ITGA4 as a Potential Prognostic and Immunotherapeutic Biomarker in Human Cancer and Its Clinical Significance in Gastric Cancer: An Integrated Analysis and Validation

Jiaxing Zhang ^1,2 Gang Wang ³ Jie Liu ^4* Futian Tang ² Song Wang ^1* Yumin Li ^1,2*

• ¹ The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
• ² Digestive System Tumor Prevention and Treatment and Translational Medicine Engineering Innovation Center of Lanzhou University, Lanzhou University, Lanzhou, China
• ³ School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province, China
• ⁴ Ecosystem Change and Population Health Research group, School of Public Health and Social Work, The Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia

Background: Integrin Subunit Alpha 4 (ITGA4), a member of the integrin protein family, is involved in the progression of malignant tumors. However, its role across different cancer types is not well understood.Methods: Utilizing multi-omics data, we comprehensively evaluated ITGA4's expression, clinical relevance, diagnostic and prognostic value, functions, mutations, and methylation status, along with its impact on immunity, mismatch repair (MMR), heterogeneity, stemness, immunotherapy responsiveness, and drug resistance in pan-cancer, with partial validation in gastric cancer (GC) using transcriptomic analysis, single-cell data, western blot (WB), wound-healing assay, flow cytometry and immunohistochemistry (IHC). We further investigated its correlation with clinicopathology and serological markers on tissues from 80 GC patients.Results: ITGA4 expression was generally low in normal tissues but varied significantly across tumor types, with higher levels in advanced stages and grades. It demonstrated diagnostic value in 20 cancer types and effectively predicted 1-, 3-, and 5-year survival rates as part of a prognostic model. ITGA4 played roles in cell adhesion, migration, immune regulation, and pathways like PI3K-Akt and TSC-mTOR. It showed alterations in 22 cancer types, with methylation at 9 sites inhibiting its expression. ITGA4 positively correlated with immune cell infiltration, immune regulatory genes, chemokines, and might reduce microsatellite instability (MSI) and tumor mutation burden (TMB) by promoting MMR gene expression. It could also predict immunotherapy efficacy and chemotherapy sensitivity. In GC, high ITGA4 expression was related to poor prognosis, promoted tumor proliferation and migration, and enhanced immune cell infiltration. ITGA4 expression was higher in GC cells and tissues than normal ones. Its downregulation inhibited GC cell migration and promoted apoptosis. Moreover, ITGA4 was correlated with N stage, pathological stage, neural and vascular invasion, serum levels of Ki-67, immune cells, CRP and CA125.Conclusion: ITGA4 is a potential biomarker and therapeutic target to enhance cancer treatment and improve patient outcomes.