Vitamin D suppresses leptin stimulation of cancer growth through microRNA.
Vitamin D suppresses leptin stimulation of cancer growth through microRNA.
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DOI：
10.1158/0008-5472.can-14-1702
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Bai W
中科院分区：
文献类型：
--
作者：
Kasiappan R;Sun Y;Lungchukiet P;Quarni W;Zhang X;Bai W
肥胖是一种流行病，也是癌症的主要危险因素。减少肥胖本来是预防癌症的有效策略，但现实是，几十年来，全球肥胖人数一直在增加，成为仅次于吸烟的主要可避免癌症风险。目前的研究表明，维生素 D 可能是降低女性肥胖相关癌症风险的有效药物。分子分析表明，瘦素通过激活卵巢癌 (OCa) 细胞中的雌激素受体 α (ERα) 来增加人端粒酶逆转录酶 (hTERT) mRNA 表达和细胞生长，而 1α,25-二羟基维生素 D3 [1,25(OH)2D3] 会抑制这种作用。当激素诱导的 miR-498 被 miRNA 海绵耗尽时，抑制作用就会受到损害。在小鼠中，高脂饮食 (HFD) 对卵巢肿瘤生长的刺激被 1,25(OH)2D3 类似物 EB1089 显着抑制，而 miR-498 海绵也会损害这种作用。 EB1089 不会改变 HFD 诱导的血清瘦素水平增加，但会增加 miR-498 并降低饮食诱导的肿瘤中 hTERT 表达。定量 RT-PCR (qRT-PCR) 分析显示，在雌激素敏感的卵巢癌、子宫内膜癌和乳腺癌中，hTERT mRNA 和 miR-498 对 1,25(OH)2D3 的反应呈负相关。研究表明，miR-498 介导的 hTERT 下调是女性雌激素敏感肿瘤中介导 1,25(OH)2D3 抗瘦素活性的关键事件。
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.