This editorial refers to “IGF2BP3 binds to FBXO32 to activate the cyclic guanosine monophosphate-protein kinase G pathway, promoting gastric cancer progression” by Si et al, 2025; https://doi.org/10.3748/wjg.v31.i46.111631.
INTRODUCTION
Gastric cancer (GC) constitutes a major contributor to the global cancer burden, with the fifth-highest incidence and third-highest mortality worldwide[1,2]. Despite advances in surgical and systemic therapies, the prognosis of advanced GC remains dismal[3], thus necessitating a deeper exploration of its molecular underpinnings. RNA modifications have emerged as pivotal determinants of cancer pathogenesis[4,5]. Among these, N6-methyladenosine (m6A) is characterized as the most abundant internal modification found in eukaryotic messenger RNAs (mRNAs), which governs mRNA stability, translation, and decay, influencing numerous oncogenic processes[6,7]. In their seminal study, Si et al[8] systematically delineate the role of the m6A reader protein IGF2BP3 in the occurrence of gastric tumorigenesis. Based on this discovery, we reviewed the expanded landscape of m6A functions in cancer, exploring how RNA methylation regulates various malignant phenotypes.
M6A MODIFICATION IN TUMOR DEVELOPMENT
The m6A modification is a dynamic, reversible post-transcriptional regulatory mechanism involving the addition of a methyl group to the N6 position of adenosine residues in RNA[9]. This process is orchestrated by three groups of regulators: Writers (methyltransferases) that install the methyl group, erasers (demethylases) that remove it, and readers that recognize the mark and mediate downstream effects[10]. As illustrated in Figure 1, the core methyltransferase complex composed of METTL3 and METTL14[11,12], along with reader proteins such as the YTHDF family which regulate mRNA translation or degradation[13], and the IGF2BP family which enhance mRNA stability[14], typically function as oncogenes. In contrast, demethylases like fat mass and obesity-associated protein and ALKBH5 exhibit context-dependent roles, acting as either oncogenes or tumor suppressors depending on the cellular environment[15-17]. By modulating the expression of downstream genes, m6A modification influences a wide array of cellular processes and physiological functions[18,19].
Figure 1 IGF2BP3 promotes gastric cancer via N6-methyladenosine modification.
N6-methyladenosine is dynamically regulated by writers, erasers, and readers. This modification participates in multiple aspects of RNA processing, including stability, translation, and decay. The IGF2BP3/FBXO32/cyclic guanosine monophosphate-protein kinase G axis represents a promising therapeutic target for gastric cancer. mRNA: Messenger RNA; m6A: N6-methyladenosine; GC: Gastric cancer; GTP: Guanosine triphosphate; cGMP: Cyclic guanosine monophosphate.
IGF2BP3 AS AN M6A READER IN CANCER
As a key component of the IGF2BP family, IGF2BP3 functions as a critical m6A reader protein. It drives tumor proliferation, chemoresistance, and stemness by post-transcriptionally stabilizing key oncogenic transcripts such as IGF2, CD44, and ABCG2[20]. Furthermore, through binding to programmed cell death ligand 1 mRNA and enhancing its stability, IGF2BP3 contributes to immune evasion across multiple tumor types[21]. A systematic pan-cancer analysis by Mancarella and Scotlandi[22] consolidated data from the cancer genome atlas and other sources and identified IGF2BP3 as frequently overexpressed in numerous malignancies[23,24]. This overexpression was linked to advanced disease stages and, in specific cancers like leukemia and pancreatic cancer, served as a powerful predictor of tumor recurrence and mortality, establishing its role as an independent prognostic biomarker across cancer types. The study by Si et al[8] demonstrated that elevated IGF2BP3 expression in GC tissues predicts adverse clinicopathological outcomes, such as lymph node metastasis, advanced tumor node metastasis stage, and the diffuse-type histological subtype. This result corroborates earlier reports by Ge et al[25], Ma et al[26], and Lin et al[27].
Using a combination of RNA sequencing, methylated RNA immunoprecipitation sequencing, and RNA immunoprecipitation sequencing, the authors identified FBXO32 as a key downstream target of IGF2BP3. As an E3 ubiquitin ligase, FBXO32 has been shown to exert both oncogenic and tumor-suppressive functions in a context-dependent manner. Zhou et al[28] demonstrated that in breast cancer, FBXO32 suppresses malignant tumor phenotypes by mediating the ubiquitination and degradation of KLF4. In contrast, Li et al[29] revealed that in liver and pancreatic cancer models, FBXO32 exerts pro-tumorigenic effects by catalyzing the polyubiquitination and stabilization of cyclin D. These findings collectively suggest that the biological function of FBXO32 is highly context-dependent. It may catalyze distinct types of ubiquitin chains in different cellular environments, thereby regulating different downstream networks and ultimately exhibiting tissue-specific and functionally opposing roles in tumor modulation.
Si et al[8] demonstrate that in GC, FBXO32 is upregulated and its protein expression is enhanced by IGF2BP3 in an m6A-dependent manner, without affecting its mRNA levels. The dual-luciferase reporter assay demonstrated that IGF2BP3 specifically binds to the m6A site at position 1427 on FBXO32 mRNA, mediating its post-transcriptional regulation. Overexpression of FBXO32 reversed the inhibitory effects of IGF2BP3 knockdown on cell proliferation, migration, and invasion in vitro. These findings collectively support a pro-tumorigenic role for FBXO32 in GC progression and highlight the high specificity of the IGF2BP3-FBXO32 regulatory axis in this malignancy. However, whether this axis is broadly present and functionally conserved in other tumor types remains to be investigated.
Furthermore, the study reveals that the IGF2BP3-FBXO32 axis activates the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway, which has received increasing attention in the role of cancer cell proliferation, migration, and survival. Through rescue experiments and pharmacological inhibition, the authors convincingly show that PKG inhibition with KT5823 attenuates the pro-tumor effects of FBXO32, underscoring the importance of this signaling pathway.
THERAPEUTIC IMPLICATIONS AND FUTURE DIRECTIONS
The development of pharmacological inhibitors against m6A regulatory proteins has not yet progressed beyond early proof-of-concept studies. A major challenge lies in their functional duality[30,31]. A single m6A regulator can modify hundreds to thousands of distinct mRNAs, whose target genes may be involved in completely opposite biological processes. Other RNA-binding proteins can interact with or compete against m6A regulators to jointly determine the fate of target transcripts. The identity of the reader occupying a given m6A site dictates whether gene expression is suppressed or promoted. Moreover, upstream cellular signals such as hypoxia or oncogene activation dynamically alter the expression, localization, or activity of m6A regulators, thereby reshaping the entire m6A epitranscriptome. Therefore, a thorough comprehension of the context-specific mechanisms of RNA methylation is essential for developing novel therapeutic interventions.
The authors confirm that IGF2BP3 is minimally expressed in normal tissues but drastically upregulated in GC cells, theoretically positioning it as an ideal clinical biomarker. Detection of IGFF2BP3 expression levels in tissue samples or liquid biopsies could be utilized for patient risk stratification and prognostic assessment. Furthermore, IGF2BP3 represents a promising therapeutic target. Gene-silencing strategies such as small interfering RNA or short hairpin RNA directed against IGF2BP3 may offer novel avenues for GC treatment.
IGF2BP3 promoting the translation of FBXO32 in an m6A-dependent manner and activating the downstream cGMP-PKG signaling pathway. These experimental findings suggest that therapeutic strategies targeting FBXO32 via knockdown, inhibiting the cGMP-PKG pathway, or combining these approaches may hold clinical potential. Figure 1 illustrates how targeting the IGF2BP3-FBXO32-cGMP-PKG axis could inform future treatment strategies for GC. However, the delivery systems for nucleic acid drugs and their tumortargeting efficiency remain unresolved key technical challenges. Moreover, the upstream regulatory networks and downstream effects of the IGF2BP3-FBXO32-cGMP-PKG axis are not fully understood. It is still unclear whether these molecules are involved in as-yet-unidentified physiological processes, whether they are indispensable in normal tissues, and whether complete inhibition of their functions might lead to unforeseen organ toxicity[32]. These unresolved issues currently limit the application of related therapies to preclinical settings, with significant hurdles remaining before clinical translation can be achieved.
CONCLUSION
In summary, the results provide deeper mechanistic insight into the role of m6A reader protein IGF2BP3 in malignant tumor and point to a promising therapeutic avenue for GC, either as monotherapy or as part of combination regimens. Future multi-center clinical studies will be essential to validate these findings.
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific quality: Grade B, Grade B, Grade B
Novelty: Grade B, Grade B, Grade C
Creativity or innovation: Grade B, Grade B, Grade B
Scientific significance: Grade B, Grade B, Grade B
P-Reviewer: Tomsuk Ö, PhD, Post Doctoral Researcher, Türkiye; Wang XD, MD, China S-Editor: Fan M L-Editor: A P-Editor: Lei YY
