SCD5 restored expression favors differentiation and epithelial-mesenchymal reversion in advanced melanoma
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Rossella Puglisi1,*, Maria Bellenghi1,*, Giada Pontecorvi1, Alessandro Gulino3, Marina Petrini1, Federica Felicetti2, Lisabianca Bottero1, Gianfranco Mattia1,# and Alessandra Carè1,#
1Center for Gender-Specific Medicine, Oncology Unit-Istituto Superiore di Sanita’, Rome, Italy
2Department of Oncology and Molecular Medicine, Istituto Superiore di Sanita’, Rome, Italy
3Department of Health Science, Tumor Immunology Unit, Human Pathology Section, Palermo University School of Medicine, Palermo, Italy
*These authors contributed equally to this work
#These authors shared seniorship
Gianfranco Mattia, email: firstname.lastname@example.org
Keywords: melanoma; SCD5; miR-221&222; differentiation; mesenchymal-to-epithelial transition
Received: August 02, 2017 Accepted: January 02, 2018 Published: January 09, 2018
Our previous data supported a role for the Stearoyl-CoA desaturase (SCD5) in protection against malignancy, whereby it appears to functionally modify tumor stroma impairing tumor spread. SCD5 is significantly expressed in primary melanoma, but becomes barely detectable at tumor advanced stages. Looking for the regulatory mechanisms underlying SCD5 reduced expression during melanoma progression, we demonstrated a significantly lower stability of SCD5 protein as well as the direct targeting of SCD5 mRNA by the oncogenic miR-221&222 in metastatic cell lines. Moreover, our results indicated the existence of a negative feedback loop between SCD5 and miR-221&222, in good agreement with their opposite functions. Also, we showed how SCD5 re-expression and the direct supplementation of its main product oleic acid (OA) can drive advanced melanoma cell lines toward differentiation and reversion of the epithelial-mesenchymal (EMT)-like process, eventually inducing a less malignant phenotype. Indeed, SCD5 re-established the sensitivity to all-trans retinoic acid in A375M metastatic melanoma, associated with increased levels of Tyrosinase, melanin production and reduced proliferation. As evidenced by the correct modulation of some key transcription factors, SCD5 managed by favoring a partial mesenchymal-to-epithelial (MET) transition in in vitro studies. Interestingly, a more complete MET, including E-cadherin re-expression correctly localized at cell membranes, was obtained in in vivo xenograft models, thus indicating the requirement of direct contacts between tumor cells and the surrounding microenvironment as well as the presence of some essential factors for SCD5 complete function.
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