Abstract
Millions of people worldwide suffer goiter, a proliferative disease of the follicular cells of the thyroid that may become neoplastic. Thyroid neoplasms have low proliferative index, low apoptotic index and a high incidence of metastasis. TGF-β is overexpressed in thyroid follicular tumor cells. To investigate the role of TGF-β in thyroid tumor progression, we established cultures of human thyrocytes from different proliferative pathologies (Grave's disease, multinodular goiter, follicular adenoma, papillary carcinoma), lymph node metastasis, and a normal thyroid sample. All cultures maintained the thyrocyte phenotype. TGF-β induced cell-cycle arrest in all cultures, in contrast with results reported for other epithelial tumors. In deprived medium, TGF-β induced apoptosis in normal thyrocyte cultures and all neoplastic cultures except the metastatic cultures. This apoptosis was mediated by a reduction in p27kip1 levels, inducing cell-cycle initiation. Antisense p27 expression induced apoptosis in the absence of TGF-β. By contrast, in cells in which p27 was overexpressed, TGF-β had a survival effect. In growth medium, a net survival effect occurs in neoplastic thyrocytes only, not normal thyrocytes, due to activation of the NF-κB survival program. Together, these findings suggest that (a) thyroid neoplasms are due to reduced apoptosis, not increased division, in line with the low proliferative index of these pathologies, and (b) TGF-β induces apoptosis in normal thyrocytes via p27 reduction, but that in neoplastic thyrocytes this effect is overridden by activation of the NF-κB program.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- NT:
-
normal thyroid
- GD:
-
Grave's disease
- MNG:
-
multinodular goiter
- FA:
-
follicular adenoma
- PC:
-
papillary carcinoma
- M:
-
ganglion metastasis
- CKI:
-
cyclin-dependent kinase inhibitor
References
Achenbach TV, Muller R and Slater EP . (2000). Clin. Cancer Res., 6, 3006–3014.
Asa SL and Ezzat S . (2001). The Cancer Handbook. Alison MR (ed). Nature Publishing Group, Macmillan: New York, Chapter 9.
Asmis LM, Kaempf J, Von Gruenigen C, Kimura ET, Wagner HE and Studer H . (1996). J. Endocrinol., 149, 485–496.
Blaydes JP and Wynford-Thomas D . (1996). Int. J. Cancer, 65, 525–530.
Barkett M and Gilmore DT . (1999). Oncogene, 18, 6910–6924.
Carneiro C, Alvarez CV, Zalvide J, Vidal A and Dominguez F . (1998). Oncogene, 16, 1455–1465.
Chan JKC . (2000). Diagnostic Histopathology of Tumors. Fletcher CDM (ed). Churchill Livingstone: New York, 2nd edn, pp. 959–1056.
Chen C, Kang RY, Siegel PM and Massagué J . (2002). Cell, 110, 19–32.
D'Agnano I, Valentini A, Fornari C, Bucci B, Starace G, Felsani A and Citro G . (2001). Oncogene, 20, 2814–2825.
de Martin R, Vanhove B, Cheng Q, Hofer E, Csizmadia V, Winkler H and Bach FH . (1993). EMBO J., 12, 2773–2779.
Derwahl M and Studer H . (2000). Bailliere's Best Pract. Res. Clin. Endocrinol. Metab., 14, 577–600.
Derwahl M and Studer H . (2002). Trends Endocrinol Metab., 13, 23–28.
Derynck R, Akhurst RJ and Balmain A . (2001). Nat. Genet., 29, 117–129.
Eymin B, Haugg M, Droin N, Sordet O, Dimanche-Boitrel MT and Solary E . (1999). Oncogene, 18, 1411–1418.
Freitas JE . (2000). Semin. Nucl. Med., 30, 88–97.
Goretzki PE, Simon D, Dotzenrath C, Schulte KM and Roher HD . (2000). World J. Surg., 24, 913–922.
Grubeck-Loebenstein B, Buchan G, Sadeghi R, Kissonerghis M, Londei M, Turner M, Pirich K, Roka R, Niederle B, Kassal H, Waldhäusl W and Feldmann M . (1989). J. Clin. Invest., 83, 764–770.
Harvey KJ, Lukovic D and Ucker DS . (2000). J. Cell Biol., 148, 59–72.
Hiromura K, Pippin JW, Fero ML, Roberts JM and Shankland SJ . (1999). J. Clin. Invest., 103, 597–604.
Jang CW, Chen CH, Chen CC, Chen JY, Su YH and Chen RH . (2002). Nat. Cell Biol., 4, 51–58.
Kammori M, Nakamura K, Kawahara M, Mimura Y, Kaminishi M and Takubo K . (2002). Exp. Gerontol., 37, 513–521.
Katoh R, Bray CE, Suzuki K, Komiyama A, Hemmi A, Kawaoi A, Oyama T, Sugai T and Sasou S . (1995). Hum. Pathol., 26, 139–146.
Khoo MLC, Beasley NJP, Ezzat S, Freeman JL and Asa SL . (2002). J. Clin. Endocrinol. Metab., 87, 1814–1818.
Kimura ET, Kopp P, Zbaeren J, Asmis LM, Ruchti C, Maciel RM and Studer H . (1999). Thyroid, 9, 119–125.
Ladha MH, Lee KY, Upton TM, Reed MF and Ewen ME . (1998). Mol. Cell. Biol., 18, 6605–6615.
Lazzereschi D, Ranieri A, Mincione G, Taccogna S, Nardi F and Colletta G . (1997). Cancer Res., 57, 2071–2076.
Lee TG, Myers RT, Marshall RB, Bond G and Kardon B . (1985). Hum. Pathol., 16, 1042–1046.
Levy O, De la Vieja A, Ginter CS, Riedel C, Dai G and Carrasco N . (1998). J. Biol. Chem., 273, 22657–22663.
Lin YZ, Yao SY, Veach RA, Torgerson TR and Hawiger J . (1995). J. Biol. Chem., 270, 14255–14258.
Loubat A, Rochet N, Turchi L, Rezzonico R, Far DF, Auberger P, Rossi B and Ponzio G . (1999). Oncogene, 18, 3324–3333.
Matthews P, Jones CJ, Skinner J, Haughton M, de Micco C and Wynford-Thomas D . (2001). J. Pathol., 194, 183–193.
Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H and Koff A . (1997). J. Biol. Chem., 272, 7093–7098.
Moore D, Ohene-Fianko D, Garcia B and Chakrabarti S . (1998). Histopathology, 32, 35–42.
Mortensen JD, Woolner LB and Bennett WA . (1955). J. Clin. Endocrinol. Metab., 15, 1270–1280.
Mothersill C . (1995). Methods Mol. Biol., 43, 25–31.
Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V and Arteaga CL . (2002). J. Clin. Invest., 109, 1551–1559.
Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z and Matsumoto K . (1999). Nature, 398, 252–256.
Perlman R, Schiemann WP, Brooks MW, Lodish HF and Weinberg RA . (2001). Nat. Cell Biol., 3, 708–714.
Rivard N, L'Allemain G, Bartek J and Pouyssegur J . (1996). J. Biol. Chem., 271, 18337–18341.
Sgambato A, Cittadini A, Faraglia B and Bernard-Weinstein I . (2000). J. Cell. Physiol., 183, 18–27.
Soares P and Sobrinho-Simoes M . (1994). Cancer, 73, 2879–2880.
Sreelekha TT, Pradeep VM, Vijayalakshmi K, Belthazar A, Chellam VG, Nair MB and Pillai MR . (2000). Thyroid, 10, 117–122.
Urbano AG, Suarez-Penaranda JM, Dieguez C and Alvarez CV . (2000). Endocrinology, 141, 1893–1896.
Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, Merlino G and Wakefield LM . (2002). J. Clin. Invest., 109, 1533–1536.
Yoshida A, Nakamura Y, Imada T, Asaga T, Shimizu A and Harada M . (1999). Surg. Today, 29, 204–208.
Acknowledgements
We thank Nancy Carrasco for the anti-NIS antibody; Anxo Vidal for the FLAG-p27 construct and for critically reading the manuscript; Mohammed Ladha and Mark Ewen for the AS-p27 construct and suggestions; Jun Ninomiya-Tsui and Kuni Matsumoto for the kB-RE construct; Ana Aranda, Juan Zalvide, Bernat Baeza and Pura Muñoz for plasmids, protocols and suggestions; Lourdes Loidi and Luis Lima for the laboratory facilities and Carlos Diéguez and Miguel A Japón for reviewing the manuscript. This work was supported by FIS and DIGICYT grants to CVA and a XUGA grant to FB.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bravo, S., Pampín, S., Cameselle-Teijeiro, J. et al. TGF-β-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-κB activation. Oncogene 22, 7819–7830 (2003). https://doi.org/10.1038/sj.onc.1207029
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207029
Keywords
This article is cited by
-
Acceleration of BRAFV600E-induced thyroid carcinogenesis by TGFβ signal deficiency in mice
Endocrine (2020)
-
Rewiring of the apoptotic TGF-β-SMAD/NFκB pathway through an oncogenic function of p27 in human papillary thyroid cancer
Oncogene (2017)
-
LDOC1 inhibits proliferation and promotes apoptosis by repressing NF-κB activation in papillary thyroid carcinoma
Journal of Experimental & Clinical Cancer Research (2015)
-
New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization
Oncogene (2012)
-
Direct promoter induction of p19Arf by Pit-1 explains the dependence receptor RET/Pit-1/p53-induced apoptosis in the pituitary somatotroph cells
Oncogene (2012)