Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer (GC) with unique epidemiological and pathogenic characteristics. Despite its clinical significance, large-scale proteomic studies on GSRCC remain scarce, limiting our molecular understanding of the disease. Advanced mass spectrometry (MS)-based proteomics is crucial for identifying key biomarkers and drug targets, thereby enabling more effective therapeutic strategies.

In a recent study published in Genes & Diseases, researchers from several institutions, including Tianjin University, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Fudan University, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Chinese Academy of Medical Sciences and Peking Union Medical College, and University of Houston, characterizes the proteomic features and molecular mechanisms of GSRCC to date.

Initially, the research team analyzed clinical data from over 10,000 patients with GC between January 2010 and December 2019. An in-depth proteomic analysis was conducted on tumor tissues from 112 GSRCC patients, each with over 70% signet ring cell content. Using advanced MS, the team identified 7322 proteins, establishing the largest tissue-specific peptide spectral library for GSRCC. Additionally, through unsupervised clustering, the team identified four novel proteomic subtypes of GSRCC: Metabolism (S-Mb), Microenvironment Dysregulation (S-Me), Migration (S-M) and Proliferation (S-PF).

Two key prognostic biomarkers were identified and validated in an independent cohort of 75 patients: PRDX2, a protein associated with favorable prognosis; and DDX27, linked to poor survival outcomes. Furthermore, proteomic profiling of 79 biomarker-negative GSRCC cases revealed marked tumor heterogeneity. Notably, unsupervised clustering identified three distinct proteomic clusters, with cluster 2 linked to the poorest prognosis.

Focusing on HER2-negative, EBV-negative, and pMMR GSRCC cases (LMT [Lack of Medical Treatment]-GSRCC), the study identified four potential drug targets: eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), eukaryotic translation initiation factor 6 (EIF6), and nuclear factor kappa B subunit 2 (NFKB2). Remarkably, high expression of these proteins was associated with poor prognosis, underscoring their relevance as promising therapeutic candidates.

Interestingly, molecular docking and cytotoxicity testing singled out neratinib—a drug approved for breast cancer treatment—as the most promising candidate. Furthermore, in vitro and in vivo studies demonstrated neratinib’s potent ability to inhibit tumor growth, cell migration, and invasion, while promoting cancer cell apoptosis, all with minimal side effects.

In conclusion, this is the first study to focus specifically on the LMT-GSRCC population, uncovering potential biomarkers and drug targets through proteomic analysis. The findings from this study not only provide a foundation for developing novel targeted therapies but also personalized treatment strategies for GSRCC.

Reference

Title of Original Paper: A comprehensive proteomic analysis uncovers novel molecular subtypes of gastric signet ring cell carcinoma: Identification of potential prognostic biomarkers and therapeutic targets

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101717

Funding Information:

• The National Key Research and Development Program of China (No. 2021YFA0910100, 2021YFA0910101)
• The Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer (China) (No. JBZX-202006)
• The Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (China) (No. ZYYCXTD-C-202208)
• The Medical Science and Technology Project of Zhejiang Province, China (No. WKJ-ZJ-2202, WKJ-ZJ-2104)
• The National Natural Science Foundation of China (No. 82074245, 81973634, 82204828)
• The Natural Science Foundation of Zhejiang Province, China (No. QKHM25H3103, LHDMY22H160008)
• The Zhejiang Leading Innovation and Entrepreneurship Team (China) (No. 2022R01006)
• The Pioneer R&D Program of Zhejiang, China (No. 2024SDYXS0003, 2023SDYXS0001)
• The Program of Zhejiang Provincial TCM Sci-Tech Plan (China) (No. GZY-ZJ-KJ-24064)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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