RCAN1 in Thyroid Cancer Progression

描述（由申请人提供）：转移性休眠被定义为剩余的转移性癌组织存活，但不会在远处侵入和进展的能力。在甲状腺癌中，小肺转移的患者通常存活数十年而无影像学或临床进展，这表明许多甲状腺癌在转移部位抑制进展是固有的。由于大多数甲状腺癌相关死亡是由于晚期进展性转移性疾病，因此确定这些癌症摆脱转移性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控因子，可能在转移进展中起到“把关”的作用。通过研究癌细胞中KiSS-1/GPR54转移抑制信号级联，我们在体外鉴定了钙调磷酸酶1-4 （RCAN1-4）的调节因子的运动抑制作用；并在转移性甲状腺癌组织样本中证实了这种蛋白质的缺失。RCAN1-4也被证明在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）中过度表达的众多基因之一。最近有研究表明，Rcan1在降低唐氏综合征相关实体瘤的发病率和进展中起着关键的功能作用。在小鼠中，两个Rcan1亚型的表达与两个主要的人类亚型Rcan1 -1和Rcan1 -4同源。最近的体内研究证实，小鼠Rcan1的短型与人Rcan1 -4同源，是肿瘤移植物新生血管中的主要诱导异构体，提示其在VEGF诱导的肿瘤血管生成中可能具有特别重要的作用，但该异构体在肿瘤进展中的功能作用尚未在体内直接测试。该建议的总体假设是，RCAN1-4是一个关键的看门者，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。我们将使用多种体内模型来验证这一假设。

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.