ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Systematic analysis of anoikis-related genes identifies SRPX2-FAK/AKT-IL-6 axis in the progression and peritoneal metastasis of gastric cancer
Provisionally accepted
Dong Hou1Jinhao Yu1
Yequan Xie2Shengning Zhou2Jintao Zeng2Mingtao Liang1Fang Zheng1Jianan Tan2
fanghai Han1,2*- 1Sun Yat-sen Memorial Hospital, Guangzhou, China
- 2Guangdong Second Provincial General Hospital, Guangzhou, China
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Based on the background that peritoneal metastasis (PM) in advanced gastric cancer (GC) is associated with poor prognosis and that anoikis resistance promotes tumor cell survival after detachment from the extracellular matrix thereby enhancing invasion and metastasis—though its specific role in GC peritoneal metastasis remains to be fully elucidated—this study utilized GC samples from TCGA and GEO databases to identify anoikis-related differentially expressed genes. Non-negative matrix factorization (NMF) clustering was employed to characterize molecular subtypes, Kaplan-Meier analysis was used to evaluate survival outcomes, and pathway enrichment scoring was applied to assess functional profiles. Weighted gene co-expression network analysis (WGCNA) combined with Lasso-Cox regression enabled the construction of a prognostic risk model, while support vector machine (SVM) and random forest (RF) algorithms were utilized to screen characteristic genes for PM to develop a diagnostic model. Experimental validation was conducted to confirm the expression and functional role of SRPX2. The results demonstrated that GC was classified into two subtypes, with Subtype A showing significant enrichment of anoikis resistance-related factors and being correlated with poor prognosis. A prognostic model based on six key genes (HEYL, SRPX2, LBH, PLAT, ITGAV, HTRA1) was established and externally validated, and a nine-gene diagnostic model (including SLC30A9, ZFHX4, CYTB, NDFIP2, NMNAT2, SRPX2, TBC1D8B, CLEC3B, CHRDL2) was constructed. SRPX2 was identified as an independent prognostic marker and a PM-associated marker, highly expressed in cancer-associated fibroblasts (CAFs), and it promotes GC progression and peritoneal metastasis by activating the FAK/AKT pathway and IL-6 paracrine signaling, thereby inducing anoikis resistance. In conclusion, this study classifies GC based on anoikis-related molecular features, develops both prognostic and diagnostic models for peritoneal metastasis, and reveals the mechanism by which anoikis resistance promotes peritoneal metastasis, offering new directions for prognosis assessment and therapeutic strategies in gastric cancer.
Keywords: Anoikis, Cancer-associated fibroblasts (CAF), gastric cancer, Peritoneal metastasis, Srpx2
Received: 30 Oct 2025; Accepted: 08 Dec 2025.
Copyright: © 2025 Hou, Yu, Xie, Zhou, Zeng, Liang, Zheng, Tan and Han. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: fanghai Han
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