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