Chromium and Hedgehog signaling

描述（由申请人提供）：六价铬（Cr（VI））广泛用于许多工业过程，包括Chrome颜料生产、Chrome电镀、不锈钢制造和皮革鞣制等。流行病学研究报告了通过吸入接触Cr（VI）的铬工人中肺癌的高发病率。虽然多种机制被认为有助于铬（VI）的致癌性，介导铬（VI）诱导的肺癌的分子和途径还没有得到很好的理解。Hedgehog（Hh）信号通路是胚胎发育过程中多种组织形成和成体干细胞群维持的关键通路。在多种人类癌症中发现了Hh信号通路的失调，包括基底细胞癌、髓母细胞瘤、结肠癌、胰腺癌和肺癌。我们的初步数据表明，刺猬相互作用蛋白（HHIP），下游目标和天然拮抗剂的Hh信号，在铬（VI）转化细胞的mRNA水平显着下降。有趣的是，Hh信号在这些细胞中被改变，下游靶基因如Gli1和Ptch1的水平增加证明了这一点，这表明Hh信号在Cr（VI）诱导的细胞转化和癌变中的潜在作用。本研究计划的主要重点是确定Hh信号在Cr（VI）诱导的细胞转化中的作用，并剖析Cr（VI）调节Hh信号的机制。首先，为了确定降低的HHIP水平和增强的Hh信号传导是否有助于Cr（VI）诱导的细胞转化和致癌，我们将调节Hh信号传导途径的主要组分的水平，并分析细胞增殖、非贴壁依赖性生长和体内肿瘤形成的变化。接下来，我们将分析HHIP启动子中的组蛋白修饰和DNA甲基化，以剖析Cr（VI）转化细胞中HHIP下调的表观遗传学机制。我们提出的研究可能是第一个链接慢性铬（VI）暴露的Hh信号通路的失调。这项研究计划的成功将显著提高我们对Cr（VI）暴露后Hh信号级联变化的理解，并可能为开发更好的Cr（VI）相关人类癌症治疗策略提供新的见解。

DESCRIPTION (provided by applicant): Hexavalent chromium, Cr(VI), is widely used in numerous industrial processes, including chrome pigment production, chrome plating, stainless steel manufacturing, and leather tanning, etc. Epidemiological studies have reported a high incidence of lung cancer among chromium workers exposed occupationally to Cr(VI) by inhalation. Although multiple mechanisms were suggested to contribute to Cr(VI) carcinogenicity, the molecules and pathways that mediate Cr(VI) induced lung cancer are not well understood. Hedgehog (Hh) signaling is a key pathway that plays important roles in the formation of multiple tissues during embryogenesis and in the maintenance of stem cell populations in adults. Dysregulation of the Hh signaling pathway was found in a variety of human cancers, including basal cell carcinomas, medulloblastomas, colon cancers, pancreatic cancers, and lung cancers. Our preliminary data demonstrated a significant decrease in mRNA levels of hedgehog-interacting protein (HHIP), a downstream target and a natural antagonist of Hh signaling, in Cr(VI) transformed cells. Interestingly, Hh signaling was altered in these cells a evidenced by increased levels of downstream target genes, such as Gli1 and Ptch1, suggesting a potential role of Hh signaling in Cr(VI) induced cell transformation and carcinogenesis. The primary focus of this research proposal is to determine the role of Hh signaling in Cr(VI) induced cell transformation and to dissect the mechanism by which Cr(VI) modulates Hh signaling. First, to determine whether decreased HHIP levels and enhanced Hh signaling contribute to Cr(VI) induced cell transformation and carcinogenesis, we will modulate the levels of major components of Hh signaling pathway and analyze the changes in cell proliferation, anchorage-independent growth and in vivo tumor formation. Next, to dissect the epigenetic mechanism underlying the down-regulation of HHIP in Cr(VI) transformed cells, we will analyze the histone modifications and DNA methylation in HHIP promoter. Our proposed study may be the first to link chronic Cr(VI) exposure to the dysregulation of the Hh signaling pathway. The success of this research proposal will significantly improve our understanding of the changes in Hh signaling cascade after Cr(VI) exposure and may provide new insights for developing a better therapeutic strategy for Cr(VI)-related human cancer.