Oncotarget

Research Papers:

FLNA is implicated in pulmonary neuroendocrine tumors aggressiveness and progression

Eleonora Vitali _, Ilena Boemi, Lorenzo Rosso, Valeria Cambiaghi, Pierluigi Novellis, Giovanna Mantovani, Anna Spada, Marco Alloisio, Giulia Veronesi, Stefano Ferrero and Andrea G. Lania

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Oncotarget. 2017; 8:77330-77340. https://doi.org/10.18632/oncotarget.20473

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Abstract

Eleonora Vitali1, Ilena Boemi1, Lorenzo Rosso2, Valeria Cambiaghi1, Pierluigi Novellis3, Giovanna Mantovani4, Anna Spada4, Marco Alloisio3,5, Giulia Veronesi3, Stefano Ferrero6 and Andrea G. Lania1,7

1Laboratory of Cellular and Molecular Endocrinology, IRCCS Clinical and Research Institute Humanitas, Milan, Italy

2Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

3Humanitas Clinical and Research Center, Thoracic Surgery Division, Milan, Italy

4Fondazione IRCCS Ospedale Maggiore Policlinico, Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

5Department of Biomedical Sciences, Humanitas University, Milan, Italy

6Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

7Endocrinology Unit, Department of Biomedical Sciences, Humanitas University and Humanitas Research Hospital, Milan, Italy

Correspondence to:

Eleonora Vitali, email: [email protected]

Keywords: pulmonary neuroendocrine tumors, Filamin A, Rap1 GTPase, cell migration, cell proliferation

Received: March 29, 2017     Accepted: July 25, 2017     Published: August 24, 2017

ABSTRACT

Pulmonary neuroendocrine tumors (PNTs) comprise different neoplasms, ranging from low grade carcinoids to the highly malignant small cell lung cancers. Several studies identified the cytoskeleton protein Filamin A (FLNA) as determinant in cancer progression and metastasis, but the role of FLNA in PNT aggressiveness and progression is still unknown.

We evaluated FLNA expression in PNTs with different grade of differentiation, the role of FLNA in cell proliferation, colony formation, angiogenesis, cell adhesion and migration in PNT cell line (H727 cells) and primary cultures and the possible interaction between FLNA and Rap1-GTPase. FLNA is highly expressed in PNTs with high malignant grade. FLNA silencing reduces cyclin D1 levels (-51±5, p<0.001) and cell proliferation in PNT cells (-37±4, p<0.05), colony formation and VEGF expression (-39±9%, p<0.01) in H727 cells.

FLNA and Rap1 co-localize in cellular protrusions and FLNA silencing up-regulates Rap1 expression (+73±18%, p<0.01).

Rap1 silencing prevents cell adhesion increase (+43%±18%, p<0.01) and cell migration decrease (-56±7%, p<0.01) induced by FLNA silencing, without affecting cell proliferation reduction. In conclusion, FLNA is implicated in PNT progression, in part through Rap1, thus providing a potential diagnostic and therapeutic target.


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