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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Graphical abstract <p>Schematic illustration of the STAMBPL1/IQGAP1/JAK2/STAT3 axis driving GC progression.</p>

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STAMBPL1 promotes the progression of gastric cancer via deubiquitinating IQGAP1 to activate the JAK2/STAT3 pathway

  • 期刊论文

  • 发表日期：

    2025年11月27日

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  • Xiaocheng Tang,
  • Jun Qiu,
  • Chunyu Chen,
  • Jiawei Zhang,
  • Rongchang Tan,
  • Weiyao Li,
  • Jintuan Huang,
  • Hao Chen,
  • Zuli Yang

摘要

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.