Mechanism of keratinocyte RXRalpha mediated melanoma skin cancer development

描述(申请人提供)：恶性黑色素瘤是美国增长最快的癌症之一，目前还没有治愈的方法。太阳紫外线(UV)辐射，尤其是儿童日照是黑色素瘤的重要病因危险因素。维甲酸X受体a(RXRA)是核受体(NR)超家族的一员，是传递多种细胞信号的中枢协调者。在研究RXRA在皮肤中的作用的背景下，我们发现了这种NR在黑色素瘤发生中的一个意想不到的新角色：RXRA[EP-/-]小鼠，特别是在表皮角质形成细胞中缺乏RXRA的小鼠，当受到两步化学致癌方案(DMBA TPA)的影响时，会高度频繁地发生类似于黑色素瘤的黑素细胞生长(MG)。我们的结果提示RXRA可能调节角质形成细胞？黑素细胞信号转导通路(S)参与控制黑素细胞的增殖。因此，我们建立了一种新的小鼠黑色素瘤发生模型。然而，RXR这些活性背后的分子机制尚不清楚。鉴于角质形成细胞在调节黑素细胞有丝分裂中的重要性，了解这种调节在黑色素瘤中如何变得异常具有重要意义，因为它可能导致开发有效的治疗策略来对抗黑色素瘤的形成和发展。我们的长期目标是确定角质形成细胞和黑素细胞之间促进黑色素瘤发展的信号转导机制。基于上述观察和初步数据，我们提出了以下两个具体目标。首先，我们建议阐明角质形成细胞控制黑素细胞有丝分裂和转化导致恶性表型的细胞和分子机制。我们的工作假设是，RXRA直接或间接地抑制角质形成细胞内皮素-1(ET-1)、SCF、POMC和FGF2的表达，这可能通过旁分泌方式调节黑素细胞的有丝分裂。其次，我们建议确定控制黑素细胞稳态和紫外线诱导的黑色素瘤发生的细胞内靶点(黑素细胞因子)。我们的工作假设是，黑素细胞因子，如细胞周期蛋白依赖性激酶-4(CDK4)，可能调节这些细胞对角质形成细胞衍生的旁分泌因子促有丝分裂的反应。我们相信，我们在本文描述的工作背景下的努力将导致对黑素细胞有丝分裂和黑色素瘤形成的机制(S)的详细理解，角质形成细胞RXRA，也许还有其他旁分泌因子通过其调节黑素细胞有丝分裂和黑色素瘤形成。这项拟议的项目具有潜在的创新性，因为我们的实验室培育了用于这些研究的RXRA[EP-/-]小鼠，并首次表征了RXRA在皮肤表皮动态平衡期间的体内作用。这一贡献是重大的，预计结果将对人类健康产生积极影响，因为这项工作的结果将为未来旨在治疗并最终治愈恶性黑色素瘤的药物战略的发展提供分子基石。

DESCRIPTION (provided by applicant): Malignant melanoma is one of the fastest increasing cancers in the United States and no curative treatment is yet available. Solar ultraviolet (UV) radiation, especially childhood sun exposure is an important etiological risk factor of melanoma. Retinoid X Receptor a (RXRa), a member of the nuclear receptor (NR) superfamily, is a central coordinator for transducing diverse cellular signals. In the context of studying the role of RXRa in skin, we have discovered an unexpected and novel role for this NR in melanomagenesis: RXRa[ep-/-] mice, specifically lacking RXRa in epidermal keratinocytes, develop melanocytic growths (MGs) resembling melanoma at high frequency when subjected to a two-step chemical carcinogenesis protocol (DMBA+TPA). Our results suggest that RXRa may regulate a keratinocyte ? melanocyte signaling pathway(s) implicated in the control of melanocytic proliferation. Thus, we have generated a new mouse model for melanomagenesis. However, the molecular mechanisms that underlie these activities of RXR are not known. Given the importance of keratinocytes in regulating melanocyte mitogenesis, understanding how this regulation becomes aberrant in melanoma is significant, since it can possibly lead to the development of effective therapeutic strategies to counteract melanoma formation and progression. Our long-term goal is to identify the mechanisms of signal transduction between keratinocytes and melanocytes that contribute to the development of melanoma. Based on the above observations and from the preliminary data, we propose the following two specific aims. First, we propose to elucidate the cellular and molecular mechanisms by which keratinocytes control melanocyte mitogenesis and transformation leading to a malignant phenotype. Our working hypothesis is that RXRa, directly or indirectly, represses keratinocytic expression of endothelin 1 (ET-1), SCF, POMC and FGF2 which may serve to regulate melanocytic mitogenesis in a paracrine manner. Second, we propose to identify intracellular targets (melanocytic factors) that control melanocyte homeostasis and UV-induced melanomagenesis. Our working hypothesis is that melanocytic factors, such as cyclin dependent kinase-4 (Cdk4), may modulate the responsiveness of these cells to the mitogenic effects of keratinocyte-derived paracrine factors. We believe that our efforts in the context of the work described herein will lead to a detailed understanding of the mechanism(s) by which melanocyte mitogenesis and melanomagenesis are regulated by keratinocytic RXRa, and perhaps other paracrine factors. The proposed project is potentially innovative as our laboratory generated the RXRa [ep-/-] mouse that has been used for these studies, and was the first to characterize the in vivo role of RXRa in skin during epidermal homeostasis. This contribution is significant and the results are expected to have a positive impact on human health, because the outcome of the work will provide the molecular cornerstone for the development of future pharmacological strategies designed to treat, and ultimately cure malignant melanoma.