title: Osteopontin facilitates ultraviolet B-induced squamous cell carcinoma development.
abstract: BACKGROUND
  Osteopontin (OPN) is a matricellular glycoprotein that is markedly expressed in cutaneous squamous cell carcinomas (cSCCs) and in actinic keratoses implicating its role in photocarcinogenesis.
  
  
  OBJECTIVE
  To determine whether OPN facilitates the development of cSCC and its function.
  
  
  METHODS
  cSCCs development was compared between wild-type (WT) and OPN-null mice subjected to UVB irradiation for 43 weeks. UVB-induced OPN expression was determined by Western blot, immunoprecipitation, ELISA, and semi-quantitative RT-PCR. Epidermal layer and TUNEL analyses assessed if OPN mediates UVB-induced epidermal hyperplasia or suppresses UVB-induced apoptosis of basal keratinocytes, respectively. In vitro experiments determined whether OPN enhances cell survival of UVB-induced apoptosis and its potential mechanisms. Immunohistochemical analyses of epidermis assessed the expression of CD44 and focal adhesion kinase (FAK), molecules that mediate OPN survival function.
  
  
  RESULTS
  Compared to female WT mice, OPN-null mice did not develop cSCCs. UVB irradiation stimulated OPN protein expression in the dorsal skin by 11h and remains high at 24-48h. OPN did not mediate UVB-induced epidermal hyperplasia; instead, it protected basal keratinocytes from undergoing apoptosis upon UVB exposure. Likewise, the addition of OPN suppressed UVB-induced OPN-null cSCC cell apoptosis, the activation of caspase-9 activity, and increased phosphorylation of FAK at Y397. Furthermore, the expression of CD44 and FAK in WT mice epidermis was greater than that of OPN-null mice prior to and during early acute UVB exposure.
  
  
  CONCLUSIONS
  These data support the hypothesis that chronic UVB-induced OPN expression protects the survival of initiated basal keratinocytes and, consequently, facilitates cSCC develop.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: plchang@uab.edu.
authors.forename: Pi-Ling
authors.initials: PL
authors.lastname: Chang
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Hsieh
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M Margaret
authors.initials: MM
authors.lastname: Juliana
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuruta
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Timares
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Elmets
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kang-Jey
authors.initials: KJ
authors.lastname: Ho
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000378:metabolism; D006965:Hyperplasia; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C506896:Spp1 protein, mouse; D053495:Osteopontin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse