Contribution of N-ras loss to metastasis of thyroid C-cell tumors

描述（申请人提供）：视网膜母细胞瘤蛋白（pRb）的肿瘤抑制活性已得到充分证实，因为视网膜母细胞瘤基因突变与多种癌症相关。pRb对肿瘤的抑制作用部分依赖于其在分化中的作用，这在很大程度上是未知的。最近，Ewen实验室已经表明Rb基因在N-ras原癌基因的上游起作用以调节小鼠的分化。此外，Rb和N-ras杂合的小鼠发生经常转移的甲状腺腺瘤。本研究拟通过检测小鼠滤泡旁细胞（C细胞）的转移潜能表型来研究Rb和N-ras基因间的相互作用。N-ras缺失导致转移的途径尚不清楚，但认为C细胞转移的迁移可能是由于发育Hox基因的异常表达引起的，该基因在正常胚胎发育中引起C细胞迁移。为了理解pRb和N-ras在转移中的作用，将确定N-ras剂量对pRb缺失转移中hox基因表达的影响。在转移和胚胎发育之间建立联系将是理解恶性肿瘤的有价值的一步。

DESCRIPTION (provided by applicant): The tumor suppression activity of the retinoblastoma protein (pRb) is well established, as mutations in the retinoblastoma gene are associated with a wide variety of cancers. Tumor suppression by pRb is partly dependent on its role in differentiation, which is largely uncharacterized. Recently, the Ewen laboratory has shown that the Rb gene acts upstream of the N-ras proto-oncogene to regulate differentiation in mice. Furthermore, mice that are heterozygous for both Rb and N-ras develop thyroid adenomas that frequently metastasize. This proposal will study the genetic interaction between Rb and N-ras in parafollicular cells (C cells) of mice by measuring their metastatic potential as phenotype. The pathway by which N-ras loss contributes to metastasis is unknown, but it is thought that the migration of C-cell metastases may arise from aberrant expression of developmental Hox genes that cause C-cell migration in normal embryonic development. To understand the role of pRb and N-ras in metastasis, the effect of N-ras dosage on hox gene expression in pRb nullizygous metastases will be determined. Making the link between metastasis and embryonic development would be a valuable step in understanding malignant cancers.