Universität zu Köln

Fuchs, Angela, Koenig, Katharina, Heukamp, Lukas C., Fassunke, Jana, Kirfel, Jutta, Huss, Sebastian, Becker, Albert J., Buettner, Reinhard and Majores, Michael (2014). Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer. Diagn. Pathol., 9. LONDON: BMC. ISSN 1746-1596

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fuchs, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenig, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fassunke, Jana UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Huss, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Albert J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Majores, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-443607
DOI:	10.1186/1746-1596-9-48
Journal or Publication Title:	Diagn. Pathol.
Volume:	9
Date:	2014
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1746-1596
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR RECEPTOR; MAMMALIAN TARGET; GENE; MTOR; MUTATIONS; ACTIVATION; EXPRESSION; RAPAMYCIN; ADENOCARCINOMA; CARCINOMAS Multiple languages Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44360