权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Oncogenic Function of Ca2+ Channel Orai1 in Esophageal Carcinogenesis

Ca2通道Orai1在食管癌发生中的致癌作用

基本信息

批准号：
8818266
负责人：
Tong Chen
金额：
$ 33.59万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818266
关键词：
Accounting Animal Model Animals Area Attention Biological Markers Cancer Biology Cancer Detection Cancer Etiology Cancer Prognosis Carcinogens Carcinoma Cell Proliferation Cell membrane Cells Cellular biology Cessation of life Coupling Data Disease Early Diagnosis Electrophysiology (science)Employee Strikes Endoplasmic Reticulum Epithelial Cells Epithelium Esophageal Esophageal Neoplasms Esophageal Squamous Cell Carcinoma Esophagus Gene Expression Genetic Transcription Goals Greek Human Hyperactive behavior Image In Vitro Investigation Kinetics Knockout Mice Life Link Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of esophagus Manuscripts Measurement Mediating Molecular Mus Mythology Names Nature Nude Mice Oncogenes Oncogenic Outcome Patients Property Proteins Rattus Regulation Reporting Research Research Project Grants Role STIM1 gene Signal Transduction Staging Stratification Structure Survival Rate Testing Therapeutic Therapeutic Intervention Transgenic Mice Tumor Tissue United States Work Xenograft procedure anticancer research cancer cell carcinogenesis cell motility cellular imaging genome-wide analysis human disease in vivo in vivo Model innovation interdisciplinary approach mortality mouse model neoplastic novel novel therapeutic intervention novel therapeutics outcome forecast prevent prognostic public health relevance sensor stoichiometry tool tumor tumor growth tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Esophageal cancer is the 6th leading cause of cancer death worldwide with more than 90% of all cases being esophageal squamous cell carcinoma (ESCC). The overall 5-year survival rate for this disease is only 13% in US, which is the fourth worst among all cancers. There is an urgent need to identify effective biomarkers for early detection, prognostic stratification as well as novel therapeutic interventions for esophageal cancer. Dysregulation in Ca2+ signaling has been linked to many human diseases including cancers. Understanding the pathophysiological roles of Ca2+ permeable channels has recently emerged as an exciting area of cancer research. We have obtained exciting preliminary data suggesting that Orai1, a plasma membrane Ca2+ channel, acts as an oncogene that contributes to the progression of esophageal cancer through regulation of intracellular Ca2+ oscillations. In tumors removed from patients with ESCC, we detected elevated expression of Orai1 which was associated with poor survival rate. In cultured human ESCC cells, we identified a striking hyperactivity in intracellular Ca2+ oscillations, in sharp contrast to the quiescent nature in non-tumor cells. Inhibition of Orai1 by either pharmacological or molecular means could harness hyper Ca2+ oscillations, which in turn suppress cell proliferation and migration in ESCC cells. Moreover, our preliminary data showed that inhibition of Orai1 prevents tumor growth in xenograft nude mice. In this project, we hypothesize that hyperactivity of Orai1-mediated Ca2+ oscillations contributes to carcinogenesis in esophageal epithelia, and targeting Orai1 function represents a potential means for treatment of esophageal cancer. First, we will identify the molecular mechanisms underlying the hyperactivity of Ca2+ oscillations resulting from elevated Orai1-SOCE. Next, we will define the oncogenic role of Orai1 during esophageal carcinogenesis in vivo. Lastly, we will target Orai1-SOCE for ESCC therapy. A multidisciplinary approach will be used including live cell imaging, ultrastructure analysis, intracellular Ca2+ measurement, robust xenograft and carcinogen-induced esophageal cancer animal models. The innovative aspects of this project include the first study on abnormal Orai1 expression and hyperactivity of intracellular Ca2+ oscillations in ESCC, identification of the first molecule mediating endoplasmic reticulum and plasma membranes junctional structures in epithelial cells, a novel transgenic mouse model in which the expression of Orai1 is controlled in an inducible and reversible manner specifically in esophageal epithelial cells. The outcome of this project will reveal the cellular mechanistic understanding of the role of Orai1-SOCE-Ca2+ oscillations in esophageal carcinogenesis. These studies will provide proof-of-principle data on therapeutic approach for ESCC by targeting Orai1 channel activity.

描述（由申请人提供）：食管癌是全球第六大癌症死亡原因，其中 90% 以上为食管鳞状细胞癌 (ESCC)。在美国，这种疾病的总体 5 年生存率仅为 13%，在所有癌症中排名第四。迫切需要确定有效的生物标志物，用于食管癌的早期检测、预后分层以及新的治疗干预措施。 Ca2+ 信号传导失调与包括癌症在内的许多人类疾病有关。了解 Ca2+ 通透通道的病理生理学作用最近已成为癌症研究的一个令人兴奋的领域。我们获得了令人兴奋的初步数据，表明 Orai1（质膜 Ca2+ 通道）作为癌基因，通过调节细胞内 Ca2+ 振荡促进食管癌的进展。在从 ESCC 患者切除的肿瘤中，我们检测到 Orai1 表达升高，这与较差的生存率相关。在培养的人类 ESCC 细胞中，我们发现细胞内 Ca2+ 振荡显着过度活跃，与非肿瘤细胞的静止性质形成鲜明对比。通过药理学或分子手段抑制Orai1可以利用高Ca2+振荡，从而抑制ESCC细胞的细胞增殖和迁移。此外，我们的初步数据表明，抑制Orai1可防止异种移植裸鼠的肿瘤生长。在这个项目中，我们假设Orai1介导的Ca2+振荡的过度活跃有助于食管上皮细胞的癌变，而靶向Orai1功能代表了治疗食管癌的潜在手段。首先，我们将确定 Orai1-SOCE 升高导致 Ca2+ 振荡过度活跃的分子机制。接下来，我们将定义Orai1在体内食管癌发生过程中的致癌作用。最后，我们将以 Orai1-SOCE 为目标进行 ESCC 治疗。将使用多学科方法，包括活细胞成像、超微结构分析、细胞内 Ca2+ 测量、稳健的异种移植和致癌物诱导的食管癌动物模型。该项目的创新点包括首次研究食管鳞癌中Orai1的异常表达和细胞内Ca2+振荡的过度活跃，鉴定出第一个介导上皮细胞内质网和质膜连接结构的分子，一种新型转基因小鼠模型，其中Orai1的表达以可诱导和可逆的方式受到控制，特别是在食管癌中。上皮细胞。该项目的成果将揭示 Orai1-SOCE-Ca2+ 振荡在食管癌发生中的作用的细胞机制理解。这些研究将通过针对 Orai1 通道活性来提供 ESCC 治疗方法的原理验证数据。