J Med Genet

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS REGISTER


[Advanced]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Add article to my folders
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vasko, V
Right arrow Articles by Ringel, M D
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vasko, V
Right arrow Articles by Ringel, M D
Journal of Medical Genetics 2004;41:161-170
© 2004 BMJ Publishing Group Ltd

ORIGINAL ARTICLE

Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer

V Vasko1,2,3,4, M Saji1,2, E Hardy2, M Kruhlak5, A Larin3, V Savchenko3, M Miyakawa6, O Isozaki6, H Murakami6, T Tsushima6, K D Burman2, C De Micco4, M D Ringel1,2

1 Ohio State University School of Medicine and Arthur G. James Cancer Center, Columbus, OH, USA
2 MedStar Research Institute/Washington Hospital Center, Washington DC, USA
3 Center for Endocrine Surgery, Kiev, Ukraine
4 INSERM U555, Mediterranean University, Marseilles, France
5 National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
6 Tokyo Women’s Medical University, Tokyo, Japan

Correspondence to:
Dr M D Ringel
Associate Professor of Medicine, Divisions of Endocrinology and Oncology, 455D McCambell Hall, 1581 Dodd Drive, Columbus, OH 43210, USA; ringel-1{at}medctr.osu.edu] Introduction: Akt activation is involved in the pathogenesis of inherited thyroid cancer in Cowden’s syndrome and in sporadic thyroid cancers. In cell culture, Akt regulates thyroid cell growth and survival; but recent data suggest that Akt also regulates cell motility in non-thyroid cell lines. We therefore sought to evaluate the role of Akt in thyroid cancer progression.

Methods: We evaluated 46 thyroid cancer, 20 thyroid follicular adenoma, and adjacent normal tissues samples by immunohistochemistry for activated Akt (pAkt), Akt 1, 2, and 3, and p27 expression. Immunoblots were performed in 14 samples.

Results: Akt activation was identified in 10/10 follicular cancers, 26/26 papillary cancers, and 2/10 follicular variant of papillary cancers, but in only 4/66 normal tissue samples and 2/10 typical benign follicular adenomas. Immunoactive pAkt was greatest in regions of capsular invasion; and was localised to the nucleus in follicular cancers and the cytoplasm in papillary cancers, except for invasive regions of papillary cancers where it localised to both compartments. Immunoactive Akt 1, but not Akt 2 or Akt 3, correlated with pAkt localisation, and nuclear pAkt was associated with cytoplasmic expression of p27. In vitro studies using human thyroid cancer cells demonstrated that nuclear translocation of Akt 1 and pAkt were associated with cytoplasmic p27 and cell invasion and migration. Cell migration and the localisation of Akt 1, pAkt, and p27 were inhibited by PI3 kinase, but not MEK inhibition.

Discussion: These data suggest an important role for nuclear activation of Akt 1 in thyroid cancer progression.

Keywords: Metastases; vascular invasion; Ret oncogene; Ras oncogene; cell migration

Abbreviations: AA, atypical adenoma; FA, follicular adenoma; FC, follicular carcinoma; FVPC, follicular variant of papillary carcinomas; IGF, insulin-like growth factor; MMP, matrix metalloproteinase; PC, papillary carcinomas




This article has been cited by other articles:


Home page
 Endocr Relat CancerHome page
S. Grozinsky-Glasberg, I. Shimon, M. Korbonits, and A. B Grossman
Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms
Endocr. Relat. Cancer, September 1, 2008; 15(3): 701 - 720.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. Lu, M. C. Willingham, F. Furuya, and S.-y. Cheng
Activation of Phosphatidylinositol 3-Kinase Signaling Promotes Aberrant Pituitary Growth in a Mouse Model of Thyroid-Stimulating Hormone-Secreting Pituitary Tumors
Endocrinology, July 1, 2008; 149(7): 3339 - 3345.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. J. Robinson-White, H.-P. Hsiao, W. W. Leitner, E. Greene, A. Bauer, N. L. Krett, M. Nesterova, and C. A. Stratakis
Protein Kinase A-Independent Inhibition of Proliferation and Induction of Apoptosis in Human Thyroid Cancer Cells by 8-Cl-Adenosine
J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1020 - 1029.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Yeager, C. Brewer, K. Q. Cai, X.-X. Xu, and A. Di Cristofano
Mammalian Target of Rapamycin Is the Key Effector of Phosphatidylinositol-3-OH Initiated Proliferative Signals in the Thyroid Follicular Epithelium
Cancer Res., January 15, 2008; 68(2): 444 - 449.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
G. Riesco-Eizaguirre and P. Santisteban
New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy
Endocr. Relat. Cancer, December 1, 2007; 14(4): 957 - 977.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
F. Furuya, C. Lu, M. C. Willingham, and S.-y. Cheng
Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer
Carcinogenesis, December 1, 2007; 28(12): 2451 - 2458.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
L. M. Porchia, M. Guerra, Y.-C. Wang, Y. Zhang, A. V. Espinosa, M. Shinohara, S. K. Kulp, L. S. Kirschner, M. Saji, C.-S. Chen, et al.
2-Amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} Acetamide (OSU-03012), a Celecoxib Derivative, Directly Targets p21-Activated Kinase
Mol. Pharmacol., November 1, 2007; 72(5): 1124 - 1131.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
F. Furuya, C. J. Guigon, L. Zhao, C. Lu, J. A. Hanover, and S.-y. Cheng
Nuclear Receptor Corepressor Is a Novel Regulator of Phosphatidylinositol 3-Kinase Signaling
Mol. Cell. Biol., September 1, 2007; 27(17): 6116 - 6126.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
G. Chiappetta, C. De Marco, A. Quintiero, D. Califano, S. Gherardi, D. Malanga, M. Scrima, C. Montero-Conde, L. Cito, M. Monaco, et al.
Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer
Endocr. Relat. Cancer, June 1, 2007; 14(2): 405 - 420.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. Kondo, L. Zheng, W. Liu, J. Kurebayashi, S. L. Asa, and S. Ezzat
Epigenetically Controlled Fibroblast Growth Factor Receptor 2 Signaling Imposes on the RAS/BRAF/Mitogen-Activated Protein Kinase Pathway to Modulate Thyroid Cancer Progression
Cancer Res., June 1, 2007; 67(11): 5461 - 5470.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Siragusa, M. Zerilli, F. Iovino, M. G. Francipane, Y. Lombardo, L. Ricci-Vitiani, G. Di Gesu, M. Todaro, R. De Maria, and G. Stassi
MUC1 Oncoprotein Promotes Refractoriness to Chemotherapy in Thyroid Cancer Cells
Cancer Res., June 1, 2007; 67(11): 5522 - 5530.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
P. Hou, D. Liu, Y. Shan, S. Hu, K. Studeman, S. Condouris, Y. Wang, A. Trink, A. K. El-Naggar, G. Tallini, et al.
Genetic Alterations and Their Relationship in the Phosphatidylinositol 3-Kinase/Akt Pathway in Thyroid Cancer
Clin. Cancer Res., February 15, 2007; 13(4): 1161 - 1170.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. Yeager, A. Klein-Szanto, S. Kimura, and A. Di Cristofano
Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis
Cancer Res., February 1, 2007; 67(3): 959 - 966.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
I. Plante, M. Charbonneau, and D. G. Cyr
Activation of the integrin-linked kinase pathway downregulates hepatic connexin32 via nuclear Akt
Carcinogenesis, September 1, 2006; 27(9): 1923 - 1929.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. W. B. de Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra
RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors
Endocr. Rev., August 1, 2006; 27(5): 535 - 560.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Mesa Jr., M. Mirza, N. Mitsutake, M. Sartor, M. Medvedovic, C. Tomlinson, J. A Knauf, G. F. Weber, and J. A. Fagin
Conditional Activation of RET/PTC3 and BRAFV600E in Thyroid Cells Is Associated with Gene Expression Profiles that Predict a Preferential Role of BRAF in Extracellular Matrix Remodeling.
Cancer Res., July 1, 2006; 66(13): 6521 - 6529.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
K. Nadra, S. I. Anghel, E. Joye, N. S. Tan, S. Basu-Modak, D. Trono, W. Wahli, and B. Desvergne
Differentiation of Trophoblast Giant Cells and Their Metabolic Functions Are Dependent on Peroxisome Proliferator-Activated Receptor {beta}/{delta}
Mol. Cell. Biol., April 15, 2006; 26(8): 3266 - 3281.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. Furuya, J. A. Hanover, and S.-y. Cheng
Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor
PNAS, February 7, 2006; 103(6): 1780 - 1785.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
G. Garcia-Rostan, A. M. Costa, I. Pereira-Castro, G. Salvatore, R. Hernandez, M. J.A. Hermsem, A. Herrero, A. Fusco, J. Cameselle-Teijeiro, and M. Santoro
Mutation of the PIK3CA Gene in Anaplastic Thyroid Cancer
Cancer Res., November 15, 2005; 65(22): 10199 - 10207.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
V. Guarino, P. Faviana, G. Salvatore, M. D. Castellone, A. M. Cirafici, V. De Falco, A. Celetti, R. Giannini, F. Basolo, R. M. Melillo, et al.
Osteopontin Is Overexpressed in Human Papillary Thyroid Carcinomas and Enhances Thyroid Carcinoma Cell Invasiveness
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5270 - 5278.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
T. Guida, G. Salvatore, P. Faviana, R. Giannini, G. Garcia-Rostan, L. Provitera, F. Basolo, A. Fusco, F. Carlomagno, and M. Santoro
Mitogenic Effects of the Up-Regulation of Minichromosome Maintenance Proteins in Anaplastic Thyroid Carcinoma
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4703 - 4709.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Wu, E. Mambo, Z. Guo, S. Hu, X. Huang, S. M. Gollin, B. Trink, P. W. Ladenson, D. Sidransky, and M. Xing
Uncommon Mutation, but Common Amplifications, of the PIK3CA Gene in Thyroid Tumors
J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4688 - 4693.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. N. Younes, O. G. Yigitbasi, Y. W. Park, S.-J. Kim, S. A. Jasser, V. S. Hawthorne, Y. D. Yazici, M. Mandal, B. N. Bekele, C. D. Bucana, et al.
Antivascular Therapy of Human Follicular Thyroid Cancer Experimental Bone Metastasis by Blockade of Epidermal Growth Factor Receptor and Vascular Growth Factor Receptor Phosphorylation
Cancer Res., June 1, 2005; 65(11): 4716 - 4727.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Weber, L. Shen, M. A. Aldred, C. D. Morrison, A. Frilling, M. Saji, F. Schuppert, C. E. Broelsch, M. D. Ringel, and C. Eng
Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasia Based on a Three-Gene Combination
J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2512 - 2521.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
J Di Cristofaro, V Vasko, V Savchenko, S Cherenko, A Larin, M D Ringel, M Saji, M Marcy, J F Henry, P Carayon, et al.
ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients
Endocr. Relat. Cancer, March 1, 2005; 12(1): 173 - 183.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. L. Motti, D. Califano, G. Troncone, C. De Marco, I. Migliaccio, E. Palmieri, L. Pezzullo, L. Palombini, A. Fusco, and G. Viglietto
Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway: Regulation of p27kip1 Expression and Localization
Am. J. Pathol., March 1, 2005; 166(3): 737 - 749.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
F. Cappuzzo, E. Magrini, G. L. Ceresoli, S. Bartolini, E. Rossi, V. Ludovini, V. Gregorc, C. Ligorio, A. Cancellieri, S. Damiani, et al.
Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non-Small-Cell Lung Cancer
J Natl Cancer Inst, August 4, 2004; 96(15): 1133 - 1141.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS REGISTER
Terms and conditions relating to subscriptions purchased online  ¦  Website terms and conditions  ¦  Privacy policy
Copyright © 2004 by the BMJ Publishing Group Ltd.