MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer.

Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using bioinformatics predictions and mRNA/miRNA expression profiles, we performed an integrated analysis to identify inversely correlated miRNA-mRNA pairs in ACC. We identified N-myc downstream-regulated gene family members 2 and 4 (NDRG2 and NDRG4) as targets of miR-483-5p and miR-139-5p, respectively. NDRG2 and NDRG4 expressions were inversely correlated respectively with miR-483-5p and miR-139-5p levels in aggressive ACC samples from two independent cohorts of 20 and 44 ACC. Moreover, upregulation of miR-139-5p and downregulation of NDRG4 demonstrated a striking prognostic value. A direct interaction between miR-483-5p or miR-139-5p and their targets was demonstrated in reporter assays. Downregulation of miR-483-5p or miR-139-5p in the ACC cell lines NCI-H295R and SW13 increased NDRG2 or NDRG4 mRNA and protein expression, compromised adrenocortical cancer cell invasiveness and anchorage-independent growth. MiR-483-5p or miR-139-5p overexpression and NDRG2 or NDRG4 inhibition produce similar changes, which are rescued by NDRG2 or NDRG4 ectopic expression. We established that key factors mediating epithelial-to-mesenchymal transition are downstream effectors of miR-483-5p/NDRG2 and miR-139-5p/NDRG4 pathways. Collectively, our data show for the first time that miR-483-5p/NDRG2 and miR-139-5p/NDRG4 axes promote ACC aggressiveness, with potential implications for prognosis and therapeutic interventions in adrenocortical malignancies.

Treatment Discontinuation Following Bariatric Surgery in Obstructive Sleep Apnea: a Controlled Cohort Study.

BACKGROUND: Uncontrolled studies looking at the discontinuation of obstructive sleep apnea (OSA) treatment after bariatric surgery (BS) have suggested that surgery improves OSA. However, this discontinuation of OSA treatment by BS patients has never been compared to a matched population without BS. The objectives of this study are to evaluate whether BS increases OSA treatment discontinuation compared to that in matched patients without BS and to identify predictive factors of OSA treatment discontinuation in BS patients. The study took place in an ambulatory, tertiary hospital. METHODS: We included 61 OSA patients who underwent BS in a retrospective controlled cohort study. The computerized matching procedure included age, sex, body mass index, year of starting OSA treatment, treatment type, and duration selected 59 controls matched to 28 patients with BS. The main outcome was OSA treatment discontinuation within 2 years after BS. RESULTS: Patients with BS stopped OSA treatment more often than controls, usually between 6 months and 1 year after BS: hazards ratio (HR (95 %, CI)) 15.93 (3.29, 77.00). Before 6 months or beyond 1 year after BS, treatment discontinuation was not different between BS patients and controls. In univariate analyses, female gender, absence of co-morbidities, greater weight loss, and lower baseline OSA severity were associated with stopping OSA treatment after BS. No factor remained independently associated in multivariate analysis. CONCLUSIONS: Apneic patients having BS stop OSA treatment more than matched controls. Treatment discontinuation may be attributed to recovery or to abandonment. The effect of BS on OSA may have been overestimated in uncontrolled BS studies that ignored basal OSA treatment discontinuation in routine clinical practice.