Oncotarget

Research Papers:

MICAL2 is a novel human cancer gene controlling mesenchymal to epithelial transition involved in cancer growth and invasion

Sara Mariotti, Ivana Barravecchia, Carla Vindigni, Angela Pucci, Michele Balsamo, Rosaliana Libro, Vera Senchenko, Alexey Dmitriev, Emanuela Jacchetti, Marco Cecchini, Franco Roviello, Michele Lai, Vania Broccoli, Massimiliano Andreazzoli, Chiara M. Mazzanti and Debora Angeloni _

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Oncotarget. 2016; 7:1808-1825. https://doi.org/10.18632/oncotarget.6577

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Abstract

Sara Mariotti1,*, Ivana Barravecchia1,*, Carla Vindigni2, Angela Pucci3, Michele Balsamo1, Rosaliana Libro4, Vera Senchenko5, Alexey Dmitriev5, Emanuela Jacchetti6, Marco Cecchini6, Franco Roviello7, Michele Lai1,8, Vania Broccoli9, Massimiliano Andreazzoli10, Chiara M. Mazzanti8, Debora Angeloni1

1Institute of Life Sciences, Scuola Superiore Sant’Anna, 56124 Pisa, Italy

2U.O.C. Anatomia Patologica, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, 53100 Siena, Italy

3U.O.C. Anatomia Patologica, Azienda Ospedaliera Universitaria Pisana, 56100 Pisa, Italy

4BIOS Doctoral School in Life Sciences, University of Pisa, 56124 Pisa, Italy

5Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

6NEST, National Enterprise for nanoScience and nanoTechnology, CNR and Scuola Normale Superiore, 56127 Pisa, Italy

7Department of Human Pathology and Oncology, University of Siena, 53100 Siena, Italy

8Pisa Science Foundation, 56100 Pisa, Italy

9DIBIT H San Raffaele, 20132 Milan, Italy

10Department of Biology, University of Pisa, 56127 Pisa, Italy

*These authors contributed equally to this work

Correspondence to:

Debora Angeloni, e-mail: [email protected] and [email protected]

Keywords: MICAL2, kidney cancer, gastric cancer, epythelial to mesenchymal transition, metastasis

Received: April 24, 2015     Accepted: November 14, 2015     Published: December 12, 2015

ABSTRACT

The MICAL (Molecules Interacting with CasL) proteins catalyze actin oxidation-reduction reactions destabilizing F-actin in cytoskeletal dynamics.

Here we show for the first time that MICAL2 mRNA is significantly over-expressed in aggressive, poorly differentiated/undifferentiated, primary human epithelial cancers (gastric and renal). Immunohistochemistry showed MICAL2-positive cells on the cancer invasive front and in metastasizing cancer cells inside emboli, but not at sites of metastasis, suggesting MICAL2 expression was 'on' in a subpopulation of primary cancer cells seemingly detaching from the tissue of origin, enter emboli and travel to distant sites, and was turned 'off' upon homing at metastatic sites.

In vitro, MICAL2 knock-down resulted in mesenchymal to epithelial transition, reduction of viability, and loss of motility and invasion properties of human cancer cells. Moreover, expression of MICAL2 cDNA in MICAL2-depleted cells induced epithelial to mesenchymal transition.

Altogether our data indicate that MICAL2 over-expression is associated with cancer progression and metastatic disease. MICAL2 might be an important regulator of epithelial to mesenchymal transition and therefore a promising target for anti-metastatic therapy.


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