Oncotarget

Research Papers:

Deciphering the molecular basis of invasiveness in Sdhb-deficient cells

Céline Loriot, Mélanie Domingues, Adeline Berger, Mélanie Menara, Maëva Ruel, Aurélie Morin, Luis-Jaime Castro-Vega, Éric Letouzé, Cosimo Martinelli, Alexis-Pierre Bemelmans, Lionel Larue, Anne-Paule Gimenez-Roqueplo and Judith Favier _

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Oncotarget. 2015; 6:32955-32965. https://doi.org/10.18632/oncotarget.5106

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Abstract

Céline Loriot1,2, Mélanie Domingues2,3, Adeline Berger4,5, Mélanie Menara1,2, Maëva Ruel1,2, Aurélie Morin1,2, Luis-Jaime Castro-Vega1,2, Éric Letouzé6, Cosimo Martinelli1,2, Alexis-Pierre Bemelmans7,8, Lionel Larue3, Anne-Paule Gimenez-Roqueplo1,2,9,10, Judith Favier1,2

1INSERM, UMR970, Paris Cardiovascular Research Centre, F-75015 Paris, France

2Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France

3INSERM, U1021, CNRS UMR3347, Institut Curie, F-91405 Orsay, France

4INSERM, U968, Institut de la vision, F-75012 Paris, France

5Université Pierre et Marie Curie Paris 06, F-75005 Paris, France

6Programme Cartes d’Identité des Tumeurs, Ligue Nationale Contre Le Cancer, F-75013 Paris, France

7CEA, DSV, I2BM, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France

8CNRS, CEA URA 2210, F-92265 Fontenay-aux-Roses, France

9Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, France

10Rare Adrenal Cancer Network-Cortico Médullosurrénale Tumeurs Endocrines, Institut National du Cancer, F-75014 Paris, France

Correspondence to:

Judith Favier, e-mail: judith.favier@inserm.fr

Keywords: paraganglioma, SDHB, metastasis, EMT, keratin 19

Received: May 11, 2015     Accepted: September 25, 2015     Published: October 08, 2015

ABSTRACT

Metastatic pheochromocytomas and paragangliomas (PPGL) are malignant neuroendocrine tumors frequently associated with germline mutations in the SDHB gene. SDHB-mutated PPGL display a hypermethylator phenotype associated with hallmarks of epithelial-to-mesenchymal transition (EMT). In the present study, we report the characterization of a unique model of Sdhb knockout in mouse chromaffin cells. Sdhb deficient cells exhibit a metastatic phenotype as highlighted by increased individual cell migration (characterized by faster motility and increased persistence) as well as high invasive and adhesion abilities. This phenotype is associated with the modulation of Twist1, Twist2, Tcf3, Snai1, N-cadherin or Krt19 expression, reflecting an EMT-like reprogramming of cells. Krt19 is epigenetically silenced in Sdhb-deficient cells and re-expressed after treatment by the demethylating agent decitabine. Krt19 rescue by lentiviral transduction in Sdhb-deficient cells and Krt19 inhibition by RNA interference in wild-type cells were performed. Both studies revealed the involvement of KRT19 in the invasive phenotype by modulating collective and individual migration and cell/extra-cellular matrix adhesion properties. These findings underline the role of hypermethylation and EMT in the in vitro acquisition of metastatic properties, following SDHB loss of function.


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