The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways.
The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways.
复制标题
肿瘤抑制基因ARHI（DIRAS3）通过抑制Stat3和FAK/Rho信号通路来抑制卵巢癌细胞的迁移。
DOI：
10.1038/onc.2011.213
复制
发表时间：
2012-01-05
期刊：
影响因子：
8
通讯作者：
Bast, R. C., Jr.
中科院分区：
文献类型：
--
作者：
Badgwell, D. B.;Lu, Z.;Le, K.;Gao, F.;Yang, M.;Suh, G. K.;Bao, J-J;Das, P.;Andreeff, M.;Chen, W.;Yu, Y.;Ahmed, A. A.;Liao, W. S-L;Bast, R. C., Jr.
卵巢癌在腹膜腔表面上迁移和转移。因此，限制细胞迁移的机制失调可能在疾病的发病机制中特别重要。ARHI是一种印迹肿瘤抑制基因，在>60%的卵巢癌中下调，其缺失与无进展生存期降低相关。ARHI编码一个26 kDa的GT3，与Ras同源。与Ras相反，ARHI抑制细胞生长，但它是否也调节细胞运动性以前没有研究过。在这里，我们报告ARHI的重新表达降低了IL-6和EGF刺激的SKOv 3和Hey卵巢癌细胞的运动性，抑制了趋化性和趋触性。ARHI结合并隔离细胞质中的Stat 3，防止其易位至细胞核并定位在粘着斑复合物中。Stat 3 siRNA或JAK 2抑制剂AG 490产生类似的运动抑制。然而，ARHI表达与Stat 3敲低或抑制的组合在卵巢癌细胞迁移中产生了最大的抑制，与Stat 3依赖性和Stat 3非依赖性机制一致。与两种不同的信号通路一致，Stat 3的敲低选择性抑制IL-6刺激的迁移，而FAK的敲低优先抑制EGF刺激的迁移。在EGF刺激的卵巢癌细胞中，ARHI的再表达抑制FAKY 397和SrcY 416磷酸化，破坏粘着斑，并阻断FAK介导的RhoA信号传导，导致GTP-RhoA水平降低。ARHI的再表达也以FAK和RhoA依赖的方式破坏了肌动蛋白应力纤维的形成。因此，ARHI在卵巢癌细胞迁移的调节中起着关键的和以前未表征的作用，对两种不同的信号通路产生抑制作用。
Ovarian cancers migrate and metastasize over the surface of the peritoneal cavity. Consequently, dysregulation of mechanisms that limit cell migration may be particularly important in the pathogenesis of the disease. ARHI is an imprinted tumor suppressor gene that is down regulated in >60% of ovarian cancers and its loss is associated with decreased progression-free survival. ARHI encodes a 26 kDa GTPase with homology to Ras. In contrast to Ras, ARHI inhibits cell growth, but whether it also regulates cell motility has not been previously studied Here we report that re-expression of ARHI decreases motility of IL-6- and EGF-stimulated SKOv3 and Hey ovarian cancer cells, inhibiting both chemotaxis and haptotaxis. ARHI binds and sequesters Stat3 in the cytoplasm, preventing its translocation to the nucleus and localization in focal adhesion complexes. Stat3 siRNA or the JAK2 inhibitor AG490 produced similar inhibition of motility. However, the combination of ARHI expression with Stat3 knockdown or inhibition produced greatest inhibition in ovarian cancer cell migration, consistent with Stat3-dependent and Stat3-independent mechanisms. Consistent with two distinct signaling pathways, knockdown of Stat3 selectively inhibited IL-6-stimulated migration, whereas knockdown of FAK preferentially inhibited EGF-stimulated migration. In EGF-stimulated ovarian cancer cells, re-expression of ARHI inhibited FAKY397 and SrcY416 phosphorylation, disrupted focal adhesions, and blocked FAK-mediated RhoA signaling, resulting in decreased levels of GTP-RhoA. Re-expression of ARHI also disrupted formation of actin stress fibers in a FAK- and RhoA-dependent manner. Thus, ARHI plays a critical and previously uncharacterized role in regulation of ovarian cancer cell migration, exerting inhibitory effects on two distinct signaling pathways.
登录
查看更多内容
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Debidda, M;Wang, L;Zheng, Y
通讯作者：
Zheng, Y
影响因子：
3.5
作者：
Forcet, C;Etienne-Manneville, S;Billaud, M
通讯作者：
Billaud, M
DOI：
10.1083/jcb.200708194
发表时间：
2008-01-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lim Y;Lim ST;Tomar A;Gardel M;Bernard-Trifilo JA;Chen XL;Uryu SA;Canete-Soler R;Zhai J;Lin H;Schlaepfer WW;Nalbant P;Bokoch G;Ilic D;Waterman-Storer C;Schlaepfer DD
通讯作者：
Schlaepfer DD
DOI：
10.1083/jcb.200707022
发表时间：
2008-05-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kakinuma N;Roy BC;Zhu Y;Wang Y;Kiyama R
通讯作者：
Kiyama R