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TGF-β-induced apoptosis in human thyrocytes is mediated by p27kip1 reduction and is overridden in neoplastic thyrocytes by NF-κB activation

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.

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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.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

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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.

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Correspondence to Clara V Alvarez.

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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

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