Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling.
Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling.
复制标题
DOI：
10.18632/oncotarget.12420
复制
发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
El-Tanani M
中科院分区：
文献类型：
--
作者：
Yuen HF;Chan KK;Platt-Higgins A;Dakir el-H;Matchett KB;Haggag YA;Jithesh PV;Habib T;Faheem A;Dean FA;Morgan R;Rudland PS;El-Tanani M
先前已经表明，具有激活的致癌途径（包括Met激活）的癌细胞需要Ran来生长和存活。在这里，我们表明，敲低Ran导致几种乳腺癌和肺癌细胞系中Met受体表达减少。这反过来又抑制了HGF表达和Met介导的Akt通路活化，以及细胞粘附、迁移和侵袭。在细胞系模型中，Met扩增先前已被证明有助于吉非替尼耐药性，Ran敲低使细胞对吉非替尼介导的Akt和ERK 1/2磷酸化抑制敏感，从而降低细胞增殖。我们进一步证明，Met还原介导的敲低RAN，发生在转录后水平，可能通过基质金属蛋白酶。此外，免疫反应Ran和Met的水平在人乳腺癌标本中呈正相关，表明高水平的Ran可能是Met过表达的先决条件。有趣的是，高水平的免疫反应性Ran决定了Met的预后意义，表明Met和Ran的共过表达可能与癌症进展相关，并且可以组合用作预后指标。
It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator.