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Carcinogenesis Advance Access published online on February 17, 2005
Carcinogenesis, doi:10.1093/carcin/bgi050
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received August 10, 2004
Revised January 18, 2005
Accepted February 8, 2005

CANCER BIOLOGY

Downregulation of E-cadherin expression contributes to the loss of p27kip1-mediated mechanism of contact inhibition in thyroid anaplastic carcinomas

Maria Letizia Motti 1, Daniela Califano 2, Gustavo Baldassare 3, Angela Celetti 4, Francesco Merolla 1, Floriana Forzati 1, Maria Napolitano 2, Barbara Tavernise 5, Alfredo Fusco 1, and Giuseppe Viglietto 6*

1 Dipartimento di Biologia e Patologia Cellulare e Molecolare "L Califano" Facoltà di Medicina e Chirurgia, Università Federico II, via S. Pansini 5, 80131, Napoli, Italy
2 Istituto Nazionale Tumori, via M. Semmola, 80131, Napoli, Italy
3 Divisione di Oncologia Sperimentale 2, CRO National Cancer Institute, Via Pedemontana Occidentale 28, 33081 Aviano, Italy
4 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare "L.Califano" Facoltà di Medicina e Chirurgia, Università Federico II, via S. Pansini 5, 80131, Napoli, Italy
5 Laboratorio Oncologia Molecolare III, Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia, Università "Magna Graecia", Campus Universitario Germaneto - Viale Europa - 88100 Catanzaro, Italy
6 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare "L.Califano" Facoltà di Medicina e Chirurgia, Università Federico II, via S. Pansini 5, 80131, Napoli, Italy; Laboratorio Oncologia Molecolare III, Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia, Università "Magna Graecia", Campus Universitario Germaneto - Viale Europa - 88100 Catanzaro, Italy

* To whom correspondence should be addressed.
Giuseppe Viglietto, E-mail: viglietto{at}sun.ceos.na.cnr.it


  Abstract

In the present study, we have characterized several human thyroid cancer cell lines of different histotypes for their responsiveness to contact inhibition. We found that cells derived from differentiated carcinoma (TPC-1, WRO) arrest in G1 at confluence whereas cells derived from anaplastic carcinoma (ARO, FRO and FB1) continue to grow after reaching confluence. Furthermore, we provide experimental evidence that the axis E-cadherin/{beta}-catenin/p27Kip1 represents an integral part of the regulatory mechanism that controls proliferation at high cell density, whose disruption may play a key role in determining the clinical behaviour of thyroid cancer This conclusion derives from the finding that: (i) the expression of p27Kip1 is enhanced at high cell density only in cells responsive to contact inhibition (TPC-1, WRO), but not in contact-inhibition resistant cells (ARO, FRO or FB1 cells); (ii) the increase in p27Kip1 also resulted in increased levels of p27Kip1 bound to cyclin E-Cdk2 complex, a reduction in cyclin E-Cdk2 activity and dephosphorylation of the retinoblastoma protein; (iii) antisense inhibition of p27Kip1 up-regulation at high cell density in confluent sensitive cells completely prevents confluence-induced growth arrest; (iv) proper expression and/or membrane localization of E-cadherin is observed only in cells responsive to contact inhibition (TPC-1, NPA, WRO) but not in unresponsive cells (ARO, FRO or FB1); (v) disruption of E-cadherin-mediated cell-cell contacts at high cell density induced by an anti-E-cadherin neutralizing antibody, inhibits induction of p27kip1 and restores proliferation in contact-inhibited cells; (vi) re-expression of E-cadherin into cells unresponsive to contact inhibition (ARO, FB1) induces p27kip1 expression and growth arrest. In summary our data indicate that the altered response to contact inhibition exhibited by thyroid anaplastic cancer cells is due to the failure to up-regulate p27Kip1 in response to cell-cell interactions.

Keywords: Thyroid anaplastic cancer; Contact inhibition; p27kip1; E-cadherin.
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