THE ROLE OF CALCIUM SIGNALING ON PTEN REGULATION

描述(申请人提供)：胰腺癌是一种致命的疾病，占所有胃肠道癌症的15%。仅在美国，胰腺癌的发病率在2008年就增加到37680例新病例和34290例死亡。胰腺癌占胰腺癌的90%以上，具有生存率低、对放化疗耐药等特点，迫切需要新的治疗策略。肿瘤的形成和生长建立在细胞增殖增加和/或细胞凋亡减少的基础上，而肿瘤的侵袭和转移与细胞迁移的增加有关。我们以前的研究发现，PTEN是一种重要的肿瘤抑制因子，TGF2通过诱导胞浆内游离钙浓度([Ca2+]Cyt)下调PTEN的表达。[Ca~(2+)]Cyt对细胞增殖、细胞凋亡和细胞迁移是必不可少的。癌细胞内[Ca~(2+)]-Cyt水平经常升高，使[Ca~(2+)]-Cyt动态平衡成为当前癌症研究的重要焦点。细胞内[Ca~(2+)]动态平衡是由膜钙通道和转运体控制的，其中钙离子通道(SOC)是重要的候选通道。SOC是非兴奋性上皮细胞内[Ca~(2+)]Cyt的主要调节者。尽管SOC的分子特性仍不确定，但这一领域的工作主要集中在瞬时受体潜在规范(TRPC)通道上，因为观察到TRPC的表达导致由受体激活和存储耗尽激活的钙通透通道的形成3，4。目前公认的是，TRPC1在肠上皮细胞5，6中起SOC的作用。尽管TRPC最近被证明在胃癌和卵巢癌的发生中发挥重要作用，但它在胰腺癌中的作用迄今尚未被研究。我们的初步数据表明，TGF2诱导的[Ca~(2+)]Cyt导致PTEN表达下调，并且TRPC1在胰腺癌细胞中的表达促进了Ca~(2+)内流，从而促进了胰腺肿瘤的发生。因此，本研究的目的是验证这一假说，即钙离子通过TRPC1编码的SOC促进TGF2介导的PTEN下调和胰腺癌细胞迁移。 公共卫生相关性：临床意义在于PTEN似乎在胰腺肿瘤的发生和转移中起着重要作用。胰腺癌是一种致命的疾病，癌细胞对传统的一次性转移具有抵抗力。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