MMRN1 as a Potential Oncogene in Gastric Cancer: Functional Evidence from In Vitro Studies and Computational Prediction of NEDD4L-Mediated Ubiquitination

TL;DR

This study identifies MMRN1 as a potential driver of gastric cancer and suggests personalized treatment strategies based on patient risk profiles and drug sensitivity.

Contribution

The study introduces MMRN1 as a novel oncogene in gastric cancer and proposes a 10-gene signature for prognosis and treatment guidance.

Findings

MMRN1 upregulation promotes gastric cancer cell proliferation and migration.

High-risk patients show better response to proteasome inhibitors, while low-risk patients benefit more from taxane-based chemotherapy.

Molecular docking suggests NEDD4L may regulate MMRN1 through ubiquitination.

Abstract

Background: Gastric cancer (GC) remains a leading cause of cancer mortality. E3 ubiquitin ligases, as central regulators of protein stability and signaling within the ubiquitin–proteasome system, have been implicated in tumor progression, but their functional roles in GC are not well established. Methods: We integrated bioinformatics analysis of TCGA and GEO datasets, in vitro experiments (including cell proliferation, migration, and apoptosis assays), and computational modeling to identify key prognostic factors in GC. Results: We established two molecular subtypes (E3GC1/E3GC2) with distinct clinical outcomes and developed a 10-gene prognostic signature. The model showed moderate predictive accuracy (AUC: 0.61–0.71) and was validated externally. MMRN1 was upregulated in GC cells and its knockdown significantly inhibited malignant phenotypes. Critically, drug sensitivity analysis revealed high-risk patients were more sensitive to proteasome inhibitors (bortezomib), while low-risk patients responded better to taxane-based chemotherapy (docetaxel). Molecular docking predicted a high-confidence interaction between MMRN1 and NEDD4L, suggesting potential ubiquitination regulation. Conclusions: MMRN1 drives GC cell proliferation and migration in vitro and may be regulated by NEDD4L-mediated ubiquitination. Our study provides a foundation for E3 ligase-based patient stratification and personalized therapy selection in GC. While this study provides comprehensive multi-omics evidence supporting the role of MMRN1 in GC progression, its clinical translation is limited by the lack of in vivo validation and direct experimental evidence of NEDD4L-MMRN1 physical interaction. Further studies using animal models and clinical specimens are warranted to confirm these findings.

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