Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression

Donna M. Brennan-Crispi, Andrew M. Overmiller, Lukas Tamayo-Orrego, Molly R. Marous, Joya Sahu, Kathleen P. McGuinn, Felicia Cooper, Ioanna Ch Georgiou, Maxwell Frankfurter, Julio C. Salas-Alanis, Frédéric Charron, Sarah E. Millar, Mỹ G. Mahoney, Natalia A. Riobo-Del Galdo

Research output: Contribution to journalArticle

Abstract

Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ mice) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1–/– BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.

Original languageEnglish
Pages (from-to)300-307
Number of pages8
JournalJournal of Investigative Dermatology
Volume139
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

Fingerprint

Desmoglein 2
Basal Cell Nevus Syndrome
Basal Cell Carcinoma
Cells
Desmosomal Cadherins
Chemical activation
Phosphorylation
Hedgehogs
Tumors
Interleukin-6
Loss of Heterozygosity
Epidermis
Staining and Labeling
Cell Line

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Brennan-Crispi, D. M., Overmiller, A. M., Tamayo-Orrego, L., Marous, M. R., Sahu, J., McGuinn, K. P., ... Riobo-Del Galdo, N. A. (2019). Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression. Journal of Investigative Dermatology, 139(2), 300-307. https://doi.org/10.1016/j.jid.2018.09.009
Brennan-Crispi, Donna M. ; Overmiller, Andrew M. ; Tamayo-Orrego, Lukas ; Marous, Molly R. ; Sahu, Joya ; McGuinn, Kathleen P. ; Cooper, Felicia ; Georgiou, Ioanna Ch ; Frankfurter, Maxwell ; Salas-Alanis, Julio C. ; Charron, Frédéric ; Millar, Sarah E. ; Mahoney, Mỹ G. ; Riobo-Del Galdo, Natalia A. / Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression. In: Journal of Investigative Dermatology. 2019 ; Vol. 139, No. 2. pp. 300-307.
@article{549d109090984549917812df3cec4340,
title = "Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression",
abstract = "Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ mice) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1–/– BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.",
author = "Brennan-Crispi, {Donna M.} and Overmiller, {Andrew M.} and Lukas Tamayo-Orrego and Marous, {Molly R.} and Joya Sahu and McGuinn, {Kathleen P.} and Felicia Cooper and Georgiou, {Ioanna Ch} and Maxwell Frankfurter and Salas-Alanis, {Julio C.} and Fr{\'e}d{\'e}ric Charron and Millar, {Sarah E.} and Mahoney, {Mỹ G.} and {Riobo-Del Galdo}, {Natalia A.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1016/j.jid.2018.09.009",
language = "English",
volume = "139",
pages = "300--307",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "2",

}

Brennan-Crispi, DM, Overmiller, AM, Tamayo-Orrego, L, Marous, MR, Sahu, J, McGuinn, KP, Cooper, F, Georgiou, IC, Frankfurter, M, Salas-Alanis, JC, Charron, F, Millar, SE, Mahoney, MG & Riobo-Del Galdo, NA 2019, 'Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression', Journal of Investigative Dermatology, vol. 139, no. 2, pp. 300-307. https://doi.org/10.1016/j.jid.2018.09.009

Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression. / Brennan-Crispi, Donna M.; Overmiller, Andrew M.; Tamayo-Orrego, Lukas; Marous, Molly R.; Sahu, Joya; McGuinn, Kathleen P.; Cooper, Felicia; Georgiou, Ioanna Ch; Frankfurter, Maxwell; Salas-Alanis, Julio C.; Charron, Frédéric; Millar, Sarah E.; Mahoney, Mỹ G.; Riobo-Del Galdo, Natalia A.

In: Journal of Investigative Dermatology, Vol. 139, No. 2, 01.02.2019, p. 300-307.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression

AU - Brennan-Crispi, Donna M.

AU - Overmiller, Andrew M.

AU - Tamayo-Orrego, Lukas

AU - Marous, Molly R.

AU - Sahu, Joya

AU - McGuinn, Kathleen P.

AU - Cooper, Felicia

AU - Georgiou, Ioanna Ch

AU - Frankfurter, Maxwell

AU - Salas-Alanis, Julio C.

AU - Charron, Frédéric

AU - Millar, Sarah E.

AU - Mahoney, Mỹ G.

AU - Riobo-Del Galdo, Natalia A.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ mice) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1–/– BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.

AB - Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ mice) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1–/– BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.

UR - http://www.scopus.com/inward/record.url?scp=85058212321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058212321&partnerID=8YFLogxK

U2 - 10.1016/j.jid.2018.09.009

DO - 10.1016/j.jid.2018.09.009

M3 - Article

C2 - 30291846

AN - SCOPUS:85058212321

VL - 139

SP - 300

EP - 307

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 2

ER -