The Role of HEF1 in Ovarian Cancer Development, Progression, and Metastasis

HEF1 在卵巢癌发生、进展和转移中的作用

• 批准号: 8460153
• 负责人: DENISE C CONNOLLY
• 金额: $ 30.39万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460153
• 关键词: Abdominal Cavity; Adenocarcinoma; Affect; Anti-Mullerian Hormone Receptor Type II; Apoptosis; Ascites; Bilateral; Binding; Biological Models; Cancer Patient; Cancer cell line; Cell Line; Cell Proliferation; Cell division; Centrosome; Clear Cell; Clinical; Clinical Data; Complex; Data; Development; Diagnostic Neoplasm Staging; Disease; Employee Strikes; Epithelial ovarian cancer; Female; Focal Adhesion Kinase 1; Focal Adhesions; Glioblastoma; Goals; Growth; Histologic; Human; In Vitro; Interphase; Knockout Mice; Laboratories; Link; Lung Neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Metastatic to; Mitosis; Molecular; Morbidity - disease rate; Mucinous; Mus; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Organ; Ovarian Carcinoma; Ovary; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Penetrance; Peritoneal; Play; Prevention; Production; Proteins; RNA Interference; Recurrence; Regulation; Role; Scaffolding Protein; Serous; Serous Cystadenocarcinoma; Signal Pathway; Signal Transduction; Simian virus 40; Skin Cancer; Staging; Stat3 protein; Testing; Therapeutic Intervention; Tissue Microarray; Transgenic Mice; Transgenic Organisms; Treatment outcome; Tumor Debulking; Tumor stage; Viral Tumor Antigens; Woman; Work; base; cancer cell; cancer diagnosis; cell motility; chemotherapy; improved; in vitro Assay; in vitro Model; in vivo; lung Carcinoma; malignant ascites; malignant breast neoplasm; melanoma; migration; mortality; mouse model; neoplastic cell; novel; ovarian neoplasm; overexpression; promoter; protein activation; protein expression; public health relevance; small hairpin RNA; therapeutic target; tumor; tumor microenvironment; tumor xenograft

DESCRIPTION (provided by applicant): HEF1/NEDD9/Cas-L (HEF1) is a molecular scaffolding protein that mediates cellular signaling from focal adhesions during interphase and at centrosomes during mitosis. Over the past two years, alterations in expression of HEF1 have been shown to play a significant role in cancer metastasis. Increased expression of HEF1 has been shown to induce invasion in glioblastoma and promote melanoma and lung carcinoma metastasis in humans and mice. Perturbations of HEF1 expression have also been linked to breast cancer metastasis. More than 70% of cases of epithelial ovarian cancer (EOC) are diagnosed at advanced stage, when disease has spread (metastasized) beyond the ovary. While ovarian cancer patients often initially respond well after surgical debulking and chemotherapy, most suffer disease recurrence and ultimately succumb to metastatic disease. Recent studies have shown that HEF1 is commonly overexpressed in advanced stage serous EOC, the most common type of EOC. Importantly, several oncogenic proteins that are activated by HEF1 have also been shown to be activated or overexpressed in EOC. Among these are focal adhesion kinase (FAK), Src and signal transducer and activator of transcription 3 (STAT3). An association of HEF1 overexpression to activation of FAK, Src and STAT3 in ovarian cancer has not yet been established. The goal of this proposal is to understand the cellular mechanisms by which HEF1 overexpression influences ovarian carcinoma development, progression and metastasis and ultimately to validate HEF1 and the signaling pathways activated by HEF1 as targets for therapeutic intervention in ovarian cancer patients. This proposal has three aims. In Aim 1 we will use inducible HEF1/Hef1 expression constructs and RNA interference (RNAi) strategies to determine the effects of enforced expression or depletion of endogenous human HEF1 or murine Hef1 in human and murine ovarian carcinoma cell lines. This aim will also investigate the role of HEF1 in regulation of STAT3 activation and STAT3-mediated migration and invasion. In Aim 2, we will use in vivo mouse model systems to determine the specific requirement(s) of Hef1 expression in tumor cells and/or the tumor microenvironment in EOC development, progression and metastasis. In Aim 3, we will comprehensively evaluate HEF1 and its critical binding partners relevant to cell migration and invasion (e.g., FAK, pFAK, Src, pSrc, STAT3 and pSTAT3) in primary human ovarian tumors. Using human EOC tissue microarrays, we will determine the patterns and relationship of expression of these proteins in normal ovaries as well as in borderline, early and late stage tumors of each histologic subtype (e.g., serous, endometrioid, mucinous and clear cell cancers) and correlate these patterns with clinical data including pathology, treatment and outcome.

描述（由申请人提供）：HEF1/NEDD9/Cas-L (HEF1) 是一种分子支架蛋白，可介导间期期间和有丝分裂期间中心体处粘着斑的细胞信号传导。在过去的两年里，HEF1表达的改变已被证明在癌症转移中发挥着重要作用。 HEF1 表达增加已被证明可诱导胶质母细胞瘤的侵袭并促进人类和小鼠的黑色素瘤和肺癌转移。 HEF1 表达的扰动也与乳腺癌转移有关。 超过 70% 的上皮性卵巢癌 (EOC) 病例在晚期被诊断出来，此时疾病已扩散（转移）到卵巢以外。虽然卵巢癌患者在手术减瘤和化疗后通常最初反应良好，但大多数患者会出现疾病复发并最终死于转移性疾病。最近的研究表明，HEF1 在晚期浆液性 EOC（最常见的 EOC 类型）中通常过度表达。重要的是，HEF1 激活的几种致癌蛋白也已被证明在 EOC 中被激活或过度表达。其中包括粘着斑激酶 (FAK)、Src 以及信号转导子和转录激活子 3 (STAT3)。卵巢癌中 HEF1 过表达与 FAK、Src 和 STAT3 激活之间的关联尚未确定。 该提案的目的是了解HEF1过表达影响卵巢癌发生、进展和转移的细胞机制，并最终验证HEF1和HEF1激活的信号通路作为卵巢癌患者治疗干预的靶标。 该提案有三个目标。在目标 1 中，我们将使用诱导型 HEF1/Hef1 表达构建体和 RNA 干扰 (RNAi) 策略来确定人和鼠卵巢癌细胞系中内源性人 HEF1 或鼠 Hef1 的强制表达或耗竭的影响。该目标还将研究 HEF1 在调节 STAT3 激活和 STAT3 介导的迁移和侵袭中的作用。在目标 2 中，我们将使用体内小鼠模型系统来确定肿瘤细胞和/或肿瘤微环境中 Hef1 表达在 EOC 发展、进展和转移中的具体要求。在目标 3 中，我们将全面评估 HEF1 及其与原发性人类卵巢肿瘤中细胞迁移和侵袭相关的关键结合伴侣（例如 FAK、pFAK、Src、pSrc、STAT3 和 pSTAT3）。使用人类EOC组织微阵列，我们将确定这些蛋白质在正常卵巢以及每种组织学亚型（例如浆液性、子宫内膜样、粘液性和透明细胞癌）的交界性、早期和晚期肿瘤中的表达模式和关系，并将这些模式与临床数据（包括病理学、治疗和结果）相关联。