Abstract
The biological role of miR-3188 has not yet been reported in the context of cancer. In this study, we observe that miR-3188 not only reduces cell-cycle transition and proliferation, but also significantly prolongs the survival time of tumour-bearing mice as well as sensitizes cells to 5-FU. Mechanistic analyses indicate that miR-3188 directly targets mTOR to inactivate p-PI3K/p-AKT/c-JUN and induces its own expression. This feedback loop further suppresses cell-cycle signalling through the p-PI3K/p-AKT/p-mTOR pathway. Interestingly, we also observe that miR-3188 direct targeting of mTOR is mediated by FOXO1 suppression of p-PI3K/p-AKT/c-JUN signalling. In clinical samples, reduced miR-3188 is an unfavourable factor and negatively correlates with mTOR and c-JUN levels but positively correlates with FOXO1 expression. Our studies demonstrate that as a tumour suppressor, miR-3188 directly targets mTOR to stimulate its own expression and participates in FOXO1-mediated repression of cell growth, tumorigenesis and NPC chemotherapy resistance.
Highlights
OPEN miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mammalian target of rapamycin (mTOR)–p-PI3K/AKT-c-JUN
Our studies demonstrate that as a tumour suppressor, miR-3188 directly targets mTOR to stimulate its own expression and participates in FOXO1-mediated repression of cell growth, tumorigenesis and Nasopharyngeal carcinoma (NPC) chemotherapy resistance
More than threefold increase in miR-3188 expression was observed in HONE1-Epstein-Barr virus (EBV) and SUNE1 cells treated with miR3188 mimics compared with the control group by qRT-PCR (Student’s t-test, with Po0.05 for both) (Supplementary Fig. 1A)
Summary
We found that mTOR overexpression induced expression of c-JUN and CCND1 but reduced p27 and p21 (Fig. 3e) These results indicate that mTOR overexpression can overcome NPC cell growth suppression induced by miR-3188. We found that levels of mTOR, p-mTOR, p-PI3K, p-AKT, CCND1 and c-JUN were significantly decreased, while p27 and p21 were elevated after mTOR siRNA treatment (Fig. 3f) These results were consistent with miR-3188 overexpression, suggesting that mTOR is a direct target of miR-3188 responsible for suppressing cell growth and inducing NPC sensitization to 5-FU. Three c-JUN-binding motifs at À 492 to À 498, À 1,628 to À 1,634 and À 2,356 to À 2,362 were identified inside the putative miR-3188 promoter region These three transcription factor-binding sites (TFBSs) were named A, B and C (Fig. 4a).
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