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首页> 外文期刊>Frontiers in Physiology >Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer
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Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer

机译：角质形成细胞中维生素D和钙信号的破坏易患皮肤癌。

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1,25 dihydroxyvitamin D (1,25(OH)_(2)D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)_(2)D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis (~(epid) Vdr ~(?∕?)and~(epid) Casr ~(?∕?)). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro , associated with altered hedgehog (HH) and β–catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr ~(?∕?)mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the~(epid) Vdr ~(?∕?)or~(epid) Casr ~(?∕?). But in mice with epidermal specific deletion of both Vdr and Casr (~(epid) Vdr ~(?∕?)/~(epid) Casr ~(?∕?)[DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β–catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.
机译：1,25二羟基维生素D（1,25（OH）_（2）D），维生素D的活性代谢产物和钙调节表皮分化。 1,25（OH）_（2）D通过维生素D受体（VDR）发挥作用，VDR是核激素受体家族中的转录因子，而钙则通过钙敏感受体（Casr）（膜结合的成员）发挥作用。 G蛋白偶联受体家族。我们已经开发了其中在表皮中删除了Vdr和Casr的鼠标模型（〜（癫痫病）Vdr〜（Δ∕？）和〜（癫痫病）Casr〜（Δ∕？））。两种基因型在体内和体外均表现出钙诱导的表皮分化异常，与改变的刺猬（HH）和β-catenin信号有关，当异常表达时会分别导致基底细胞癌（BCC）和毛囊毛细胞瘤。 Vdr〜（？^？）小鼠在UVB或化学致癌物暴露后易于形成肿瘤。最近，我们发现这些小鼠的角质形成细胞过度表达长的非编码RNA（lncRNA）致癌基因（例如H19），而表达lncRNA肿瘤抑制因子（例如lincRNA-21）。在（缓慢的）Vdr〜（Δβ）或（缓慢的）Casr〜（Δβ）中均未观察到自发性肿瘤。但是在具有Vdr和Casr的表皮特异性缺失的小鼠中（〜（epid）Vdr〜（？∕？））/〜（epid）Casr〜（？∕？）[DKO]），放置DKO小鼠时会自发发生肿瘤形成低钙饮食。这些结果证明了维生素D和钙信号通过各自的受体之间的重要相互作用，这些信号被破坏时会导致癌症。讨论了β-catenin，hedgehog和lncRNA通路在维生素D和钙信号传导受到破坏时易使表皮形成肿瘤的作用。

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