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Background: SH3-domain binding protein-1 (SH3BP1), which specifically inactivates Rac1 and its target protein Wave2, has been shown to be an important regulator of cancer metastasis. However, the effects of SH3BP1 in melanoma progression remain unclear. The current study aimed to explore the function of SH3BP1 in melanoma and its possible molecular mechanism. Methods: TCGA database was used to analyze the expression of SH3BP1 in melanoma. Then, reverse transcription–quantitative polymerase chain reaction was performed to detect the expression of SH3BP1 in melanoma tissues and cells. Next, genes related to SH3BP1 were analyzed by LinkedOmics database, and protein interactions were analyzed by STRING database. These genes were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, the signaling pathway of SH3BP1 action was screened by bioinformatics analysis. Finally, the function of SH3BP1 and its mediated signaling pathway in melanoma progression were investigated in vitro and in vivo. Results: SH3BP1 was significantly upregulated in melanoma tissues and cells. The pathways regulated by SH3BP1 are closely related to the occurrence and development of tumors. And we found that overexpression of SH3BP1 promoted the proliferation, migration, and invasion of melanoma cells by increasing Rac1 activity and Wave2 protein levels in vitro. Similarly, overexpression of SH3BP1 facilitated melanoma progression by upregulating Wave2 protein expression in vivo. Conclusion: In summary, this study revealed for the first time that SH3BP1 promoted melanoma progression through Rac1/Wave2 signaling pathway, providing a new therapeutic target for melanoma.

Gastric cancer (GC) presents striking survival disparities: 85–100% for early-stage versus only 5–20% for advanced disease. Glucose metabolic reprogramming (GMS)—a cancer hallmark linked to the Warburg effect—fuels tumor progression and immune evasion via lactate. This study uses multi-omics data to delineate GMS heterogeneity and its clinical relevance in GC. Single-cell, spatial, and bulk transcriptomic data were integrated. BayesPrism deconvoluted bulk data, CytoTRACE2, CellChat, and NicheNet analyzed cell trajectories, communication, and ligand–receptor regulation, respectively. MOVICS performed multi-omics (mRNA, methylation, mutation, and lncRNA) clustering of TCGA-STAD. Mime1 integrated machine learning to build a prognostic model based on GMS-related genes and CS2/TOP2A features. Differential expression and functional enrichment explored mechanisms. Verification of expression differences in key genes using qPCR. In gastric cancer research, GMS scores exhibit significant enrichment. Single-cell analysis identified a TOP2A + epithelial subtype characterized by high GMS scores, strong stemness, elevated proliferative activity, and poor prognosis. Further analysis suggests this subtype may be regulated by the EFNB2-EPHB2 signaling pathway originating from GABRP⁺ cells, activating cell cycle pathways via ligands such as CKLF. Multi-omics clustering defined the CS2 subtype, exhibiting enrichment in GMS score, cell cycle, and glucose metabolism pathways and correlating with poor prognosis. A prognostic model constructed using eight genes demonstrated robust predictive performance across TCGA and multiple independent cohorts, with high-risk patients potentially exhibiting ‘cold tumor’ characteristics. Among these, the core gene SH3BP1 was identified as a potential tumor suppressor (HR = 0.87), whose overexpression correlated with lower tumor stage and enhanced CD8⁺ T cell killing and infiltration. This study is the first to systematically characterize GMS heterogeneity in GC via integrated multi-omics. It identifies the aggressive TOP2A⁺ subtype, establishes the clinically relevant CS2 classification, and develops a robust 8-gene prognostic model—useful for stratifying patients with immunologically “cold” tumors. Critically, tumor suppressor SH3BP1 (a key regulator) correlates with reduced tumor progression and enhanced CD8 + T cell anti-tumor immunity when highly expressed. These findings underscore that SH3BP1 may represent a promising therapeutic target for precise intervention in GMS-immune interactions in GC.

Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI‐induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI‐mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI‐mediated apoptosis and eventually leading to TKI resistance. Clinically, the expression patterns of Cobll1, PACSIN2, and SH3BP1 are highly correlated with severe progression in BC‐CML patients. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance in CML and presents a potential pharmacological target to overcome TKI resistance and BC progression in CML.