Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor
Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor
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DOI：
10.1038/ng1703
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发表时间：
2006-01-01
期刊：
影响因子：
30.8
通讯作者：
Ewen, ME
中科院分区：
文献类型：
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作者：
Takahashi, C;Contreras, B;Ewen, ME
编码视网膜母细胞瘤肿瘤抑制因子的基因突变使人类和小鼠易于发生肿瘤（1，2）。在这里，我们评估了Nras基因缺失对Rb 1杂合子小鼠肿瘤发展的影响。一个或两个Nras等位基因的丢失显示出通过增强其分化而显著降低Rb 1（+/-）动物中产生的垂体肿瘤的严重程度。相比之下，Rb 1（+/-）小鼠中发生的C细胞甲状腺腺瘤在Nras缺失后进展为转移性髓样癌。在Rb 1（+/-）Nras（+/-）动物中，甲状腺髓样癌远处转移与剩余野生型Nras等位基因的丢失相关。Rb 1缺陷型C细胞中Nras的缺失导致Ras同源家族A（RhoA）活性升高，这与这些细胞的侵袭性和转移行为有因果关系。这些发现表明，在某些细胞环境中的原癌基因Nras的丢失可以促进恶性肿瘤的进展。
Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development(1,2). Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-) Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A ( RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.