<p>A panel of collagen genes are associated with prognosis of patients with gastric cancer and regulated by microRNA-29c-3p: an integrated bioinformatics analysis and experimental validation</p>

Abstract

Background: The systematic expression characteristics and functions of collagen genes in gastric cancer (GC) have not been reported. Through public data integration, combined with bioinformatics analysis, we identified a panel of collagen genes overexpressed in GC. The functions of these genes were analyzed and validated in a GC-related cohort. microRNAs that may potentially target such genes were investigated in vitro. Methods: Four GC-related datasets retrieved from the Gene Expression Omnibus (GEO) were used to extract differentially expressed genes (DEGs) in GC. Functional annotation was performed to identify the potential roles of the identified DEGs. The association of candidate genes involved in the prognosis of GC patients (n=876) was determined using data provided by the Kaplan-Meier-plotter database, The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) repository, and a GC-related dataset (GSE15459). The expression characteristics of candidate genes and their associations with clinical parameters were validated in our in-house cohort (n=58). MicroRNAs able to target the identified candidate genes were predicted and confirmed using qRT-PCR, Western blotting, and dual-luciferase reporter assays in vitro. Results: After the integration of four GEO datasets, 76 DEGs were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that these DEGs were significantly enriched in ECM-related functions and pathways. A group of collagen genes was significantly upregulated in the GC tissues and constituted a proteinprotein interaction network as important nodes. Some of these collagen genes were closely associated with poor prognosis in GC patients. Overexpression of COL1A1 and COL4A1 was confirmed in our in-house cohort, and this was related to prognosis and certain clinicopathological parameters. We found that microRNA-29c-3p could directly target COL1A1 and COL4A1 in BGC-823 cells. Conclusions: Collagen genes identified in this study were associated with patient prognosis in GC and may represent diagnostic markers or potential therapeutic targets. Aberrant expression of such candidate genes may be induced by microRNA-29c-3p.

The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression

“…Guszczyn and Sobolewski reported the enhancement of collagen turnover in gastric cancer tissues, which could contribute to disorganization of the ECM [59]. Several collagen genes were found to be overexpressed in gastric cancer and, among these, COL1A1 and COL4A1 were closely associated with overall survival of gastric cancer patients and could be regarded as risk factors for poor prognosis [9]. The expression of COL12A1 was also found upregulated in gastric cancer and positively correlated with tumor invasiveness, metastasis, and advanced clinical stage [8].…”

“…Overexpression correlated with overall survival. [9] COL11A1 Differentially expressed in pre-malignant and malignant lesions of the human stomach.…”

“…Abnormal ECM and integrin profiles are frequently reported in cancer corroborating the functional relevance and the specificity of both ECM In gastric cancer, the role of the ECM has been undeniably demonstrated in all steps of the disease, from initiation to metastases. For instance, increased expression of tenascin has been detected in pre-malignant and malignant gastric epithelia [7], whereas collagens have been shown to be deregulated in more advanced stages [8][9][10]. Notably, a subset of collagen genes have been suggested as powerful independent prognostic markers and are able to distinguish pre-malignant from malignant lesions [8][9][10].…”

“…Several studies have provided evidence that the ECM contributes to cancer pathogenesis by (i) stimulating integrin-dependent signaling that promotes invasion and proliferation; (ii) promoting an advantageous microenvironmental niche for metastatic cells; (iii) serving as a reservoir of growth factor and cytokines; (iv) interfering with the communication between cancer and immune cells; and (v) forming a physical barrier to anti-cancer agents ( Figure 1) [4,6].In gastric cancer, the role of the ECM has been undeniably demonstrated in all steps of the disease, from initiation to metastases. For instance, increased expression of tenascin has been detected in pre-malignant and malignant gastric epithelia [7], whereas collagens have been shown to be deregulated in more advanced stages [8][9][10]. Notably, a subset of collagen genes have been suggested as powerful independent prognostic markers and are able to distinguish pre-malignant from malignant lesions [8][9][10].…”

“…For instance, increased expression of tenascin has been detected in pre-malignant and malignant gastric epithelia [7], whereas collagens have been shown to be deregulated in more advanced stages [8][9][10]. Notably, a subset of collagen genes have been suggested as powerful independent prognostic markers and are able to distinguish pre-malignant from malignant lesions [8][9][10]. It is thus foreseen that ECM components and interactors hold great clinical potential as prognostic biomarkers and pharmacological targets in gastric cancer.This review comprises a comprehensive analysis of the main studies concerning ECM remodeling and integrin alterations during gastric cancer development.…”