Vitamin D Suppresses Leptin Stimulation of Cancer Growth through microRNA

Abstract

Obesity is a pandemic and major risk factor for cancers. The reduction of obesity would have been an effective strategy for cancer prevention, but the reality is that worldwide obesity has kept increasing for decades, remaining a major avoidable cancer risk secondary only to smoke. The present studies suggest that vitamin D may be an effective agent to reduce obesity-associated cancer risks in women. Molecular analyses showed that leptin increased human telomerase reverse transcriptase (hTERT) mRNA expression and cell growth through estrogen receptor alpha (ERα) activation in ovarian cancer (OCa) cells, which was suppressed by 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The suppression was compromised when miR-498 induction by the hormone was depleted with miRNA sponges. In mice, high-fat diet (HFD) stimulation of ovarian tumor growth was remarkably suppressed by 1,25(OH)2D3 analogue EB1089, which was also compromised by miR-498 sponges. EB1089 did not alter HFD-induced increase in serum leptin levels but increased miR-498 and decreased the diet-induced hTERT expression in tumors. Quantitative RT-PCR (qRT-PCR) analyses revealed an inverse correlation between hTERT mRNA and miR-498 in response to 1,25(OH)2D3 in estrogen-sensitive ovarian, endometrial and breast cancers. The studies suggest that miR-498-mediated hTERT down regulation is a key event mediating the anti-leptin activity of 1,25(OH)2D3 in estrogen-sensitive tumors in women.

Suppression of epithelial ovarian cancer invasion into the omentum by 1α,25-dihydroxyvitamin D3 and its receptor

“…Our published studies have documented an important role for 1,25D 3 and EB1089 in suppressing EOC growth in multiple human EOC cell lines both in vitro [15,16,23] and in vivo in mouse tumor models [17,18,43]. This study is the first to reveal a role for 1,25D 3 in suppressing EOC invasion.…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Another mechanism by which leptin is thought to promote cancer development is via human telomerase reverse transcriptase (hTERT) expression. This was suppressed by treatment with activated vitamin D 3 via induction of miR-498 in cell line models [102].…”

RIPK1 binds to vitamin D receptor and decreases vitamin D-induced growth suppression

“…Reactions were run with the following parameters: 95°C for 3 minutes followed by 40 cycles of 95°C for 10 seconds, 55°C for 1 minute and GAPDH was run as a control for CYP24A1 expression. ΔCt values and fold of induction were calculated as described previously [12]. Each data point represents three independent analyses (n=3) presented as mean ± SEM.…”

“…Our published studies in ovarian cancer have shown that 1,25D3 inhibits cancer growth by arresting cells at specific cell cycle checkpoints [7–9]. Further analyses have demonstrated that 1,25D3 induces microRNA target genes to decrease telomerase expression for cell death induction [10, 11] and to inhibit leptin and estrogen-induced tumor growth [12], suggesting that 1,25D3 has an important role in cutting down obesity-associated cancer risks in women [13]. More recent studies have shown that ovarian cancer invasion is suppressed by 1,25D3 through the cooperative actions of epithelial and stromal VDR [14].…”