c-Kit Is Suppressed in Human Colon Cancer Tissue and Contributes to L1-Mediated Metastasis

Abstract

The transmembrane neural cell adhesion receptor L1 is a Wnt/b-catenin target gene expressed in many tumor types. In human colorectal cancer, L1 localizes preferentially to the invasive front of tumors and when overexpressed in colorectal cancer cells, it facilitates their metastasis to the liver. In this study, we investigated genes that are regulated in human colorectal cancer and by the L1-NF-kB pathway that has been implicated in liver metastasis. c-Kit was the most highly suppressed gene in both colorectal cancer tissue and the L1-NF-kB pathway. c-Kit suppression that resulted from L1-mediated signaling relied upon NF-kB, which directly inhibited the transcription of SP1, a major activator of the c-Kit gene promoter. Reconstituting c-Kit expression in L1-transfected cells blocked the biological effects conferred by L1 overexpression in driving motility and liver metastasis. We found that c-Kit expression in colorectal cancer cells is associated with a more pronounced epithelial morphology, along with increased expression of E-cadherin and decreased expression of Slug. Although c-Kit overexpression inhibited the motility and metastasis of L1-expressing colorectal cancer cells, it enhanced colorectal cancer cell proliferation and tumorigenesis, arguing that separate pathways mediate tumorigenicity and metastasis by c-Kit. Our findings provide insights into how colorectal cancer metastasizes to the liver, the most common site of dissemination in this cancer. Cancer Res; 73(18); 5754-63. Ó2013 AACR.

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

“…16 L1 expression in CRC cells results in the growth of such cells in small colonies and also in three-dimensional aggregates that are mediated through L1-L1 cell-cell adhesions (Figure 4c). 7,9 The suppression of endogenous SMOC-2 levels in L1-expressing cells resulted in a flatter, more epithelial colony morphology (Figure 4d, compare with Figure 4c) and an increase in E-cadherin levels (Figure 4h), suggesting that SMOC-2 expression in CRC cells confers a more mesenchymal and motile phenotype by a mechanism reminiscent of EMT.…”

“…Gene expression patterns for CRC cells overexpressing L1, L1+shRNA to ezrin, SMOC-2 and the NF-κB p65 subunit were obtained as previously described [8][9][10] and these gene expression patterns were compared with that obtained for Lgr5 + mouse intestinal stem cells. 12 The results of these comparisons are presented in Supplementary Tables 1 and 2. Chromatin immunoprecipitation assays Rabbit anti-p65 (sc-109, Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used for the immunoprecipitation and rabbit anti-IgG (Jackson ImmunoResearch Laboratories, West Grove, PA, USA) as control antibody.…”

“…7,8 Analysis of gene expression patterns in CRC cells overexpressing L1 revealed a number of genes whose expression is also altered in a large set of human CRC tissue samples from patients. 8,9 L1 confers these tumorigenic capacities in CRC cells by mechanisms involving the recruitment (by L1) of the cytoskeletal protein ezrin and the NF-κB regulator IκB into a submembranal complex resulting in increased phosphorylation and proteasomal degradation of IκB, followed by the activation of NF-κB target gene transcription. 10 The analysis of one such target gene, insulin-like growth factor-binding protein 2, 11 revealed that besides its increased expression in CRC tissue, it is specifically localized in cells at the bottom of normal colonic crypts, 11 reminiscent of the site where Lgr5 + intestinal stem cells were detected in the mouse intestine.…”

Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples

“…Moreover, oncodomain hotspots are able to identify genes that are known to be associated with particular cancer types where traditional methods may fail. For example the seven genes identified by oncodomain hotspots for COAD ( ERBB2 [109,110], EGFR [111,112], KIT [113,114], BRAF [115–117], RET [118,119], CDK4 [120–122], ALK [123–125], and MAPK1 [126–128]) are reported to have been involved with COAD. Interestingly, all of these genes were found to be mutated in only six or fewer patients with the exception of BRAF , which was mutated in 32 patients but was still not identified by MutSigCV or CHASM in S2 Fig.…”

CD117 expression in breast phyllodes tumors correlates with adverse pathologic parameters and reduced survival

“…On binding of KIT ligand at the extracellular domain, CD117 is activated and this initiates various downstream signaling pathways mediating cell survival, migration, and proliferation depending on the cell type. 1 Since the KIT gene was identified in the 1980s as a proto-oncogene, it has been implicated in various tumors including gastrointestinal stromal tumors (GISTs), 2 colon cancer, 3 and melanomas. 4 Phyllodes tumors are fibroepithelial neoplasms of the breast, characterized by a double-layered epithelial component arranged in leafy fronds formed by hypercellular spindle-cell stroma.…”