Multilevel Proteomic Analyses Reveal Molecular Diversity Between Diffuse-type and Intestinal-type Gastric Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Feb 14

PMID 36788224

Authors

Wenhao Shi

Yushen Wang

Chen Xu

Yan Li

Sai Ge

Bin Bai

Kecheng Zhang

Yunzhi Wang

Nairen Zheng

Juan Wang

Shiqi Wang

Gang Ji

Jipeng Li

Yongzhan Nie

Wenquan Liang

Xiaosong Wu

Jianxin Cui

Yi Wang

Lin Chen

Qingchuan Zhao

Lin Shen

Fuchu He

Jun Qin

Chen Ding

Affiliations

Soon will be listed here.

Abstract

Diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC) are the major histological types of gastric cancer (GC). The molecular mechanism underlying DGC and IGC differences are poorly understood. In this research, we carry out multilevel proteomic analyses, including proteome, phospho-proteome, and transcription factor (TF) activity profiles, of 196 cases covering DGC and IGC in Chinese patients. Integrative proteogenomic analysis reveals ARIDIA mutation associated with opposite prognostic effects between DGC and IGC, via diverse influences on their corresponding proteomes. Systematical comparison and consensus clustering analysis identify three subtypes of DGC and IGC, respectively, based on distinct patterns of the cell cycle, extracellular matrix organization, and immune response-related proteins expression. TF activity-based subtypes demonstrate that the disease progressions of DGC and IGC were regulated by SWI/SNF and NFKB complexes. Furthermore, inferred immune cell infiltration and immune clustering show Th1/Th2 ratio is an indicator for immunotherapeutic effectiveness, which is validated in an independent GC anti-PD1 therapeutic patient group. Our multilevel proteomic analyses enable a more comprehensive understanding of GC and can further advance the precision medicine.

Citing Articles

Natural products based on Correa's cascade for the treatment of gastric cancer trilogy: Current status and future perspective.

Liao W, Wang J, Li Y J Pharm Anal. 2025; 15(2):101075.

PMID: 39957902 PMC: 11830317. DOI: 10.1016/j.jpha.2024.101075.

Preoperative liquid biopsy transcriptomic panel for risk assessment of lymph node metastasis in T1 gastric cancer.

Ding P, Wu J, Wu H, Ma W, Li T, Yang P J Exp Clin Cancer Res. 2025; 44(1):43.

PMID: 39915770 PMC: 11804050. DOI: 10.1186/s13046-025-03305-x.

Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics.

Shou S, Maolan A, Zhang D, Jiang X, Liu F, Li Y Exp Hematol Oncol. 2025; 14(1):8.

PMID: 39871386 PMC: 11771031. DOI: 10.1186/s40164-025-00597-9.

Multi-omics perspective: mechanisms of gastrointestinal injury repair.

Zhao H, Zhang Z, Liu H, Ma M, Sun P, Zhao Y Burns Trauma. 2025; 13():tkae057.

PMID: 39845194 PMC: 11752642. DOI: 10.1093/burnst/tkae057.

Establishment and characterization of a new mouse gastric carcinoma cell line, MCC.

Wang Y, Li X, Wang Y, Qin J Cancer Cell Int. 2025; 25(1):9.

PMID: 39800685 PMC: 11727671. DOI: 10.1186/s12935-024-03633-6.

References

Cristescu R, Lee J, Nebozhyn M, Kim K, Ting J, Wong S . Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015; 21(5):449-56. DOI: 10.1038/nm.3850. View

LAUREN P . THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. Acta Pathol Microbiol Scand. 1965; 64:31-49. DOI: 10.1111/apm.1965.64.1.31. View

Jiang Y, Sun A, Zhao Y, Ying W, Sun H, Yang X . Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019; 567(7747):257-261. DOI: 10.1038/s41586-019-0987-8. View

van Dekken H, van Marion R, Vissers K, Hop W, Dinjens W, Tilanus H . Molecular dissection of the chromosome band 7q21 amplicon in gastroesophageal junction adenocarcinomas identifies cyclin-dependent kinase 6 at both genomic and protein expression levels. Genes Chromosomes Cancer. 2008; 47(8):649-56. DOI: 10.1002/gcc.20570. View

Wang R, Dang M, Harada K, Han G, Wang F, Pizzi M . Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma. Nat Med. 2021; 27(1):141-151. PMC: 8074162. DOI: 10.1038/s41591-020-1125-8. View

Hayes J, Dinkova-Kostova A, Tew K . Oxidative Stress in Cancer. Cancer Cell. 2020; 38(2):167-197. PMC: 7439808. DOI: 10.1016/j.ccell.2020.06.001. View

Jimenez Fonseca P, Carmona-Bayonas A, Hernandez R, Custodio A, Cano J, Lacalle A . Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry. Br J Cancer. 2017; 117(6):775-782. PMC: 5589993. DOI: 10.1038/bjc.2017.245. View

Baluapuri A, Wolf E, Eilers M . Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol. 2020; 21(5):255-267. PMC: 7611238. DOI: 10.1038/s41580-020-0215-2. View

Whary M, Sundina N, Bravo L, Correa P, Quinones F, Caro F . Intestinal helminthiasis in Colombian children promotes a Th2 response to Helicobacter pylori: possible implications for gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2005; 14(6):1464-9. DOI: 10.1158/1055-9965.EPI-05-0095. View

10.

Mohammadi M, Nedrud J, Redline R, Lycke N, Czinn S . Murine CD4 T-cell response to Helicobacter infection: TH1 cells enhance gastritis and TH2 cells reduce bacterial load. Gastroenterology. 1997; 113(6):1848-57. DOI: 10.1016/s0016-5085(97)70004-0. View

11.

Sies H, Jones D . Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020; 21(7):363-383. DOI: 10.1038/s41580-020-0230-3. View

12.

Jiang Y, Xie J, Huang W, Chen H, Xi S, Han Z . Tumor Immune Microenvironment and Chemosensitivity Signature for Predicting Response to Chemotherapy in Gastric Cancer. Cancer Immunol Res. 2019; 7(12):2065-2073. DOI: 10.1158/2326-6066.CIR-19-0311. View

13.

Malumbres M, Barbacid M . Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9(3):153-66. DOI: 10.1038/nrc2602. View

14.

Mashtalir N, DAvino A, Michel B, Luo J, Pan J, Otto J . Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes. Cell. 2018; 175(5):1272-1288.e20. PMC: 6791824. DOI: 10.1016/j.cell.2018.09.032. View

15.

Teng S, Li Y, Yang M, Qi R, Huang Y, Wang Q . Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer. Cell Res. 2019; 30(1):34-49. PMC: 6951341. DOI: 10.1038/s41422-019-0259-z. View

16.

Hornbeck P, Kornhauser J, Latham V, Murray B, Nandhikonda V, Nord A . 15 years of PhosphoSitePlus®: integrating post-translationally modified sites, disease variants and isoforms. Nucleic Acids Res. 2018; 47(D1):D433-D441. PMC: 6324072. DOI: 10.1093/nar/gky1159. View

17.

Ying W . Phenomic Studies on Diseases: Potential and Challenges. Phenomics. 2023; 3(3):285-299. PMC: 9867904. DOI: 10.1007/s43657-022-00089-4. View

18.

Ding C, Chan D, Liu W, Liu M, Li D, Song L . Proteome-wide profiling of activated transcription factors with a concatenated tandem array of transcription factor response elements. Proc Natl Acad Sci U S A. 2013; 110(17):6771-6. PMC: 3637693. DOI: 10.1073/pnas.1217657110. View

19.

Mittal P, Roberts C . The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020; 17(7):435-448. PMC: 8723792. DOI: 10.1038/s41571-020-0357-3. View

20.

Wilkerson M, Hayes D . ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-3. PMC: 2881355. DOI: 10.1093/bioinformatics/btq170. View