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: 8238368
• 负责人: DENISE C CONNOLLY
• 金额: $ 32.3万
• 依托单位: FOX CHASE CANCER CENTER
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238368
• 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; Health; 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; Public Health; 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; small hairpin RNA; therapeutic target; tumor; 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. PUBLIC HEALTH RELEVANCE: Changes in HEF1 protein expression have been linked to metastasis of breast, brain, skin and lung cancers. HEF1 overexpression has also been detected in ovarian cancer, a highly metastatic disease. The proposed work will define the role of HEF1 overexpression and activation of oncogenic signaling pathways in ovarian cancer. These studies may reveal several important molecular pathways regulated by HEF1 that can be targeted for treatment of ovarian cancer patients.

描述（由申请人提供）：HEF1/NEDD9/CAS-L（HEF1）是一种分子脚手架蛋白，可在相互作用期间和有丝分裂过程中介导细胞信号传导。在过去的两年中，HEF1表达的改变已被证明在癌症转移中起着重要作用。 HEF1的表达增加已显示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。 当疾病在卵巢以外传播（转移）时，在晚期诊断出70％以上的上皮卵巢癌病例（EOC）。虽然卵巢癌患者通常在手术缓解和化学疗法后通常反应良好，但大多数疾病复发，最终屈服于转移性疾病。最近的研究表明，HEF1通常在晚期浆液EOC（最常见的EOC类型）中过表达。重要的是，在EOC中，HEF1激活的几种致癌蛋白也已被激活或过表达。其中包括焦点粘附激酶（FAK），SRC和信号传感器以及转录3的激活因子（STAT3）。 HEF1过表达与FAK，SRC和STAT3激活卵巢癌的关联尚未建立。 该提案的目的是了解HEF1过表达影响卵巢癌的发育，进展和转移的细胞机制，并最终验证HEF1以及HEF1作为卵巢癌患者治疗干预的靶标。 该提议有三个目标。在AIM 1中，我们将使用诱导的HEF1/HEF1表达构建体和RNA干扰（RNAI）策略来确定内源性人HEF1或鼠类HEF1在人和鼠类卵巢癌细胞系中的效果。该目标还将研究HEF1在STAT3激活和STAT3介导的迁移和侵袭中的作用。在AIM 2中，我们将使用体内小鼠模型系统来确定肿瘤细胞中HEF1表达和/或肿瘤微环境在EOC发育，进展和转移中的特定需求。在AIM 3中，我们将全面评估HEF1及其与细胞迁移和侵袭相关的关键结合伙伴（例如FAK，PFAK，SRC，PSRC，PSRC，STAT3和PSTAT3）在原发性人类卵巢肿瘤中。使用人EOC组织微阵列，我们将确定这些蛋白质在正常卵巢中以及在每个组织学亚型的早期和晚期肿瘤中的表达模式和关系，例如，浆液性，子宫内膜细胞，粘液和透明细胞癌），并将这些模式与临床数据相关联，包括病理学，治疗和病理学。 公共卫生相关性：HEF1蛋白表达的变化与乳房，脑，皮肤和肺癌的转移有关。在高度转移性疾病的卵巢癌中，还发现了HEF1过表达。拟议的工作将定义HEF1过表达的作用和卵巢癌中致癌信号通路的激活。这些研究可能揭示了由HEF1调节的几种重要分子途径，这些途径可用于治疗卵巢癌患者。