficiency. As a result, it exerts a significant influence on numerous biological processes, such as cell proliferation, tumorigenesis, and interactions between RNA and proteins [1]. These processes involve the participation of m 6 A methyltransferases ("writers"), demethylases ("erasers"), and RNA-binding proteins ("readers") in dynamic regulation of m 6 A modifications.…”