High miR-100 expression is associated with aggressive features and modulates TORC1 complex activation in lung carcinoids
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Ida Rapa1, Arianna Votta1, Gaia Gatti1, Stefania Izzo1, Nicola Lo Buono2, Elisa Giorgio2, Simona Vatrano1, Francesca Napoli1, Aldo Scarpa3, Giorgio Scagliotti1, Mauro Papotti1 and Marco Volante1
1Department of Oncology at San Luigi Hospital, University of Turin, Turin, Italy
2Department of Medical Sciences, University of Turin, Turin, Italy
3ARC-NET Applied Research on Cancer Centre at Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
Marco Volante, email: [email protected]
Keywords: miRNAs; miR-100; lung carcinoids; rapamycin sensitivity; mTOR
Received: November 09, 2017 Accepted: May 14, 2018 Published: June 08, 2018
Purpose: Mammalian target of rapamycin (mTOR) is a promising therapeutic target in advanced lung carcinoid patients. However, the mechanisms of mTOR modulation and of responsiveness to mTOR inhibitors are largely unclear. Our aim was to analyze the expression and functional role of specific miRNAs in lung carcinoids as an alternative mechanism targeting mTOR pathway.
Experimental design: Seven miRNAs, selected by bioinformatic tools and literature search, were analyzed in 142 lung neuroendocrine neoplasms (92 carcinoids and a control group of 50 high grade neuroendocrine carcinomas), and compared with mTOR mRNA expression and clinical/pathological parameters. Tissue results were validated in vitro in two lung carcinoid cell lines by specific RNA interference and biological/pharmacological tests.
Results: Tissutal expression of five miRNAs (miR-99b, miR-100, miR-155, miR-193a-3p, miR-193a-5p) was inversely correlated with mTOR mRNA expression, supporting their role in the negative regulation of mTOR transcription. High expression of miR-100, miR-193a-3p and miR-193a-5p was associated with aggressive features and, for the former two, with shorter time to progression. In H727 and UMC11 lung carcinoid cells, miR-100 modulated mTOR RNA and TORC1 complex protein expression, positively promoted cell migration and negatively influenced cell proliferation. Moreover, miR-100 directly influenced responsiveness of H727 and UMC11 cells to rapamycin.
Conclusions: MiR-100 actively participates to the regulation of mTOR expression in lung carcinoids and represents a novel candidate prognostic biomarker for this tumor type; moreover, inhibition of its expression is associated to increased responsiveness to mTOR inhibitors and might represent a novel strategy to sensitize lung carcinoids to these target agents.
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