Background:Telomerase is essential for cancer cell growth. Results: MiR-498 is a novel 1,25(OH) 2 D 3 target gene that decreases telomerase, induces cell death, and suppresses tumor growth. Conclusion: MiR-498 is an important mediator of the anti-tumor activity of 1,25(OH) 2 D 3 . Significance: The studies define a new mechanism of telomerase regulation by small non-coding RNAs in response to 1,25(OH) 2 D 3 .
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.
Tumor necrosis factor alpha (TNFα) and its receptor TNFR1 play a central role in the development of colitis-associated colon cancer. To understand a role for the extracellular calcium-sensing receptor (CaSR) and its non-canonical Wnt mediators, Wnt5a/Ror2, we used reductionistic systems. We added lipopolysaccharide (LPS) to mouse peritoneal macrophages, RAW264.7 cells, a murine macrophage cell line, and 18Co colonic myofibroblasts, to stimulate TNFα secretion and then activated endogenous CaSR. CaSR activation inhibited TNFα secretion, which in RAW264.7 cells knockdown of CaSR by short-interfering RNA (siRNA) duplex reversed. LPS-stimulated NFκB promoter activity in RAW264.7 cells was inhibited by CaSR activation with Ca2+ or other polyvalent CaSR agonists. Reducing CaSR expression with siRNA duplex prevented this inhibition. Following LPS addition to CaSR–HEK cells or RAW264.7 macrophages, CaSR stimulation deneddylated Cullin1. Wnt5a added to HT-29 cells which overexpressed Ror2 or T84 monolayers treated with 3 mM Ca2+ reduced TNFR1 protein expression ∼70%. TNFα/INFγ addition to high resistance T84 monolayers reduced transepithelial resistance 50% within 4 h. CaSR activation (3 mM Ca2+) together with rhWnt5a (200 ng/ml) prevented this reduction while Wnt3a addition had no effect. LPS-stimulated TNFα secretion from RAW264.7 cells was not effected by rhWnt5a but increased 10-fold by Wnt3a. Together our results suggest that following LPS challenge, CaSR activation will inhibit NFκB activity and reduce TNFα secretion from macrophages and stroma while Wnt5a/Ror2 engagement on intestinal epithelia reduces TNFR1 expression, allowing TNFα signaling to be titrated. Our results also suggest that canonical Wnt signaling may enhance TLR4 stimulation of TNFα secretion from murine macrophages.
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