RCAN1 in Thyroid Cancer Progression

RCAN1 在甲状腺癌进展中的作用

• 批准号: 8235810
• 负责人: Matthew D Ringel
• 金额: $ 33.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-03 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235810
• 关键词: Address; Back; Behavior; Biological Markers; Biological Models; Calcineurin; Cancer Model; Cancer Patient; Cessation of life; Chromosomes, Human, Pair 21; Clinical; Clinical Data; Clinical Trials; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Down Syndrome; Endothelial Cells; Genes; Goals; Growth; Histology; Human; In Vitro; Incidence; Invaded; KISS1 gene; KISS1R gene; Laboratories; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of thyroid; Mediating; Metastasis Suppressor Genes; Metastasis Suppressor Proteins; Modeling; Mus; Neoplasm Metastasis; Patients; Play; Process; Protein Isoforms; Proteins; Reporting; Rest; Role; Signal Transduction; Site; Solid Neoplasm; Staging; Testing; Thyroid Gland; Tissue Sample; Tissues; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Xenograft procedure; angiogenesis; base; body system; cancer cell; cell growth; cell motility; effective therapy; in vivo; in vivo Model; inhibitor/antagonist; knock-down; mouse model; neovascularization; neovasculature; novel; overexpression; public health relevance; response; restraint; success; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Metastatic dormancy is defined as the ability of rests of metastatic cancer tissue to survive, but not invade and progress at distant sites. In thyroid cancer, patients with small lung metastases often survive for decades without radiographic or clinical progression, suggesting that restraint of progression at metastatic sites is intrinsic to many thyroid cancers. Because most thyroid cancer- related deaths are due to late-stage progressive metastatic disease, it is crucial to define mechanisms that by which these cancers escape from metastatic dormancy. Metastasis suppressors are negative regulators of cancer metastasis and growth that may serve a "gate-keeping" role in metastatic progression. By interrogating the KiSS-1/GPR54 metastasis inhibitory signaling cascade in cancer cells, we identified a motility-suppressor role for regulator of calcineurin 1-4 (RCAN1-4) in vitro; and demonstrated loss of this protein in metastatic thyroid cancer tissue samples. RCAN1-4 has also been shown to play a central role in VEGF-induced endothelial cell growth and motility. Interestingly, the RCAN1 (DSCR1) gene that encodes all RCAN1 isoforms is located on chromosome 21, and is one of many genes overexpressed in Down's syndrome (trisomy 21). It was recently demonstrated that Rcan1 plays a critical functional role in the reduced solid tumor incidence and progression associated with Down's syndrome. In mouse two Rcan1 isoforms are expressed that are homologous to the two dominant primary human isoforms, RCAN1-1 and RCAN1-4. Recent in vivo studies confirmed that short form of Rcan1 in mouse, which is homologous to human RCAN1-4, is the primary induced isoform in the neovasculature of tumor grafts, suggesting that it may be specifically important in tumor angiogenesis induced by VEGF However the functional role of this isoform on cancer progression has not been directly tested in vivo. The overall hypothesis of this proposal is that RCAN1-4 is a key gate-keeper that restrains thyroid cancer progression by inhibiting cancer cell invasion and by inhibiting endothelial cell response to VEGF and other angiogenic signals. We will use a variety of in vivo models to test this hypothesis. PUBLIC HEALTH RELEVANCE: Project Narrative Metastatic dormancy, or the ability of cancer cells in metastatic sites to survive without progressing, is common in thyroid cancer, thus, this malignancy serves as an excellent model to study this important process. Moreover, defining mechanisms by which metastatic dormancy is maintained and/or lost has potential to identify new biomarkers and therapeutic targets for patients with progressive metastatic thyroid cancer for which there are no effective therapies. Based on preliminary laboratory and clinical data, we hypothesize in the current proposal that RCAN1-4 is a critical and highly regulated protein that maintains metastatic dormancy of thyroid cancer.

描述（由申请人提供）：转移性休眠被定义为转移性癌组织的剩余部分存活的能力，但不侵入和在远处部位进展。在甲状腺癌中，具有小肺转移的患者通常存活数十年而没有放射学或临床进展，这表明转移部位的进展抑制是许多甲状腺癌的内在原因。由于大多数甲状腺癌相关死亡是由于晚期进行性转移性疾病，因此确定这些癌症逃离转移休眠的机制至关重要。转移抑制因子是癌症转移和生长的负调节因子，其可在转移进展中起到"守门"作用。通过询问癌细胞中KiSS-1/GPR54转移抑制信号级联，我们在体外鉴定了钙调神经磷酸酶1 - 4（RCAN 1 - 4）调节因子的运动抑制作用;并证明了这种蛋白在转移性甲状腺癌组织样本中的丢失。RCAN1 - 4也已被证明在VEGF诱导的内皮细胞生长和运动中发挥核心作用。有趣的是，编码所有RCAN1亚型的RCAN1（DSCR1）基因位于21号染色体上，是唐氏综合征（21三体）中过度表达的许多基因之一。最近证明，Rcan 1在降低实体瘤发病率和与唐氏综合征相关的进展中起着关键的功能作用。在小鼠中表达两种Rcan 1同种型，其与两种主要的主要人类同种型RCAN 1 - 1和RCAN 1 - 4同源。最近的体内研究证实，与人RCAN1 - 4同源的小鼠RCAN1的短形式是肿瘤移植物的新生血管中的主要诱导同种型，这表明它可能在VEGF诱导的肿瘤血管生成中特别重要。该建议的总体假设是RCAN 1 - 4是通过抑制癌细胞侵袭和抑制内皮细胞对VEGF和其他血管生成信号的反应来抑制甲状腺癌进展的关键守门人。我们将使用各种体内模型来检验这一假设。 公共卫生相关性：转移性休眠，或转移部位的癌细胞存活而不进展的能力，在甲状腺癌中很常见，因此，这种恶性肿瘤是研究这一重要过程的极好模型。此外，定义转移性休眠维持和/或丧失的机制有可能为没有有效治疗方法的进行性转移性甲状腺癌患者确定新的生物标志物和治疗靶点。基于初步的实验室和临床数据，我们假设RCAN1 - 4是维持甲状腺癌转移休眠的关键和高度调节的蛋白质。