RCAN1 in Thyroid Cancer Progression

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/GPR 54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。RCAN 1 -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RCAN 1亚型的RCAN 1（DSCR 1）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RCAN 1 -4同源的小鼠RCAN 1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。该提案的总体假设是，RCAN 1 -4是一个关键的守门人，通过抑制癌细胞侵袭以及抑制内皮细胞对VEGF和其他血管生成信号的反应来抑制甲状腺癌进展。我们将使用各种体内模型来检验这一假设。

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.