Aug 2026· International Journal of Molecular Sciences· Vol 27· 0 citations· 162 references
Medicine
TL;DR
This review describes the structural organization of IGF2BP3, the molecular basis of RNA recognition, and the mechanisms underlying its dysregulation across human cancers and discusses emerging therapeutic approaches, including direct inhibition of IGF2BP3–RNA interactions and indirect strategies that rewire IGF2BP3 expression or activity through epigenetic, epitranscriptomic, and signaling pathways.
Abstract
RNA-binding proteins (RBPs) remain underexplored as small-molecule targets, although their dysregulation contributes to numerous human diseases, including cancer. RBPs are key regulators of post-transcriptional gene expression, controlling multiple stages of RNA metabolism. Among them, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is an oncofetal RBP that is highly expressed during embryonic development, largely absent in adult tissues, and re-expressed in multiple malignancies. A growing body of evidence supports IGF2BP3 as a diagnostic and prognostic biomarker and a potent oncogenic driver across tumor types, underscoring its potential as a therapeutic target. However, the development of effective IGF2BP3-targeting compounds remains in its early stages. In this review, we first describe the structural organization of IGF2BP3, the molecular basis of RNA recognition, and the mechanisms underlying its dysregulation across human cancers. We then discuss emerging therapeutic approaches, including direct inhibition of IGF2BP3–RNA interactions and indirect strategies that rewire IGF2BP3 expression or activity through epigenetic, epitranscriptomic, and signaling pathways. By critically highlighting the opportunities and limitations of these approaches and their impact on cancer progression, we provide an integrated perspective combining structural biology, medicinal chemistry, and cancer biology to support the development of next-generation IGF2BP3-targeted therapies.
Beyond enabling the discovery of several new potent and selective small molecules, these studies have allowed us to elucidate key parameters for potency, selectivity, and metabolic stability that should aid future efforts in RBP drug discovery.
G. M. Scherer, Jacob P. Sorrentino, A. K. Jaiswal et al.· Journal of Medicinal Chemist...· 0 citations
This comprehensive literature review delves into the multifaceted roles of RNA-binding motif protein 3 in cellular processes, disease pathogenesis, and therapeutic potential and underscores the pivotal role of RBPs, particularly RBM3, in disease progression and highlights the need for continued investigation to harness their therapeutic potential effectively.
M. A. Larbi, R. Getzenberg, Dmitriy Minond· Current Issues in Molecular...· 0 citations
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing but clinical outcomes remain poor and new treatments are required. IGF2BP3 is an oncofetal m6A-reading RNA regulatory protein whose expression is commonly observed in PDAC and which may represent an important therapeutic target. IGF2BP3 protein is expressed in >95% of primary tumours whilst RNA expression ranges from 3 to 3000-fold above normal epithelium. siRNA knockdown reveals IGF2BP3 to strongly support expression of gene programs related to DNA replication, cell cycle and apoptosis, TNF signalling and epithelial-mesenchymal transition. Direct sequencing of native RNA further reveals IGF2BP3-mediated enhancement of 863 RNA isoforms with suppression of 389 isoforms. m6A, m5C and pseudouridine (ψ) RNA modifications were seen in 97% of transcripts within the PDAC transcriptome and enriched within MYC gene targets. IGF2BP3 regulated the pattern of RNA modification with a substantial impact on m5C modifications of miRNA and scRNA, and genes associated with regulation of TNF signalling. Knockdown of IGF2BP3 expression in primary tumour organoid cultures suppressed proliferation and elicited apoptosis, indicating a critical requirement for IGF2BP3 within malignant stem cells. These data show that IGF2BP3 is expressed consistently in PDAC, plays a dominant role in regulation of RNA splicing and modification, and supports cancer stem cell proliferation and survival. IGF2BP3 therefore occupies a critical position within the RNA regulon of PDAC and represents an important therapeutic target in this tumour of unmet need.
Sandra Margielewska-Davies, W. Croft, Hayden Pearce et al.· Oncogene· 0 citations
Esophageal squamous cell carcinoma (ESCC) has a consistently high incidence and poor prognosis. The RNA-binding protein insulin-like growth factor 2-binding protein 3 (IGF2BP3) has been implicated in the progression of various malignant tumors. However, the contribution of IGF2BP3 in ESCC and its underlying molecular mechanisms remain elusive. Here, we found that IGF2BP3 was upregulated in ESCC tissues, and elevated IGF2BP3 expression correlates with reduced overall survival. Through gain- and loss-of-function assays, IGF2BP3 significantly enhanced ESCC cell proliferation and migration in vitro and accelerated tumor growth and metastasis in vivo. Mechanistically, IGF2BP3 directly binds to multiple ribosomal protein L (RPL) mRNAs (e.g., RPL12, RPL8, RPL17) and enhances their stability, thereby promoting ribosomal assembly and improving global translation efficiency. This leads to substantial upregulation of oncoproteins such as c-Myc and β-catenin. Collectively, our findings reveal an oncogenic role of IGF2BP3 in ESCC progression and highlight it as a promising molecular target for further therapeutic exploration in ESCC.
Gu-Ha A-Lai, Shuangyan Tan, Wenrong Liu et al.· Biochimica et Biophysica Act...· 0 citations
Simple Summary PIK3CA is one of the most frequently altered cancer-related genes and has become an important focus of precision oncology. However, the biological and clinical implications of PIK3CA alterations vary considerably across tumor types, and translating this knowledge into effective treatments remains challenging. This review provides a comprehensive, updated, and comparative overview of PIK3CA biology, its molecular alterations across human cancers, their prognostic and therapeutic relevance, and the current development of treatments targeting the pathway activated by PIK3CA. We critically examine both established evidence and remaining limitations, including treatment toxicity and resistance, and discuss emerging therapeutic and molecular approaches. By bringing these different aspects together, we aim to provide oncologists and researchers with a practical framework for understanding the current state of the field, interpreting available evidence, identifying unresolved questions, and designing future clinical and translational studies.
A. Ottaiano, Carmine Picone, M. Santorsola et al.· Cancers· 0 citations
Human epidermal growth factor receptor 2 (
HER2
, also known as
ERBB2
) is aberrantly expressed in multiple malignancies and serves as both a key molecular tumor classification marker and an important therapeutic target. Although monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates targeting HER2 have significantly improved patient outcomes, challenges such as treatment resistance and disease relapse remain. To address these unmet clinical needs, circular RNAs (circRNAs) have emerged as key regulators of tumorigenesis, therapeutic resistance, and immune modulation because of their structural stability, tissue specificity, and multifaceted regulatory capabilities. Accumulating evidence indicates that circRNAs derived from the HER2 gene, particularly circular RNA ERBB2 (circERBB2), participate in cancer progression through multiple mechanisms, including microRNA sponging, functional peptide translation (e.g., HER2-103), and rDNA transcriptional regulation. Moreover, circRNAs have been shown to modulate HER2 heterodimerization and downstream signaling activation, thereby promoting tumorigenesis and drug resistance. Beyond their mechanistic roles, circRNAs hold translational potential as diagnostic biomarkers, prognostic indicators, and therapeutic targets, with applications ranging from liquid biopsy-based assays to circRNA-targeted therapies and vaccines. This review summarizes the current advances in circRNA-mediated regulation of HER2 and its heterodimers, focusing on circERBB2, and highlights emerging insights that may help overcome treatment resistance and improve HER2-targeted therapeutic strategies.
Zhu-Meng Gu, Hui Liu, Sixiang Zheng et al.· Cell Communication and Signa...· 0 citations
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