CXCL13-CXCR5 signaling and its co-expression network are associated with colorectal cancer cell growth and poor prognosis

Abstract

Abstract The heterogeneity of colorectal cancer (CRC) and its microenvironment has molecular traits of immune cells, and is driven by dysregulated WNT, RAS-RAF-MAPK, TGF-β, and PI3K-AKT pathways. CXCL13-CXCR5 signaling has been shown to induce PI3K- and Ras-dependent activation of MAPK/ERK1-2 to promote cancer cell survival, invasion, and growth. The hypothesis tested in this study is CXCL13-CXCR5 signaling and co-expression networks mediate CRC progression, cell growth, and survival. RNAseq data from CRC cases, along with matched controls, were acquired from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) elucidated gene networks that significantly correlated with CRC poor prognosis. CXCL13, CXCR5, and other co-expressed genes were identified in the WGCNA designated brown module (M3). The canonical pathways and their upstream regulators of this module were analyzed using Ingenuity Pathway Analysis (IPA). M3 hub genes XCL1, CCL19, PIK3AP1, FLT3, and WNT1 were significantly and positively correlated with PI3K, WNT, ERK1 and ERK2 activation, which promotes cell proliferation and survival. Next, we measured the CRC cell line growth effected by CXCL13 using a XTT assay. In confirmation, CXCL13 treatment of CRC cell lines significantly increased CRC cell line proliferation, but had no direct influence on cell survival. Our findings strongly support CXCL13-CXCR5 signaling and its co-expression networks activates important pathways associated with CRC progression and tumor growth.