title: Tetraspanin CD151 plays a key role in skin squamous cell carcinoma.
abstract: Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared with other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3 (signal transducers and activators of transcription), a regulator of cell proliferation and apoptosis. CD151 also supports protein kinase C (PKC)α-α6β4 integrin association and PKC-dependent β4 S1424 phosphorylation, while regulating α6β4 distribution. CD151-PKCα effects on integrin β4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including 7,12-dimethylbenz[α]anthracene (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting epidermal growth factor receptor, PKC, Jak2/Tyk2 and STAT3. Hence, CD151 'co-targeting' may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151/laminin-binding integrin complexes.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors: Q
authors: Q
authors: Li
authors: X H
authors: XH
authors: Yang
authors: F
authors: F
authors: Xu
authors: C
authors: C
authors: Sharma
authors: H-X
authors: HX
authors: Wang
authors: K
authors: K
authors: Knoblich
authors: I
authors: I
authors: Rabinovitz
authors: S R
authors: SR
authors: Granter
authors: M E
authors: ME
authors: Hemler
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D060185:Tetraspanin 24 / Q000378:metabolism* / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C554715:CD151 protein, human; D002273:Carcinogens; C554716:Cd151 protein, mouse; D039161:Integrin alpha6beta4; D050796:STAT3 Transcription Factor; D060185:Tetraspanin 24; D015127:9,10-Dimethyl-1,2-benzanthracene; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha