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Nidogen 1 and Nuclear Protein 1: novel targets of ETV5 transcription factor involved in endometrial cancer invasion

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Abstract

Endometrial cancer is the most frequent malignancy of the female genital tract in western countries. Our group has previously characterized the upregulation of the transcription factor ETV5 in endometrial cancer with a specific and significant increase in those tumor stages associated with myometrial invasion. We have shown that ETV5 overexpression in Hec1A endometrial cancer cells induces epithelial to mesenchymal transition resulting in the acquisition of migratory and invasive capabilities. In the present work, we have identified Nidogen 1 (NID1) and Nuclear Protein 1 (NUPR1) as direct transcriptional targets of ETV5 in endometrial cancer cells. Inhibition of NID1 and NUPR1 in ETV5 overexpressing cells reduced cell migration and invasion in vitro and reduced tumor growth and dissemination in an orthotopic endometrial cancer model. Importantly, we confirmed a significant increase of NUPR1 and NID1 protein expression in the invasion front of the tumor compared to their paired superficial zone, concomitant to ETV5 overexpression. Altogether, we conclude that NID1 and NUPR1 are novel targets of ETV5 and are actively cooperating with ETV5 at the invasion front of the tumor in the acquisition of an invasive phenotype to jointly drive endometrial cancer invasion.

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Abbreviations

EMT:

Epithelial to Mesenchymal Transition

NID1:

Nidogen 1

NUPR1:

Nuclear Protein 1

H:

Hec1A cells

HG:

Hec1A cells transfected with the pEGFP-C2 vector alone

HGE:

Hec1A cells transfected with the pEGFP-hETV5

HGEshNID1:

HGE with downregulation of NID1

HGEshNUPR1:

HE with downregulation of NUPR1

HGEshC:

HE with shControl

ChIP:

Chromatin immunoprecipitation

RTqPCR:

Real time quantitative PCR

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Acknowledgments

We thank Marie-Noé Lavaut for technical assistance. This work has been supported by the Spanish Ministry of Science and Innovation (SAF2011-26548), the Spanish Ministry of Health (RD12/0036/0035), the AECC (Grupos Estables de Investigacion 2011—AECC- GCB 110333 REVE), the Fundació La Marató TV3 (2/C/2013), the CIRIT Generalitat de Catalunya (2014 SGR 1330) and the European Commission EU FP7-PEOPLE-2010-IRSES (PROTBIOFLUID-269285). La Ligue Contre le Cancer, INCa, Canceropole PACA, DGOS (labellisation SIRIC) and INSERM to JLI. EM is recipient of a fellowship from the Ministry of Education, Culture and Sport (Spain) (FPU12/05571).

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    Authors and Affiliations

    1. Biomedical Research Group in Ginaecology, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain

      Núria Pedrola, Laura Devis, Marta Llauradó, Irene Campoy, Elena Martinez-Garcia, Marta Garcia, Eva Colas, Jaume Reventós & Anna Ruiz

    2. Translational Laboratory/Medical Oncology Department, Complexo Hospitalario Universitario de Santiago/SERGAS, Santiago De Compostela, Spain

      Laura Muinelo-Romay, Lorena Alonso-Alconada & Miguel Abal

    3. Pathology Department, Hospital del Mar, Barcelona, Spain

      Francesc Alameda

    4. Gynecology Department, Hospital del Mar, Barcelona, Spain

      Gemma Mancebo & Ramon Carreras

    5. Pathology Department, Vall d’Hebron University Hospital, Barcelona, Spain

      Josep Castellví

    6. Gynecological Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain

      Sílvia Cabrera & Antonio Gil-Moreno

    7. Pathology Department, Hospital Arnau de Vilanova, Lleida, Spain

      Xavier Matias-Guiu & Eva Colas

    8. INSERM U1068, CRCM, Cell Stress, Marseille, France

      Juan L. Iovanna

    9. Basic Sciences Department, Universitat Internacional de Catalunya, Barcelona, Spain

      Jaume Reventós

    10. Genetics Department, UDIAT, Corporació Sanitaria Parc Taulí Institut Univesitari (UAB), Barcelona, Spain

      Anna Ruiz

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    1. Núria Pedrola
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    Corresponding authors

    Correspondence to Eva Colas or Anna Ruiz.

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    Jaume Reventós and Anna Ruiz have contributed equally to this work.

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    Pedrola, N., Devis, L., Llauradó, M. et al. Nidogen 1 and Nuclear Protein 1: novel targets of ETV5 transcription factor involved in endometrial cancer invasion. Clin Exp Metastasis 32, 467–478 (2015). https://doi.org/10.1007/s10585-015-9720-7

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