Molecular basis of pancreatic cancer progression and metastsis

描述（由申请人提供）：胰腺癌是一种致命的疾病，表现为快速进展和早期形成的区域和远处转移，以及对常规治疗的耐药性。胰腺癌进展和转移的潜在分子基础尚不清楚，这是最近深入研究的主要焦点。近年来的研究表明，诱导型一氧化氮合酶在胰腺癌的进展和转移中起着重要的调节作用。我们已经提供了因果证据，在肿瘤中生理和升高的诱导型一氧化氮合酶表达和一氧化氮产生抑制肿瘤的生长和转移。然而，我们也证明了在生长中的胰腺癌中有明确的诱导型一氧化氮合酶活性，而由此产生的一氧化氮水平在没有产生一氧化氮抗性的情况下是抑瘤的。这一关键的观察结果使我们确定了红细胞分化调节因子（Erdr1）基因，该基因在具有诱导型一氧化氮合酶活性的生长胰腺肿瘤中大量且持续地过表达。在这项应用中，我们试图确定Erdr1是否在胰腺癌的进展和转移中起关键作用。为了验证这一假设，我们在三个特定目的下设计了几组实验，以确定Erdr1对胰腺癌进行性生长和转移的因果机制作用；判断Erdr1的上调是否由一氧化氮直接引起；确定Erdr1表达的变化及其在人类胰腺癌发病机制中的临床意义。我们的研究将有助于更好地了解胰腺癌进展和转移的机制基础，特别是Erdr1在胰腺癌发病机制中的具体作用。作为我们的长期目标，完成我们提出的研究所产生的新知识也将有助于潜在有效的预防和治疗策略的转化研究，以控制人类胰腺癌的进展和转移。公共卫生相关性：红细胞分化调节因子是胰腺癌中新发现的一氧化氮抗性相关基因。然而，红细胞分化调节因子及其信号传导在人胰腺癌进展和转移中的关键作用尚不清楚。

DESCRIPTION (provided by applicant): Pancreatic cancer is a lethal disease as manifested by rapid progression and early formation of regional and distant metastasis, and resistance to conventional therapies. The underlying molecular basis of pancreatic cancer progression and metastasis is unclear and has been the major focus of recent intensive investigations. Recent studies in our laboratory and others indicate that inducible nitric oxide synthase plays an important role in the regulation of pancreatic cancer progression and metastasis. We have provided causal evidence that both physiological and elevated inducible nitric oxide synthase expression and nitric oxide production in tumor suppress tumor growth and metastasis. However, we also have demonstrated a definitive inducible nitric oxide synthase activity in growing pancreatic cancer, whereas the resultant levels of nitric oxide production would have been tumor- suppressive without development of nitric oxide resistance. This critical observation led us to the identification of erythroid differentiation regulator (Erdr1) gene, which is substantially and consistently overexpressed in growing pancreatic tumors having inducible nitric oxide synthase activity. In this application, we sought to determine whether Erdr1 play a critical role in pancreatic cancer progression and metastasis. To test this hypothesis, we have designed several sets of experiments in three specific aims to determine the causal mechanistic effects of Erdr1 on the progressive growth and metastasis of pancreatic cancer; to determine whether Erdr1 upregulation is caused by nitric oxide directly; and to determine the changes of Erdr1 expression and delineate their clinical significance in human pancreatic cancer pathogenesis Our proposed studies will help better understand the mechanistic basis of pancreatic cancer progression and metastasis in general and the specific role of Erdr1 in pancreatic cancer pathogenesis in particular. As our long-term goal, the new knowledge generated from completion of our proposed studies also will aid in translational investigation of potentially effective preventive and therapeutic strategies to control human pancreatic cancer progression and metastasis. PUBLIC HEALTH RELEVANCE: Erythroid differentiation regulator is a newly identified nitric oxide-resistance-related gene in pancreatic cancer. However, the critical role of erythroid differentiation regulator and its signaling in human pancreatic cancer progression and metastasis is unclear.