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SPON2, a newly identified target gene of MACC1, drives colorectal cancer metastasis in mice and is prognostic for colorectal cancer patient survival

Item Type:Article
Title:SPON2, a newly identified target gene of MACC1, drives colorectal cancer metastasis in mice and is prognostic for colorectal cancer patient survival
Creators Name:Schmid, F. and Wang, Q. and Huska, M.R. and Andrade-Navarro, M.A. and Lemm, M. and Fichtner, I. and Dahlmann, M. and Kobelt, D. and Walther, W. and Smith, J. and Schlag, P.M. and Stein, U.
Abstract:MACC1 (metastasis associated in colon cancer 1) is a prognostic biomarker for tumor progression, metastasis and survival of a variety of solid cancers including colorectal cancer (CRC). Here we aimed to identify the MACC1-induced transcriptome and key players mediating the MACC1-induced effects in CRC. We performed microarray analyses using CRC cells ectopically overexpressing MACC1. We identified more than 1300 genes at least twofold differentially expressed, including the gene SPON2 (Spondin 2) as 90-fold upregulated transcriptional target of MACC1. MACC1-dependent SPON2 expression regulation was validated on mRNA and protein levels in MACC1 high (endogenously or ectopically) and low (endogenously or by knockdown) expressing cells. Chromatin immunoprecipitation analysis demonstrated the binding of MACC1 to the gene promoter of SPON2. In cell culture, ectopic SPON2 overexpression induced cell viability, migration, invasion and colony formation in endogenously MACC1 and SPON2 low expressing cells, whereas SPON2 knockdown reduced proliferative, migratory and invasive abilities in CRC cells with high endogenous MACC1 and SPON2 expression. In intrasplenically transplanted NOD/SCID mice, metastasis induction was analyzed with control or SPON2-overexpressing CRC cells. Tumors with SPON2 overexpression induced liver metastasis (vs control animals without any metastases, P=0.0036). In CRC patients, SPON2 expression was determined in primary tumors (stages I-III), and survival time was analyzed by Kaplan-Meier method. CRC patients with high SPON2 expressing primary tumors demonstrated 8 months shorter metastasis-free survival (MFS) compared with patients with low SPON2 levels (P=0.053). Combining high levels of SPON2 and MACC1 improved the identification of high-risk patients with a 20-month shorter MFS vs patients with low biomarker expression. In summary, SPON2 is a transcriptional target of the metastasis gene MACC1. SPON2 induces cell motility in vitro and CRC metastasis in mice. In patients, SPON2 serves as prognostic indicator for CRC metastasis and survival, and might represent a promising target for therapeutic approaches.
Keywords:Animal Disease Models, Cell Movement, Cell Proliferation, Cell Survival, Cluster Analysis, Colorectal Neoplasms, Computational Biology, Extracellular Matrix Proteins, Gene Expression Profiling, Gene Knockdown Techniques, Gene Ontology, Heterografts, Neoplasm Metastasis, Neoplasm Proteins, Neoplasm Staging, Neoplastic Gene Expression Regulation, Prognosis, Protein Binding, ROC Curve, Transcription Factors, Tumor Biomarkers, Animals, Mice
Publisher:Nature Publishing Group (U.K.)
Page Range:5942-5952
Date:17 November 2016
Official Publication:https://doi.org/10.1038/onc.2015.451
PubMed:View item in PubMed

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