title: 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/β-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-κB 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-κB pathway. c-Kit suppression that resulted from L1-mediated signaling relied upon NF-κB, 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.
authors.affiliation: Authors' Affiliations: Departments of Molecular Cell Biology; and Physics and Complex Systems, The Weizmann Institute of Science Rehovot, Israel.
authors.forename: Nancy
authors.initials: N
authors.lastname: Gavert
authors.forename: Anna
authors.initials: A
authors.lastname: Shvab
authors.forename: Michal
authors.initials: M
authors.lastname: Sheffer
authors.forename: Amir
authors.initials: A
authors.lastname: Ben-Shmuel
authors.forename: Gal
authors.initials: G
authors.lastname: Haase
authors.forename: Eszter
authors.initials: E
authors.lastname: Bakos
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.forename: Avri
authors.initials: A
authors.lastname: Ben-Ze'ev
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D016328:NF-kappa B; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger; D051176:beta Catenin; D019009:Proto-Oncogene Proteins c-kit