Occludin is involved in adhesion, apoptosis, differentiation and Ca2+-homeostasis of human keratinocytes: implications for tumorigenesis
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Occludin is involved in adhesion, apoptosis, differentiation and Ca2+-homeostasis of human keratinocytes: implications for tumorigenesis. / Rachow, Susanne; Zorn-Kruppa, Michaela; Ohnemus, Ulrich; Kirschner, Nina; Vidal Y Sy, Sabine; von den Driesch, Peter; Börnchen, Christian; Eberle, Jürgen; Mildner, Michael; Vettorazzi, Eik; Rosenthal, Rita; Moll, Ingrid; Brandner, Johanna M.
in: PLOS ONE, Jahrgang 8, Nr. 2, 01.01.2013, S. e55116.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Occludin is involved in adhesion, apoptosis, differentiation and Ca2+-homeostasis of human keratinocytes: implications for tumorigenesis
AU - Rachow, Susanne
AU - Zorn-Kruppa, Michaela
AU - Ohnemus, Ulrich
AU - Kirschner, Nina
AU - Vidal Y Sy, Sabine
AU - von den Driesch, Peter
AU - Börnchen, Christian
AU - Eberle, Jürgen
AU - Mildner, Michael
AU - Vettorazzi, Eik
AU - Rosenthal, Rita
AU - Moll, Ingrid
AU - Brandner, Johanna M
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Tight junction (TJ) proteins are involved in a number of cellular functions, including paracellular barrier formation, cell polarization, differentiation, and proliferation. Altered expression of TJ proteins was reported in various epithelial tumors. Here, we used tissue samples of human cutaneous squamous cell carcinoma (SCC), its precursor tumors, as well as sun-exposed and non-sun-exposed skin as a model system to investigate TJ protein alteration at various stages of tumorigenesis. We identified that a broader localization of zonula occludens protein (ZO)-1 and claudin-4 (Cldn-4) as well as downregulation of Cldn-1 in deeper epidermal layers is a frequent event in all the tumor entities as well as in sun-exposed skin, suggesting that these changes result from chronic UV irradiation. In contrast, SCC could be distinguished from the precursor tumors and sun-exposed skin by a frequent complete loss of occludin (Ocln). To elucidate the impact of down-regulation of Ocln, we performed Ocln siRNA experiments in human keratinocytes and uncovered that Ocln downregulation results in decreased epithelial cell-cell adhesion and reduced susceptibility to apoptosis induction by UVB or TNF-related apoptosis-inducing ligand (TRAIL), cellular characteristics for tumorigenesis. Furthermore, an influence on epidermal differentiation was observed, while there was no change of E-cadherin and vimentin, markers for epithelial-mesenchymal transition. Ocln knock-down altered Ca(2+)-homeostasis which may contribute to alterations of cell-cell adhesion and differentiation. As downregulation of Ocln is also seen in SCC derived from other tissues, as well as in other carcinomas, we suggest this as a common principle in tumor pathogenesis, which may be used as a target for therapeutic intervention.
AB - Tight junction (TJ) proteins are involved in a number of cellular functions, including paracellular barrier formation, cell polarization, differentiation, and proliferation. Altered expression of TJ proteins was reported in various epithelial tumors. Here, we used tissue samples of human cutaneous squamous cell carcinoma (SCC), its precursor tumors, as well as sun-exposed and non-sun-exposed skin as a model system to investigate TJ protein alteration at various stages of tumorigenesis. We identified that a broader localization of zonula occludens protein (ZO)-1 and claudin-4 (Cldn-4) as well as downregulation of Cldn-1 in deeper epidermal layers is a frequent event in all the tumor entities as well as in sun-exposed skin, suggesting that these changes result from chronic UV irradiation. In contrast, SCC could be distinguished from the precursor tumors and sun-exposed skin by a frequent complete loss of occludin (Ocln). To elucidate the impact of down-regulation of Ocln, we performed Ocln siRNA experiments in human keratinocytes and uncovered that Ocln downregulation results in decreased epithelial cell-cell adhesion and reduced susceptibility to apoptosis induction by UVB or TNF-related apoptosis-inducing ligand (TRAIL), cellular characteristics for tumorigenesis. Furthermore, an influence on epidermal differentiation was observed, while there was no change of E-cadherin and vimentin, markers for epithelial-mesenchymal transition. Ocln knock-down altered Ca(2+)-homeostasis which may contribute to alterations of cell-cell adhesion and differentiation. As downregulation of Ocln is also seen in SCC derived from other tissues, as well as in other carcinomas, we suggest this as a common principle in tumor pathogenesis, which may be used as a target for therapeutic intervention.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Calcium
KW - Carcinoma, Squamous Cell
KW - Cell Adhesion
KW - Cell Differentiation
KW - Cell Transformation, Neoplastic
KW - Claudins
KW - Epithelial-Mesenchymal Transition
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Homeostasis
KW - Humans
KW - Keratinocytes
KW - Male
KW - Middle Aged
KW - Neoplasm Grading
KW - Occludin
KW - RNA, Small Interfering
KW - Signal Transduction
KW - Skin Neoplasms
KW - Tight Junctions
KW - Young Adult
KW - Zonula Occludens-1 Protein
U2 - 10.1371/journal.pone.0055116
DO - 10.1371/journal.pone.0055116
M3 - SCORING: Journal article
C2 - 23390516
VL - 8
SP - e55116
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 2
ER -
