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Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer

BACKGROUND: Hamartin (TSC1) and tuberin (TSC2), encoded by the tuberous sclerosis complex (TSC) genes, form a tumor-suppressor heterodimer which is implicated in PI3K-Akt signaling and acts as a functional inhibitor of the mammalian target of rapamycin (mTOR). Dysregulation of mTOR has been assigned...

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Autores principales: Fuchs, Angela, König, Katharina, Heukamp, Lukas C, Fassunke, Jana, Kirfel, Jutta, Huss, Sebastian, Becker, Albert J, Büttner, Reinhard, Majores, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975884/
https://www.ncbi.nlm.nih.gov/pubmed/24593867
http://dx.doi.org/10.1186/1746-1596-9-48
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author Fuchs, Angela
König, Katharina
Heukamp, Lukas C
Fassunke, Jana
Kirfel, Jutta
Huss, Sebastian
Becker, Albert J
Büttner, Reinhard
Majores, Michael
author_facet Fuchs, Angela
König, Katharina
Heukamp, Lukas C
Fassunke, Jana
Kirfel, Jutta
Huss, Sebastian
Becker, Albert J
Büttner, Reinhard
Majores, Michael
author_sort Fuchs, Angela
collection PubMed
description BACKGROUND: Hamartin (TSC1) and tuberin (TSC2), encoded by the tuberous sclerosis complex (TSC) genes, form a tumor-suppressor heterodimer which is implicated in PI3K-Akt signaling and acts as a functional inhibitor of the mammalian target of rapamycin (mTOR). Dysregulation of mTOR has been assigned to carcinogenesis and thus may be involved in cancer development. We have addressed the role of hamartin, phospho-tuberin (p-TSC2) and phospho-mTOR (p-mTOR) in a series of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) samples. METHODS: We collected 166 NSCLC and SCLC samples for immunohistochemical studies and performed western blot analyses in NSCLC and SCLC cell lines as well as comparative analyses with EGFR phosphorylation and downstream effectors. RESULTS: In cell lines we found an inverse correlation between hamartin and p-mTOR expression. In surgical specimens cytoplasmic hamartin expression was observed in more than 50% of adenocarcinoma (AC) and squamous cell carcinoma (SCC) compared to 14% of SCLC. P-mTOR and p-TSC2 staining was found in a minority of cases. There was a significant correlation between p-EGFR Tyr-1068, p-EGFR Tyr-992 and hamartin, and also between p-mTOR and p-EGFR Tyr-1173 in AC. In SCC an inverse correlation between hamartin and p-EGFR Tyr-992 was detected. Phosphorylation of TSC2 was associated with expression of MAP-Kinase. Hamartin, p-TSC2 and p-mTOR expression was not dependant of the EGFR mutation status. Hamartin expression is associated with poorer survival in SCC and SCLC. CONCLUSIONS: Our findings confirm the inhibitory role of the tuberous sclerosis complex for mTOR activation in lung cancer cell lines. These results reveal hamartin expression in a substantial subset of NSCLC and SCLC specimens, which may be due to EGFR signaling but is not dependant on EGFR mutations. Our data provide evidence for a functional role of the tuberous sclerosis complex in lung cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9274845161175223.
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spelling pubmed-39758842014-04-05 Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer Fuchs, Angela König, Katharina Heukamp, Lukas C Fassunke, Jana Kirfel, Jutta Huss, Sebastian Becker, Albert J Büttner, Reinhard Majores, Michael Diagn Pathol Research BACKGROUND: Hamartin (TSC1) and tuberin (TSC2), encoded by the tuberous sclerosis complex (TSC) genes, form a tumor-suppressor heterodimer which is implicated in PI3K-Akt signaling and acts as a functional inhibitor of the mammalian target of rapamycin (mTOR). Dysregulation of mTOR has been assigned to carcinogenesis and thus may be involved in cancer development. We have addressed the role of hamartin, phospho-tuberin (p-TSC2) and phospho-mTOR (p-mTOR) in a series of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) samples. METHODS: We collected 166 NSCLC and SCLC samples for immunohistochemical studies and performed western blot analyses in NSCLC and SCLC cell lines as well as comparative analyses with EGFR phosphorylation and downstream effectors. RESULTS: In cell lines we found an inverse correlation between hamartin and p-mTOR expression. In surgical specimens cytoplasmic hamartin expression was observed in more than 50% of adenocarcinoma (AC) and squamous cell carcinoma (SCC) compared to 14% of SCLC. P-mTOR and p-TSC2 staining was found in a minority of cases. There was a significant correlation between p-EGFR Tyr-1068, p-EGFR Tyr-992 and hamartin, and also between p-mTOR and p-EGFR Tyr-1173 in AC. In SCC an inverse correlation between hamartin and p-EGFR Tyr-992 was detected. Phosphorylation of TSC2 was associated with expression of MAP-Kinase. Hamartin, p-TSC2 and p-mTOR expression was not dependant of the EGFR mutation status. Hamartin expression is associated with poorer survival in SCC and SCLC. CONCLUSIONS: Our findings confirm the inhibitory role of the tuberous sclerosis complex for mTOR activation in lung cancer cell lines. These results reveal hamartin expression in a substantial subset of NSCLC and SCLC specimens, which may be due to EGFR signaling but is not dependant on EGFR mutations. Our data provide evidence for a functional role of the tuberous sclerosis complex in lung cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9274845161175223. BioMed Central 2014-03-04 /pmc/articles/PMC3975884/ /pubmed/24593867 http://dx.doi.org/10.1186/1746-1596-9-48 Text en Copyright © 2014 Fuchs et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Fuchs, Angela
König, Katharina
Heukamp, Lukas C
Fassunke, Jana
Kirfel, Jutta
Huss, Sebastian
Becker, Albert J
Büttner, Reinhard
Majores, Michael
Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
title Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
title_full Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
title_fullStr Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
title_full_unstemmed Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
title_short Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
title_sort tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975884/
https://www.ncbi.nlm.nih.gov/pubmed/24593867
http://dx.doi.org/10.1186/1746-1596-9-48
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