RCAN1 in Thyroid Cancer Progression

RCAN1 在甲状腺癌进展中的作用

• 批准号: 8403904
• 负责人: Matthew D Ringel
• 金额: $ 31.35万
• 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/8403904
• 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 microenvironment; 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.

描述（由申请人提供）：转移休眠被定义为转移性癌组织的其余部分存活但不侵袭远处部位并进展的能力。在甲状腺癌中，患有小肺转移的患者通常可以存活数十年而没有放射学或临床进展，这表明转移部位进展的抑制是许多甲状腺癌所固有的。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所致，因此确定这些癌症摆脱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，可能在转移进展中发挥“把关”作用。通过研究癌细胞中的 KiSS-1/GPR54 转移抑制信号级联，我们在体外确定了钙调神经磷酸酶 1-4 (RCAN1-4) 调节剂的运动抑制作用；并证明转移性甲状腺癌组织样本中这种蛋白质丢失。 RCAN1-4 也被证明在 VEGF 诱导的内皮细胞生长和运动中发挥着核心作用。有趣的是，编码所有 RCAN1 同工型的 RCAN1 (DSCR1) 基因位于 21 号染色体上，是唐氏综合症（21 三体）中过度表达的众多基因之一。最近的研究表明，Rcan1 在降低与唐氏综合症相关的实体瘤发病率和进展方面发挥着关键的功能作用。在小鼠中，表达了两种 Rcan1 同工型，它们与两种主要的人类主要同工型 RCAN1-1 和 RCAN1-4 同源。最近的体内研究证实，小鼠中的短形式 Rcan1 与人 RCAN1-4 同源，是肿瘤移植物新血管系统中主要诱导的亚型，这表明它可能在 VEGF 诱导的肿瘤血管生成中特别重要。然而，该亚型对癌症进展的功能作用尚未在体内直接测试。该提议的总体假设是，RCAN1-4 是一个关键的看门人，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的进展。我们将使用各种体内模型来检验这一假设。