Jintuan Huang

Background Gastric cancer (GC) is a highly aggressive malignancy with limited therapeutic options and poor clinical outcomes. Aberrant regulation of the ubiquitin–proteasome system contributes to tumorigenesis by disrupting protein homeostasis and signal transduction. STAMBPL1, a JAMM family deubiquitinase (DUB) implicated in several cancers, remains poorly characterized in GC, and its mechanistic relevance to disease progression warrants investigation. Methods Transcriptomic analyses and clinical specimen profiling were conducted to assess STAMBPL1 expression and prognostic significance in GC. Functional effects were evaluated using in vitro assays, patient-derived organoids, and multiple mouse models. Mechanistic studies included mass spectrometry, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, and pharmacologic blockade of downstream signaling pathways. Results STAMBPL1 was significantly overexpressed in GC tissues and strongly associated with advanced T stage, distant metastasis, higher clinical stage, and unfavorable prognosis. Functionally, STAMBPL1 promotes GC cell proliferation, migration, invasion, and organoid growth in vitro, and drives subcutaneous tumor growth, peritoneal dissemination, and lung metastasis in vivo. Mechanistically, STAMBPL1 directly binds IQ-domain GTPase-activating protein 1 (IQGAP1), specifically catalyzing the removal of K48- and K63-linked ubiquitin chains at the 1368 lysine residue, thereby stabilizing IQGAP1 protein levels. Stabilized IQGAP1 subsequently activates the JAK2/STAT3 signaling axis, potentiating GC malignant progression. Notably, pharmacological blockade of JAK2 by AG490 markedly curtailed tumor progression and abrogated the oncogenic effects of STAMBPL1/IQGAP1, underscoring the functional dependency of this axis. Conclusions These findings identify STAMBPL1 as a novel oncogenic DUB that promotes GC progression through IQGAP1 stabilization and subsequent activation of JAK2/STAT3 signaling, providing a potential therapeutic target for GC. Graphical abstract Schematic illustration of the STAMBPL1/IQGAP1/JAK2/STAT3 axis driving GC progression.

A disintegrin and metalloproteinase with thrombospondin motifs 16 (ADAMTS16) has been reported to be involved in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) is unclear. In this study, the role of ADAMTS16 in gastric cancer was investigated. The effects of ADAMTS16 on cell migration, invasion, and proliferation were investigated by functional experiments in vivo and in vitro. Downstream signal pathways of ADAMTS16 were confirmed by using bioinformatics analysis, co-immunoprecipitation, and immunofluorescence. Meanwhile, bioinformatics analysis, qRT-PCR, western blot, and dual-luciferase reporter gene analysis assays were used to identify ADAMTS16 targets. The expression of ADAMTS16 in GC was analyzed in public datasets. The expression of ADAMTS16 and its correlations with the clinical characteristics of GC were investigated by immunohistochemistry. Ectopic ADAMTS16 expression significantly promoted tumor cell migration, invasion, and growth. Bioinformatics analysis and western blot showed that ADAMTS16 upregulated the IFI27 protein through the NF-κb pathway, which was confirmed by immunofluorescence and western blot. Dual-luciferase reporter gene analysis identified a binding site between P65 and IFI27 that may be directly involved in the transcriptional regulation of IFI27. IFI27 knockdown reversed the promoting effect of ADAMTS16 on cell invasion, migration, and proliferation indicating that ADAMTS16 acts on GC cells by targeting the NF-κb/IFI27 axis. ADAMTS16 was associated with poor prognosis in clinical characteristics. ADAMTS16 promotes cell migration, invasion, and proliferation by targeting IFI27 through the NF-κB pathway and is a potential progressive and survival biomarker of GC.

A Disintegrin and Metalloproteinase with Thrombospondin motifs 19 (ADAMTS19) has been reported to participate in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) remains undocumented. Using immunohistochemistry (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR) on GC tissues and adjacent normal tissues, we found that ADAMTS19 was downregulated in GC tissues (IHC: p < 0.001; qRT-PCR: p = 0.017). Further investigation revealed that ADAMTS19 correlated with distant metastasis (p = 0.008) and perineural invasion (p = 0.018) and that patients with low ADAMTS19 had worse overall survival (p = 0.021). Gain- and loss-of-function assays showed that ADAMTS19 suppressed cell migration and invasion in vitro. Using bioinformatics analysis and co-immunoprecipitation, immunofluorescence, and dual-luciferase reporter gene assays, we confirmed that ADAMTS19 binds with cytoplasm P65, decreasing the nucleus phosphorylation of P65, a crucial transcription factor in the nuclear factor kappa-B (NF-κB) pathway, thereby downregulating S100 calcium-binding protein A16 (S100A16) expression. S100A16 acted as the downstream of ADAMTS19, reversing the suppression of cell migration and invasion by ADAMTS19 in vitro. A combination of ADAMTS19 and S100A16 expression provided the optimal prognostic indicator for GC. Patients with ADAMTS19^high-S100A16^low had better overall survival than ADAMTS19^low-S100A16^high patients (p = 0.006). These results suggest that ADAMTS19 suppresses cell migration and invasion by targeting S100A16 via the NF-κB pathway and that ADAMTS19 and S100A16 are potential metastasis and survival biomarkers for GC.