Vitamin D3 Inhibition of Hedgehog Signaling and Cancer Chemoprevention

描述（由申请人提供）：我们在该项目中的目标是阐明最近描述的维生素D3抑制hedghog信号传导的作用，作为癌症死亡率纬度变化的潜在机制。这种变化已经知道了近70年，阳光产生的维生素D储存的主要作用已经被假定为30年的机械联系。尽管如此，将增加维生素D储存与降低癌症相对风险联系起来的确切证据仍然难以捉摸。基底细胞癌（BCC）是研究这种联系的理想肿瘤，因为异常的hedghog信号传导对它们的发展和维持至关重要，有流行病学发现与紫外线辐射不仅在它们的发生中而且在它们的抑制中的作用一致，并且现在有强大的工具可用于它们的研究。我们将整合实验室小鼠模型和人类样本来解决这个问题。具体而言，我们（i）将比较局部与口服维生素D3对Ptch 1小鼠BCC致癌作用的影响，其中Cyp 27 B1可被条件性缺失，因此建立在我们的初步数据上，表明局部D3抑制hedghog抑制实验性小鼠BCC致癌作用（ii），将比较北方与南方对维生素D3抵抗的BCC的相对比例，预计维生素D3-在暴露于更多阳光的患者中，耐药性BCC将更高，并且（iii）将比较患有BCC的受试者中UV诱导的维生素D3产生与患有皮肤鳞状细胞癌的人中的这种产生。总的来说，我们期望这些研究将提供数据，为进行局部维生素D3的抗基底细胞癌化学预防功效的正式人体试验提供令人信服的案例，并将形成将这些研究扩展到皮肤外肿瘤（如结肠肿瘤）的基础和模板，对于这些肿瘤，证据对于hedgehog信号传导的纬度梯度和病理生理作用都是有利的。这项研究现在特别密切，因为越来越多的人担心皮肤科医生为预防皮肤癌而不懈地建议避免阳光照射可能会增加皮外癌症的相对风险，并且因为增加推荐的每日维生素D摄入量的势头越来越大，因为未经证实的希望口服维生素D补充剂将明尼苏达州的癌症风险转换为亚利桑那州的癌症风险。因此，迫切需要进一步研究维生素D3与癌症风险的关系。 公共卫生相关性：目前许多专家急于建议增加剂量的补充口服D3的癌症化学预防的人口强调了获得进一步的数据的紧迫性，更不用说这种建议的安全性可能的有效性。我们提出了一个重点系列的小鼠和人类的研究，将阐明化学预防机制的维生素D的最常见的人类癌症，基底细胞癌。这不仅将开发BCC化学预防干预试验所需的信息，而且非常重要，这些研究将作为一个模型，为未来研究维生素D对结肠癌和其他更致命的皮外癌症风险的影响提供信息。

DESCRIPTION (provided by applicant): Our goal in this Project is the elucidation of the role of the recently described inhibition of hedghog signaling by vitamin D3 as a mechanism underlying latitudinal variation in cancer mortality. Such variation has been known for nearly 70 years, and a prime role for sunlight-produced vitamin D stores has been postulated to be the mechanistic connection for three decades. Nonetheless, definitive proof linking increased vitamin D stores and reduction in relative risk of cancer remains elusive. Basal cell carcinomas (BCCs) are an ideal tumor in which to study this connection since aberrant hedghog signaling is pivotal to their development and maintenance, there are epidemiologic findings consistent with a role of ultraviolet radiation not only in their genesis but also in their restraint, and formidable tools now are available for their study. We will integrate both laboratory mouse models and human samples to address this question. Specifically we (i) will compare the effects of topical vs. oral vitamin D3 on BCC carcinogenesis in Ptch1 mice in which Cyp27B1 can be conditionally deleted, thus building on our preliminary data indicating that hedghog inhibition by topical D3 inhibits experimental murine BCC carcinogensis (ii) will compare the relative proportions of BCCs that are resistant to vitamin D3 inhibtion in the North vs. in the South in expectation that the proportion of vitamin D3-resistant BCCs will be higher in patients exposed to more sunlight and (iii) will compare UV-induced vitamin D3 production in subjects who have had BCCs with such production in persons who have had skin squamous cell carcinomas. Overall we expect that these studies will provide data making a compelling case for the conducting of a formal human trial of the anti-basal cell carcinoma chemopreventive efficacy of topical vitamin D3 and will form the foundation and template for extending these studies into extra-cutaneous tumors such as those of the colon, for which evidence is good for both a latitudinal gradient and a pathophysiologic role for hedgehog signaling. This Study is particularly germane now because growing concern that Dermatologists' relentless recommendations for sun avoidance to prevent skin cancers may be increasing the relative risk of extracutaneous cancers and because of the gathering momentum to increase the recommended daily vitamin D intake for the enitire population in unproved hopes that oral vitamin D supplements will convert the cancer risk of Minnesotans to that of Arizonans. Thus there is urgent need for further investigation into the relation of vitamin D3 to cancer risk. PUBLIC HEALTH RELEVANCE: The current rush by many experts to recommend increasing doses of supplemental oral D3 for cancer chemoprevention for the population emphasizes the urgency of obtaining further data bearing on the likely efficacy, let alone safety, of such recommendations. We propose a focused series of mouse and human studies that will illuminate the mechanism of chemoprevention by vitamin D of the most common human cancer, basal cell carcinoma. Not only will this develop the information needed for an interventional trial of BCC chemoprevention but also of great importance, these studies will serve as a model to inform future studies of the influence of vitamin D on the risk of colon and other more deadly extracutaneous cancers.