Abstract
PurposeMammalian 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 designSeven 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.ResultsTissutal 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.ConclusionsMiR-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.
Highlights
The mammalian target of rapamycin is a downstream effector of PI3K/AKT kinases and acts through two complexes, mTORC1 and mTORC2
MiR-100 actively participates to the regulation of Mammalian target of rapamycin (mTOR) expression in lung carcinoids and represents a novel candidate prognostic biomarker for this tumor type; 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
Few studies in lung carcinoid cells demonstrated a significant efficacy of mTOR inhibition strategies [3, 4], and supported the current indications for mTOR inhibitors present in the most recent clinical guidelines [5, 6]; a recent prospective clinical trial indicates a significant improvement of survival in patients with progressive lung neuroendocrine tumors treated with everolimus [7]
Summary
The mammalian target of rapamycin (mTOR) is a downstream effector of PI3K/AKT kinases and acts through two complexes, mTORC1 and mTORC2. Rapamycin and its derivatives, such as everolimus, are selective mTOR inhibitors that have been shown to block mTOR modulation of cell cycle progression, angiogenesis and apoptosis in several tumor cell models [2]. Few studies in lung carcinoid cells demonstrated a significant efficacy of mTOR inhibition strategies [3, 4], and supported the current indications for mTOR inhibitors present in the most recent clinical guidelines [5, 6]; a recent prospective clinical trial indicates a significant improvement of survival in patients with progressive lung neuroendocrine tumors treated with everolimus [7]. Data obtained from primary tumor cell cultures, only, claim that patients with high levels of mTOR activation are associated with better responses [9]
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