Consensus-Expressed CXCL8 and MMP9 Identified by Meta-Analyzed Perineural Invasion Gene Signature in Gastric Cancer Microarray Data

Abstract

As an underrecognized route of cancer metastasis, perineural invasion (PNI) is defined as the neoplastic invasion of nerves, which can be targeted to inhibit the metastasis of malignant cancer. However, the mechanism underlying PNI in cancer is largely unknown. We constructed a PNI gene signature based on a Pathway Studio-mediated literature screen and investigated the relevant genes in a gastric cancer model. Thus, a total of 467 studies/datasets were retrieved from the Gene Expression Omnibus database using the keyword "gastric cancer," among which 13 studies that focused on gene expression profiling were further manually inspected and selected. Furthermore, the constructed PNI gene signature (104 genes) expression was meta-analyzed, and the consensusexpressed C-X-C motif chemokine ligand 8 (CXCL8) and matrix metallopeptidase 9 (MMP9) (p < 0.01, |log fold change| >1) were detected. Importantly, the disease-free survival was significantly worse in patients with high expressions of CXCL8 and MMP9 than in those with low expressions (p = 0.05). Moreover, multiple linear regression analysis showed that the population region (country) was associated with the expressions of both CXCL8 and MMP9. In conclusion, these data suggest that the coexpression of CXCL8 and MMP9 could be an early detection marker for PNI, with a potential to be utilized as individual therapy targets for early treatment to prevent PNI-related cancer metastasis. Keywords: the cancer genome atlas, gene expression omnibus, fixed-effects model, random-effects model, gene expression profiling interactive analysis Conflict of Interest Statement: Author ML was employed by company Hangzhou Beiwo Meditech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis

“…Studies have found that CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1+ macrophages in GC [ 60 ]. CXCL8 could be an early detection marker for perineural invasion-related GC, with a potential to be utilized as individual therapy targets [ 61 ]. CXCL8 inhibitors may drive antitumor response, providing potential therapeutic effects for patients with gastric cancer.…”

Analysis of Key Pathways, Genes and Immune Cell Infiltration in Metastatic Esophageal Squamous Cell Carcinoma Based on Bioinformatics

“…The same results were also confirmed in prostate cancer 9 , knockout of CXCL8 in PC-3M-LN4 cells decreased the expression of MMP9, while up-regulation of CXCL8 increased the expression of MMP9. A study on the analysis of gastric cancer microarray data showed that the co-expression of CXCL8 and MMP9 could be an early detection marker of perineural invasion(PNI) 27 . To sum up, these three hub genes are of great value and significance as tumor markers and prognostic indicators of ESCC.…”

Beyond Chemotherapy, PD-1, and HER-2: Novel Targets for Gastric and Esophageal Cancer

“…However, gastric mucosal cell malignancy results in CLDN18.2 epitope exposure and enables it to become a target unique to cancer cells [13]. Zolbetuximab is a chimeric monoclonal antibody that targets CLDN18.2 epitopes and initiates cell death by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity [17]. In a phase I trial, Zolbetuximab showed single-agent efficacy and manageable toxicity in patients with heavily pretreated advanced CLDN18.2-positive gastric/gastroesophageal junction (G/GEJ) cancer [17].…”

“…Zolbetuximab is a chimeric monoclonal antibody that targets CLDN18.2 epitopes and initiates cell death by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity [17]. In a phase I trial, Zolbetuximab showed single-agent efficacy and manageable toxicity in patients with heavily pretreated advanced CLDN18.2-positive gastric/gastroesophageal junction (G/GEJ) cancer [17]. Furthermore, in a phase II trial, Zolbetuximab monotherapy exhibited antitumor activity in patients sharing the same cancer parameters [18].…”