Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression

Abstract

Overactivation of Wnt-β-catenin signaling, including β-catenin-TCF target gene expression, is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin family of cell-adhesion receptors member L1 as a β-catenin-TCF target gene preferentially expressed at the invasive edge of human CRC tissue. L1 can confer enhanced motility and liver metastasis when expressed in CRC cells. This ability of L1-mediated metastasis is exerted by a mechanism involving ezrin and the activation of NF-κB target genes. In this study, we identified the secreted modular calcium-binding matricellular protein-2 (SMOC-2) as a gene activated by L1-ezrin-NF-κB signaling. SMOC-2 is also known as an intestinal stem cell signature gene in mice expressing Lgr5 in cells at the bottom of intestinal crypts. The induction of SMOC-2 expression in L1-expressing CRC cells was necessary for the increase in cell motility, proliferation under stress and liver metastasis conferred by L1. SMOC-2 expression induced a more mesenchymal like phenotype in CRC cells, a decrease in E-cadherin and an increase in Snail by signaling that involves integrin-linked kinase (ILK). SMOC-2 was localized at the bottom of normal human colonic crypts and at increased levels in CRC tissue with preferential expression in invasive areas of the tumor. We found an increase in Lgr5 levels in CRC cells overexpressing L1, p65 or SMOC-2, suggesting that L1-mediated CRC progression involves the acquisition of a stem cell-like phenotype, and that SMOC-2 elevation is necessary for L1-mediated induction of more aggressive/invasive CRC properties.

Protein-protein interaction between ezrin and p65 in human breast cancer cells

“…Ben-Shmuel et al (2013) found that ezrin can be phosphorylated by L1 through Rho-associated protein kinase in colorectal cancer, and that ezrin might be associated with activation of NF-κΒ pathway, which results in tumor cell motility and an increase in the expression of insulin-like growth factor-binding protein 2. These results were consistent with research by Gavert et al (2010) and Shvab et al (2015).…”

An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency

“…Many of these Arntl2-regulated secreted factors were also more highly expressed in metastasis-derived cells lines than in non-metastatic primary tumor-derived cell lines (Figure 6C). Several of these top secreted factors, including Wnt5a, Il-11, and Cxcl5 have been previously implicated in regulating metastatic ability in lung and other cancer types (Bo et al, 2013; Hanaki et al, 2012; Kang et al, 2013; Weeraratna et al, 2002; Zhou et al, 2014), while others, such as Smoc2, Grem1, and Ltbp2, are relatively poorly characterized in metastasis (Table S2 and Shvab et al, 2015). Arntl2 knock-down did not lead to changes in canonical epithelial genes Cdh1 and Epcam or lung differentiation genes Muc1 and Abca3 consistent with Arntl2 not directly affecting cancer cell differentiation (Table S2).…”

“…Smoc2 is widely expressed during embryonic development, enhances responses to angiogenic growth factors, and mediates cell adhesion(Maier et al, 2008; Rocnik et al, 2006). Smoc2 also marks intestinal stem cells, and its induction in colorectal cancer cells was shown to promote epithelial-mesenchymal transition and confer a stem cell-like phenotype (Shvab et al, 2015). …”

“…While most circulating and disseminated cancer cells seem to be single cells, a reduced requirement for metastatic self-sufficiency could be one factor that increases the metastatic ability of clusters of cancer cells (Aceto et al, 2014). While Smoc2 has not been well-studied in any disease context, it is a marker of colon stem cells, it modulates the mitogenic and angiogenic effects of several growth factors, and regulates myeloid development in zebrafish (Mommaerts et al, 2014; Rocnik et al, 2006; Shvab et al, 2015). Smoc2 has been shown to regulate keratinocyte adhesion through integrin binding.…”

A holistic approach to dissecting SPARC family protein complexity reveals FSTL-1 as an inhibitor of pancreatic cancer cell growth

“…In breast cancer, the SMOC-1 gene was found to be hypermethylated56 but otherwise very little is known about the role of SMOC-1 in human disease. There is similarly little known about the role of SMOC-2, although there is evidence that SMOC-2 has mitogenic properties and is an important regulator of proliferation57, and can synergise with VEGF and bFGF-induced angiogenesis in endothelial cells58. Like SPARC, SMOC-2 may therefore regulate growth factor signalling.…”