Mixed data analysis detected Endocrine Fibroblast Growth Factors (FGF19, FGF21, and FGF23) as Prognostic and Diagnostic Markers of Colorectal Neoplasia and Carcinoma

Abstract

BackgroundEndocrine fibroblast growth factors (eFGFs) play important roles in various cellular signaling processes such as development and differentiation. These genes were also found to be significantly related to several cancer. However, little is known about the role of eFGFs in colon neoplasia and colon adenocarcinoma (COAD). MethodsWe performed systematically and comprehensively investigated the gene expression, DNA methylation, prognostic significance, genetic alteration, co-expressed genes, protein-protein interaction, small molecules pathway, and drug interactions of eFGFs based on the TIMER2.0, GEPIA2, UALCAN, OncoDB, cBioPortal, LinkedOmics, STRING, SMPDB, htfTarget, mirTarBase, circBank and DGIdb databases. Ultimately, the correlations of eFGFs expressions between polyp and COAD tissues compared to normal mucosa were validated using qRT-PCR as a cross-sectional part of our study. ResultsThe results indicated that eFGFs are highly expressed in COAD, and abnormal gene expressions may be related to promoter methylation. In this matter, methylation analysis revealed promotor hypermethylation of FGF19 and FGF21. Conversely, FGF23 was shown to have a tendency for promotor hypomethylation. Moreover, hypermethylation of FGF21 and FGF23 and downregulation of FGF23 were found to be detrimental to the survival of COAD patients. KEGG pathway analyses indicated that the co-expressed genes of eFGF family members were mainly related to the regulation of the actin cytoskeleton and, more notably, in Ras signaling, PI3k-Akt signaling, Rap1 signaling, and cancer pathways. Based on qRT-PCR results, FGF21 was significantly overexpressed in the colon polyps compared to normal mucosa. Additionally, RNA expression of FGF21 and FGF23 was markedly elevated in adenomatous polyps as opposed to hyperplastic polyps. ConclusionCollectively, these findings reveal the critical roles of eFGFs in COAD tumorigenesis and suggest eFGF family members as promising prognostic and diagnostic markers for CRC as well as discriminating markers for high-risk from low-risk polyps.