Kasiappan Ravi, Sun Yuefeng, Lungchukiet Panida, Quarni Waise, Zhang Xiaohong, Bai Wenlong
Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, Florida.
Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, Florida. Department of Oncological Sciences, University of South Florida College of Medicine, Tampa, Florida. Program of Cancer Biology and Evolution, H. Lee Moffitt Cancer Center, Tampa, Florida.
Cancer Res. 2014 Nov 1;74(21):6194-204. doi: 10.1158/0008-5472.CAN-14-1702. Epub 2014 Sep 24.
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-α (ERα) activation in ovarian cancer cells, which was suppressed by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The suppression was compromised when miR-498 induction by the hormone was depleted with microRNA (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 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 downregulation is a key event mediating the anti-leptin activity of 1,25(OH)2D3 in estrogen-sensitive tumors in women.
肥胖是一种流行病，也是癌症的主要风险因素。减轻肥胖本可成为预防癌症的有效策略，但现实情况是，几十年来全球肥胖率持续上升，仍是仅次于吸烟的主要可避免癌症风险因素。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。分子分析显示，瘦素通过激活卵巢癌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]可抑制这种作用。当用微小RNA（miRNA）海绵耗尽该激素诱导的miR-498时，这种抑制作用就会减弱。在小鼠中，1,25(OH)2D3类似物EB1089可显著抑制高脂饮食（HFD）对卵巢肿瘤生长的刺激作用，miR-498海绵也会削弱这种作用。EB1089并未改变HFD诱导的血清瘦素水平升高，但可增加miR-498并降低饮食诱导的肿瘤中hTERT表达。定量逆转录聚合酶链反应（RT-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与miR-498在对1,25(OH)2D3的反应中呈负相关。这些研究表明，miR-498介导的hTERT下调是介导1,25(OH)2D3对女性雌激素敏感肿瘤抗瘦素活性的关键事件。
