文档介绍：中国科学技术大学
博士学位论文
Siva1抑制EMT及肿瘤转移的分子机制研究
姓名:李楠
申请学位级别:博士
专业:细胞生物学
指导教师:吴缅
2011-05-01
摘要
摘要
上皮细胞-间质细胞转化(EMT)是指上皮细胞获得间质细胞所具有的运
动性和侵润性,这一过程在生物体的发育以及肿瘤细胞的转移方面发挥着很重
要的作用。然而,上皮细胞-间质细胞转化的具体分子机制以及在癌症形成中
的作用还并没有完全的被弄清楚。
在我们的研究中,我们发现Siva1 可以和微管解聚蛋白Stathmin相互作用。
一方面,Siva1 可以直接通过蛋白相互作用抑制Stathmin的微管解聚活性;另
一方面,Siva1 可以通过钙调蛋白激酶II (CaMK II)影响Stathmin丝氨酸 16 位
的磷酸化水平来抑制Stathmin的活性。Siva1 能够促进微管的生成和稳定,阻
止焦点粘连的组装,细胞迁移以及上皮细胞-间质细胞转化。在人乳腺癌组织
样本中,转移程度高的样本里Siva1 和Stathmin丝氨酸 16 位的磷酸化均处于低
水平表达。另外,在小鼠动物模型中,敲减Siva1 可以促进肿瘤转移。这些结
果说明微管动力学在EMT中发挥重要作用,同时阐明了Siva1 在抑制细胞迁移及
EMT中的重要功能,并且提示Siva1 蛋白的下调可能有助于肿瘤转移。
综上所述,我们的实验结果提示了 Siva1 在上皮细胞-间质细胞转化(EMT)
以及肿瘤转移中发挥重要作用。

关键词: Siva1 Stathmin 上皮细胞-间质细胞转化(EMT) 肿瘤转移
I
Abstract
ABSTRACT
Epithelial–mesenchymal transition (EMT) enables epithelial cells to acquire
motility and invasiveness that are characteristic of mesenchymal cells. It plays an
important role in development and in tumor cell metastasis. However, the
mechanisms of EMT and their dysfunction in cancer cells are still not well
understood.
In our study, we report that Siva1 interacts with stathmin, a microtubule
destabilizer. Siva1 inhibits stathmin’s activity directly as well as through
Ca2+/calmodulin-dependent protein kinase II (CaMK II)-mediated phosphorylation
of stathmin at Ser16. Via the inhibition of stathmin, Siva1 enhances the formation of
microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low
levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic
states of human breast cancer cells. Furthermore, knockdown of Siva1 promotes
cancer dissemination in mouse models. These results suggest that microtubule
dynamics are critical for EMT. Furthermore, they reveal an important role for Siva1
in suppressing cell migration and EMT, and indicate that down-regulation of Siva1
may contribute to tumor cell metastasis.
In summary, these data suggest that Siva1 plays important role in