THE ROLE OF CALCIUM SIGNALING ON PTEN REGULATION

描述（由申请人提供）：胰腺癌是一种致死性疾病，占所有胃肠道癌症的15%。2008年，仅在美国，胰腺癌的发病率就增加到> 37，680例新发病例和34，290例死亡。胰腺癌占胰腺癌的90%以上，其特点是生存率低，对放化疗耐药，因此迫切需要新的治疗策略。癌症的形成和生长基于细胞增殖增加和/或细胞凋亡减少，并且癌症侵袭和转移与细胞迁移增加相关。我们的前期研究发现，PTEN是一种重要的肿瘤抑制因子，TGF-2通过诱导胞浆游离钙浓度（[Ca ~（2+）]cyt）下调其表达。[Ca2+]cyt对于细胞增殖、凋亡和细胞迁移是必需的。[Ca 2 +]cyt水平在癌细胞中经常升高，使得[Ca 2 +]cyt稳态成为当前癌症研究的重要焦点。[Ca2细胞内稳态是由膜Ca ~（2+）通道和转运蛋白控制的，其中钙库操纵的Ca ~（2+）通道（SOC）是重要的候选通道。SOC是非兴奋性上皮细胞中[Ca 2 +]cyt的主要调节剂。虽然SOC的分子身份仍然不确定，但该领域的工作集中在瞬时受体电位典型（TRPC）通道上，其基础是TRPC的表达导致通过受体活化和储存耗尽激活的Ca 2+渗透通道的形成3，4。现在公认TRPC 1在肠上皮细胞中起SOC的作用5，6。虽然TRPC最近已被证明在胃癌和卵巢癌的肿瘤发生中起重要作用，但其在胰腺癌中的作用迄今尚未研究。我们的初步数据表明，TGF 2诱导的[Ca 2 +]cyt导致PTEN下调，胰腺癌细胞中表达的TRPC 1促进Ca 2+内流，促进胰腺肿瘤发生。因此，目前的建议的目的是测试的假设，通过TRPC 1编码的SOC的Ca 2 + enrty促进TGF 2介导的PTEN下调和胰腺癌细胞迁移。 公共卫生相关性：其临床意义在于，PTEN在胰腺肿瘤的发生和转移中起重要作用。胰腺癌是一种致死性疾病，癌细胞一旦转移就对常规治疗有抵抗力。该提案的发现将为胰腺癌患者提供新的治疗策略

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is lethal disease that comprises 15% of all gastrointestinal cancers. The incidence of pancreatic cancer has increased to >37,680 new cases and 34,290 deaths due to this disease in 2008 in the U.S. alone. Pancreatic adenocarcinoma, making up over 90% of pancreatic cancer, is characterized by poor survival and resistance to radio-chemotherapy and thus novel therapeutic strategies are urgently required. Cancer formation and growth are based on increased cell proliferation and/or decreased apoptosis, and cancer invasion and metastasis are associated with increased cell migration. Our previous studies have found that PTEN is an important tumor suppressor that was downregulated by TGF2 via induction of cytosolic free Ca2+ concentration ([Ca2+]cyt). [Ca2+]cyt is essential to cell proliferation, apoptosis, and cell migration . The levels of [Ca2+]cyt are often elevated in cancer cells, making [Ca2+]cyt homeostasis an important focus in current cancer research. [Ca2+]cyt homeostasis is controlled by membrane Ca2+ channels and transporters, of which store-operated Ca2+ channels (SOC) are important candidates. SOC is a major regulator of [Ca2+]cyt in non-excitable epithelial cells. Although the molecular identity of SOC is still uncertain, work in this area has focused on transient receptor potential canonical (TRPC) channels on the basis of observations that expression of TRPC leads to the formation of Ca2+- permeable channels activated by receptor activation and store depletion3, 4. It is now accepted that TRPC1 is recognized to function as SOC in intestinal epithelial cells5, 6. Although TRPC has been shown recently to play an important role in tumorigenesis in gastric and ovarian cancers, its role in pancreatic cancer has not been studied to date. Our preliminary data demonstrated that TGF2-induced [Ca2+]cyt led to PTEN downregulation and that TRPC1 expressed in pancreatic cancer cells facilitated Ca2+ entry to promote pancreatic tumorigenesis. Therefore, the objective of the current proposal is to test the hypothesis that Ca2+ enrty through TRPC1-encoded SOC promotes TGF2-mediated PTEN downregulation and pancreatic cancer cell migration. PUBLIC HEALTH RELEVANCE: The clinical significance is from the fact that PTEN appears to play an important role in pancreatic tumorigenesis and metastasis. Pancreatic cancer is a lethal disease and cancer cells are resistant to conventional once metastasis. The findings from the proposal will shed light on novel treatment strategies to patients with pancreatic cancer