Role of Tissue Transglutaminase in Ovarian Cancer

组织转谷氨酰胺酶在卵巢癌中的作用

• 批准号: 8597374
• 负责人: Daniela E Matei
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597374
• 关键词: Abdomen; Address; Adherens Junction; Affect; Behavior; Binding; Blood Vessels; CREB1 gene; Cause of Death; Cell Survival; Cell-Matrix Junction; Cells; Cellular Structures; Complex; Cyclic AMP Response Element; Cytoskeleton; Down-Regulation; E-Cadherin; E-Cadherin Staining Method; Enzymes; Epithelial; Extracellular Matrix; Failure; Focal Adhesion Kinase 1; Funding; Gelatinase A; Genetic Transcription; Goals; Grant; Health; Healthcare; Hospitals; Integrins; Laboratories; Left; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mediator of activation protein; Membrane Proteins; Modeling; NF-kappa B; Neoplasm Metastasis; Nude Mice; Oncogenic; Organ; Ovarian; Pathway interactions; Patients; Peritoneal; Phenotype; Phosphorylation; Play; Population; Post-Translational Protein Processing; Primary Neoplasm; Process; Proteins; Proto-Oncogene Proteins c-akt; Reporting; Resistance; Role; Signal Transduction; Site; Stem cells; Testing; Time; Tissues; Transforming Growth Factors; Transglutaminases; Tumorigenicity; Veterans; Woman; Work; abstracting; arm; base; beta catenin; cancer cell; cancer recurrence; cancer stem cell; cellular engineering; chemotherapy; crosslink; epithelial to mesenchymal transition; intraperitoneal; knock-down; malignant breast neoplasm; mortality; neoplastic cell; ovarian neoplasm; overexpression; public health relevance; response; standard care; tumor; tumor progression

DESCRIPTION (provided by applicant): Abstract The overarching hypothesis for this proposal is that tissue transglutaminase (TG2), a protein we found to be up-regulated in ovarian cancer (OC) regulates epithelial to mesenchymal transition (EMT) in OC cells and the survival of ovarian cancer stem cells by enhancing 2-catenin cellular signaling. TG2, an enzyme overexpressed in several epithelial malignancies, induces Cadependent protein post-translational modifications and cross-linking. We reported for the first time that TG2 is up-regulated in OC and work in our laboratory during the current funding period demonstrated that the enzyme critically regulates the process of OC metastasis. We showed that when injected intraperitoneally or under the ovarian bursa of nude mice, OC cells engineered to express decreased levels of TG2 induced significantly less peritoneal dissemination compared to control cells. We also showed that TG2 induces EMT of OC cells and regulates formation of spheroids from OC cells. These discoveries led us to formulate the hypothesis that TG2 is critical to the process of EMT and the survival of ovarian cancer stem cells, which we will test by addressing three objectives: Aim 1: Identify the mechanisms by which TG2 regulates 2-catenin stability and study its effects on 2-catenin dependent gene transcription. We will study whether TG2 knockdown or inhibition alters 2-catenin cellular localization, phosphorylation and signaling in response to Wnt signals, contributing to EMT of OC cells. Aim 2: Determine whether TG2 induced EMT and metastasis are regulated by 2-catenin signaling. We will investigate whether 2-catenin knock-down inhibits TG2 induced-EMT and metastasis and whether its stabilization induces EMT in cells expressing low levels of TG2. Aim 3: Establish the effects of TG2 expression on the survival and functions of ovarian cancer stem cells. We will measure and compare TG2 expression in ovarian CSCs vs. whole tumors. We will knock-down TG2 or inhibit its enzymatic activity to block the functions of ovarian CSCs (e.g. survival, formation of spheroids and tumorigenicity). Significance: We are the first group studying the role of TG2 in ovarian cancer focusing on mechanisms of metastasis and EMT modulated by TG2. This proposal is timely and highly relevant as EMT has been recently linked to the cancer-stem cell phenotype. Our group has produced evidence for the presence of such a distinct population of cells in ovarian tumors. It is likely that persistence of these cells after standard treatment is responsible for the failure of chemotherapy to eliminate cancer. Therefore, demonstrating that TG2 facilitates the survival of ovarian CSCs is highly relevant, as it will identify a new pathway that can be targeted with the goal of eradicating treatment resistant stem cells and of blocking OC metastasis. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health and Health Care Issues: Ovarian cancer is the most fatal gynecological malignancy, metastasis to abdominal organs being the most common cause of mortality. Given the increasing numbers of women in the US Armed Forces and the VA, the devastating complications of OC and limited treatment options, the issue of developing better therapies is highly relevant to the health of our veterans. The number of women in the US Armed Forces has increased from 2% to 15% and 7.4% of the veterans served by VA Hospitals are women. This proposal will investigate the role of tissue transglutaminase in metastasis and the survival of ovarian cancer stem cells. It is likely that the persistence of these stem cells is responsible for the failure of chemotherapy to eliminate cancer. It is therefore important to VA patients to better understand the key molecules that regulate these cells, which give rise to metastases, treatment resistance and cancer recurrence.

描述（由申请人提供）： 摘要该提案的总体假设是，我们发现在卵巢癌（OC）中被上调的蛋白质群谷氨酰胺酶（TG2）可通过增强2-蛋白蛋白细胞信号的2蛋白质细胞信号来调节OC细胞上皮上上皮到间充质转变（EMT）。 TG2是一种在几种上皮恶性肿瘤中过表达的酶，可诱导CADEPICERT蛋白翻译后修饰和交联。我们首次报告说，TG2在OC中被上调，在当前的资金期间在我们的实验室工作表明，该酶严格调节了OC转移的过程。我们表明，当腹膜内或在裸鼠的卵巢囊下注射时，与对照细胞相比，腹部降低的TG2诱导水平的OC细胞显着降低了腹膜传播。我们还表明，TG2诱导OC细胞的EMT并调节来自OC细胞的球体形成。这些发现使我们提出了以下假设：TG2对于EMT过程和卵巢癌干细胞的存活至关重要，我们将通过解决三个目标来测试这一点：AIM 1：确定TG2调节2-catenin稳定性并研究其对2-catenin依赖基因转录的作用的机制。我们将研究TG2敲低或抑制作用会改变2-catenin细胞定位，磷酸化和信号对WNT信号的响应，从而导致OC细胞的EMT。 AIM 2：确定TG2诱导的EMT和转移是否受2-catenin信号的调节。我们将研究2-catenin敲除抑制TG2诱导的EMT和转移是否是否会在表达低水平TG2水平的细胞中诱导EMT。 AIM 3：确定TG2表达对卵巢癌干细胞生存和功能的影响。我们将测量和比较卵巢CSC与整个肿瘤中的TG2表达。我们将击倒TG2或抑制其酶促活性以阻止卵巢CSC的功能（例如生存，球体的形成和肿瘤性）。意义：我们是研究TG2在卵巢癌中的作用的第一组，重点是TG2调节的转移和EMT机制。该提议及时且高度相关，因为EMT最近与癌症细胞表型联系在一起。我们的小组为卵巢肿瘤中存在如此不同的细胞群提供了证据。在标准治疗后，这些细胞的持久性可能导致化学疗法无法消除癌症。因此，证明TG2促进卵巢CSC的存活非常重要，因为它将确定一种可以瞄准的新途径，以消除耐药性干细胞和阻断OC转移的目标。 公共卫生相关性： 与退伍军人健康和医疗保健问题有关：卵巢癌是最致命的妇科恶性肿瘤，转移到腹部器官是死亡率最常见的原因。鉴于美国武装部队和弗吉尼亚州的妇女人数越来越多，OC和有限治疗方案的毁灭性并发症，开发更好疗法的问题与我们的退伍军人的健康高度相关。美国武装部队的妇女人数已从2％增加到15％，而VA医院服务的退伍军人中有7.4％是妇女。该建议将研究组织转谷氨酰胺酶在转移和卵巢癌干细胞存活中的作用。这些干细胞的持久性很可能导致化学疗法消除癌症的失败。因此，对于VA患者而言，重要的是要更好地了解调节这些细胞的关键分子，从而导致转移，治疗耐药性和癌症复发。