OVOL2 attenuates the expression of MAP3K8 to suppress epithelial mesenchymal transition in colorectal cancer

Abstract

BackgroundInactivation of members of the OVO-like family of C2H2 zinc-finger transcription factor 2 (OVOL2) is increased after colorectal cancer (CRC) metastasis. This study investigated the functional roles and clinical relevance of OVOL2 and its downstream factors in colorectal carcinogenesis. MethodsTranscriptome RNA sequencing (RNA-seq) of HCT116 cells overexpressing OVOL2 and SW480 cells silencing OVOL2 were conducted. We cross-checked the Chromatin Immunoprecipitation sequencing (ChIP-seq, GSM1239518) positive peaks and RNA-seq differential expression genes (DEGs). In vitro functional assays, including wound-healing assay and transwell assay, were performed. The RNA expression (n = 597) and protein expression (n = 93) of OVOL2- mitogen-activated protein kinase kinase kinase 8 (MAP3K8)-C-X-C Motif Chemokine Ligand 16 (CXCL16) were evaluated in human CRC and adjacent normal tissues. CXCL16 levels in cell culture supernatants and serum samples obtained from 29 colon polyps patients and 24 CRC patients were measured using ELISA. ResultsWe found that OVOL2 inhibited the migration and epithelial mesenchymal transition (EMT) of CRC cells by blocking the MAP3K8/AKT/NF-κB signaling pathway, and also decreased levels of CXCL16, a chemokine downstream of the MAP3K8/AKT/NF-κB signaling pathway. Furthermore, patient tumor tissue samples showed a lower level of in situ OVOL2 (P = 0.005) and higher CXCL16 (P = 0.001) levels, compared to adjacent normal tissues. Survival analyses revealed that both OVOL2 (logrank P = 0.063) and CXCL16 (logrank P = 0.048) were associated with overall survival (OS) and were independent prognostic factors for CRC. Additionally, OVOL2 and CXCL16 were found to be prognostically relevant (logrank P = 0.038). CXCL16 may serve as a potential diagnostic biomarker for CRC (P = 0.010). ConclusionsThe OVOL2/ MAP3K8/CXCL16 axis is a key player in colonic tumorigenesis and metastasis, and may be a potential diagnostic and prognostic biomarker.