Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis
Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis
复制标题
DOI：
10.1158/0008-5472.can-04-4309
复制
发表时间：
2005-07-15
期刊：
影响因子：
11.2
通讯作者：
Lukanidin, E
中科院分区：
文献类型：
--
作者：
Christensen, C;Ambartsumian, N;Lukanidin, E
我们之前已经证明，信号素的表达，在轴突引导中被称为排斥线索，Sema3E，与在小鼠腺癌细胞模型中形成肺转移的能力相关。现在，除了通过显示SEMA3E在人类癌细胞系和乳腺癌患者的实体瘤中频繁表达来提供SEMA3E与人类疾病相关性的证据外，我们还展示了Sema3E的生物学活性，这支持了Sema3E在肿瘤进展和转移中的意义。在体内，Sema3E在乳腺癌细胞中的表达诱导形成实验性肺转移；在体外，Sema3E蛋白对内皮细胞和嗜铬细胞瘤细胞具有迁移和生长促进活性。这是3类信号素具有促进转移功能的第一个证据，因为到目前为止，这类基因在肿瘤生物学中只被认为是肿瘤抑制因子和生长的负调控因子。此外，我们还证明了由于依赖Furin的加工，全长的Sema3E蛋白被转化为p61-Sema3E亚型，并且通过分析加工缺陷和截断形式，我们证明了p61-Sema3E的产生对于Sema3E在肺转移、细胞迁移、侵袭性生长和细胞外信号调节激酶1/2激活中的功能是必要的和充分的。这些发现表明，某些乳腺癌细胞可能通过将生长拒绝剂Sema3E转化为生长诱导剂来增强其在肺部的定植能力，并指向一种不同于由全长二聚体3类信号素诱导的传统信号类型的信号素信号。
We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins.