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Pepsinogen C Interacts with IQGAP1 to Inhibit the Metastasis of Gastric Cancer Cells by Suppressing Rho-GTPase
Hanxi Ding1,2,3, Yingnan Liu1,2,3, Xiaodong Lu1,2,3
1Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
Aim:
This study systematically explored the biological effects and mechanisms of PGC on gastric cancer (GC) cells in vitro and in vivo.
Method:
The critical biological roles of PGC in GC were assessed via EdU staining, Hoechst staining, flow cytometry, mouse models, CCK-8, wound healing, transwell, and sphere-forming assays. The interaction study with IQ-domain GTPase-activating protein 1 (IQGAP1) was used by Liquid chromatography-mass spectrometry co-immunoprecipitation, immunofluorescence staining, CHX-chase assay, MG132 assay, and qRT-PCR.
Results:
PGC inhibited the proliferation, viability, epithelial-mesenchymal transition, migration, invasion, and stemness of GC cells and promoted GC cell differentiation. PGC suppressed subcutaneous tumor growth and peritoneal dissemination in vivo. The interaction study found PGC inhibits GC cell migration and invasion by downregulating IQGAP1 protein and IQGAP1-mediated Rho-GTPase signaling suppression. In addition, PGC disrupts the stability of the IQGAP1 protein, promoting its degradation and significantly shortening its half-life. Moreover, the expression levels of PGC and IQGAP1 in GC tissues were significantly negatively correlated.
Conclusion:
PGC may act as a tumor suppressor in the development and metastasis of GC. PGC can downregulate its interacting protein IQGAP1 and inhibit the Rho-GTPase pathway, thereby participating in the inhibition of GC cell migration and invasion.
Insights
PGC acts as a tumor suppressor in gastric cancer (GC) by inhibiting cell proliferation, migration, and invasion. It achieves this by downregulating IQGAP1 protein levels and suppressing Rho-GTPase signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Gastric cancer (GC) remains a significant global health challenge with limited effective therapeutic options.
- Understanding the molecular mechanisms underlying GC progression and metastasis is crucial for developing novel treatment strategies.
Purpose of the Study:
- To investigate the biological effects and underlying mechanisms of PGC in gastric cancer (GC) cells.
- To explore the potential of PGC as a therapeutic agent for GC.
Main Methods:
- In vitro assays including EdU staining, Hoechst staining, flow cytometry, CCK-8, wound healing, transwell, and sphere-forming assays were employed.
- In vivo studies utilized mouse models to assess tumor growth and peritoneal dissemination.
- Molecular interactions were analyzed using techniques such as co-immunoprecipitation, immunofluorescence, CHX-chase, MG132 assay, and qRT-PCR to study the PGC-IQGAP1 relationship.
Main Results:
- PGC significantly inhibited GC cell proliferation, viability, epithelial-mesenchymal transition, migration, invasion, and stemness, while promoting differentiation.
- In vivo, PGC suppressed tumor growth and peritoneal metastasis.
- PGC was found to inhibit GC cell migration and invasion by downregulating IQGAP1 protein, thereby suppressing IQGAP1-mediated Rho-GTPase signaling. PGC also destabilized IQGAP1, accelerating its degradation.
Conclusions:
- PGC functions as a tumor suppressor in gastric cancer development and metastasis.
- PGC exerts its anti-cancer effects by downregulating IQGAP1 and inhibiting the Rho-GTPase pathway, consequently suppressing GC cell migration and invasion.
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