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Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice
Squamous cell carcinoma is the second most common form of skin cancer with the incidence expected to double over the next 20 years. Inflammation is believed to be a critical component in skin cancer progression. Therefore, understanding genes involved in the regulation of inflammatory pathways is vi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574127/ https://www.ncbi.nlm.nih.gov/pubmed/23457529 http://dx.doi.org/10.1371/journal.pone.0056212 |
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author | DeCicco-Skinner, Kathleen L. Nolan, Sabrina J. Deshpande, Monika M. Trovato, Erika L. Dempsey, Taylor A. Wiest, Jonathan S. |
author_facet | DeCicco-Skinner, Kathleen L. Nolan, Sabrina J. Deshpande, Monika M. Trovato, Erika L. Dempsey, Taylor A. Wiest, Jonathan S. |
author_sort | DeCicco-Skinner, Kathleen L. |
collection | PubMed |
description | Squamous cell carcinoma is the second most common form of skin cancer with the incidence expected to double over the next 20 years. Inflammation is believed to be a critical component in skin cancer progression. Therefore, understanding genes involved in the regulation of inflammatory pathways is vital to the design of targeted therapies. Numerous studies show cyclooxygenases (COXs) play an essential role in inflammation-associated cancers. Tpl2 (MAP3K8) is a protein kinase in the MAP Kinase signal transduction cascade. Previous research using a two-stage skin carcinogenesis model revealed that Tpl2 (−/−) mice have significantly higher tumor incidence and inflammatory response than wild-type (WT) controls. The current study investigates whether cyclooxygenase-2 (COX-2) and COX-2- regulated prostaglandins and prostaglandin receptors drive the highly tumorigenic state of Tpl2(−/−) mice by investigating the relationship between Tpl2 and COX-2. Keratinocytes from newborn WT or Tpl2 (−/−) mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for various times over 24 hours. Western analysis revealed significant differences in COX-2 and COX-2 dependent prostanoids and prostanoid receptors. Additionally, in vivo experiments confirmed that COX-2 and COX-2 downstream factors were elevated in TPA-treated Tpl2(−/−) skin, as well as in papillomas from Tpl2 (−/−) mice. Use of the selective COX-2 inhibitor Celecoxib showed the increased tumorigenesis in the Tpl2(−/−) mice to primarily be mediated through COX-2. These experiments illustrate COX-2 induction in the absence of Tpl2 may be responsible for the increased tumorigenesis found in Tpl2 (−/−) mice. Defining the relationship between Tpl2 and COX-2 may lead to new ways to downregulate COX-2 through the modulation of Tpl2. |
format | Online Article Text |
id | pubmed-3574127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35741272013-03-01 Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice DeCicco-Skinner, Kathleen L. Nolan, Sabrina J. Deshpande, Monika M. Trovato, Erika L. Dempsey, Taylor A. Wiest, Jonathan S. PLoS One Research Article Squamous cell carcinoma is the second most common form of skin cancer with the incidence expected to double over the next 20 years. Inflammation is believed to be a critical component in skin cancer progression. Therefore, understanding genes involved in the regulation of inflammatory pathways is vital to the design of targeted therapies. Numerous studies show cyclooxygenases (COXs) play an essential role in inflammation-associated cancers. Tpl2 (MAP3K8) is a protein kinase in the MAP Kinase signal transduction cascade. Previous research using a two-stage skin carcinogenesis model revealed that Tpl2 (−/−) mice have significantly higher tumor incidence and inflammatory response than wild-type (WT) controls. The current study investigates whether cyclooxygenase-2 (COX-2) and COX-2- regulated prostaglandins and prostaglandin receptors drive the highly tumorigenic state of Tpl2(−/−) mice by investigating the relationship between Tpl2 and COX-2. Keratinocytes from newborn WT or Tpl2 (−/−) mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for various times over 24 hours. Western analysis revealed significant differences in COX-2 and COX-2 dependent prostanoids and prostanoid receptors. Additionally, in vivo experiments confirmed that COX-2 and COX-2 downstream factors were elevated in TPA-treated Tpl2(−/−) skin, as well as in papillomas from Tpl2 (−/−) mice. Use of the selective COX-2 inhibitor Celecoxib showed the increased tumorigenesis in the Tpl2(−/−) mice to primarily be mediated through COX-2. These experiments illustrate COX-2 induction in the absence of Tpl2 may be responsible for the increased tumorigenesis found in Tpl2 (−/−) mice. Defining the relationship between Tpl2 and COX-2 may lead to new ways to downregulate COX-2 through the modulation of Tpl2. Public Library of Science 2013-02-15 /pmc/articles/PMC3574127/ /pubmed/23457529 http://dx.doi.org/10.1371/journal.pone.0056212 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article DeCicco-Skinner, Kathleen L. Nolan, Sabrina J. Deshpande, Monika M. Trovato, Erika L. Dempsey, Taylor A. Wiest, Jonathan S. Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice |
title | Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice |
title_full | Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice |
title_fullStr | Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice |
title_full_unstemmed | Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice |
title_short | Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice |
title_sort | altered prostanoid signaling contributes to increased skin tumorigenesis in tpl2 knockout mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574127/ https://www.ncbi.nlm.nih.gov/pubmed/23457529 http://dx.doi.org/10.1371/journal.pone.0056212 |
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