title: Prolonged overexpression of Wnt10b induces epidermal keratinocyte transformation through activating EGF pathway.
abstract: Wnt10b is a signaling protein regulating skin development and homeostasis, and the expression of Wnt10b is restricted to epidermal keratinocytes in embryonic and postnatal skin. Recent studies indicate an elevated expression of Wnt10b in skin tumors. However, how Wnt10b regulates skin tumorigenesis remains largely unknown. Here we report that continuous expression of Wnt10b mediates transformation of epidermal keratinocytes through activating genes involved in EGF/MAPK signaling pathways. We first established a prolonged Wnt10b overexpression system in JB6P- cells to represent the elevated Wnt10b expression level in skin keratinocytes. Through expression assays and observations under phase-contrast microscopy, prolonged expression of Wnt10b activated Wnt/β-catenin pathway and induced morphological changes of cells showing longer protrusions and multilayer growth, indicating early-stage cell transformation. Wnt10b also increased cellular proliferation and migration according to BrdU incorporation and cell mobility assays. Furthermore, multi-doses of AdWnt10b treatment to JB6P- cells induced colony formation, stronger invasive ability in transwell system, and anchorage-independent growth in agar gel. In molecular level, AdWnt10b treatment induced increased transcriptional expressions of Egf, downstream Mapk pathway factors, and MMPs. Administration of Wnt antagonist DKK1 blocked the tumor promotion process induced by Wnt10b. Taken together, these findings clearly demonstrate that Wnt10b promotes epidermal keratinocyte transformation through induced Egf pathway.
authors.affiliation: Department of Cell Biology, the Third Military Medical University, Chongqing, 400038, People's Republic of China, lmxgoodluck@163.com.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Lei
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Lai
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Bai
authors.forename: Weiming
authors.initials: W
authors.lastname: Qiu
authors.forename: Tian
authors.initials: T
authors.lastname: Yang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liao
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chuong
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Lian
authors.forename: Julia Li
authors.initials: JL
authors.lastname: Zhong
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000502:physiology*; D004817:Epidermis / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D020782:Matrix Metalloproteinases; D020928:Mitogen-Activated Protein Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D014410:Tumor Stem Cell Assay; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C491119:WNT10B protein, human; D051153:Wnt Proteins; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases; D001973:Bromodeoxyuridine