Critical role of the Ror-family of receptor tyrosine kinases in invasion and proliferation of malignant pleural mesothelioma cells
Critical role of the Ror-family of receptor tyrosine kinases in invasion and proliferation of malignant pleural mesothelioma cells
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DOI：
10.1111/gtc.12599
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发表时间：
2018-07-01
期刊：
影响因子：
2.1
通讯作者：
Minami, Yasuhiro
中科院分区：
文献类型：
--
作者：
Saji, Takeshi;Nishita, Michiru;Minami, Yasuhiro
恶性胸膜间皮瘤（MPM）是一种高度侵袭性的肿瘤，预后差，与石棉接触密切相关。MPM是一种异质性肿瘤，主要有上皮样型、肉瘤样型和双相型三种组织学亚型，其中肉瘤样型预后最差。受体酪氨酸激酶Ror家族Ror 1和Ror 2在各种类型的肿瘤细胞中以较高水平表达，并影响其侵袭性。然而，目前尚不清楚它们是否在MPM的侵袭性中表达并参与其中。在这里，我们表明，Ror 1和Ror 2的表达在临床标本和细胞系的MPM具有不同的组织学特征。使用MPM细胞系的研究表明，Ror 2的表达与MPM细胞的高侵袭性紧密相关，而Ror 1可以在Ror 2不存在的情况下促进其侵袭。然而，Ror 1和Ror 2都促进MPM细胞的增殖。我们还表明，促进侵袭和增殖的MPM细胞的Ror信号可以介导的Rho家族的小GTP酶，Rac1，和Cdc42。这些发现阐明了Ror信号在促进MPM细胞侵袭和增殖中的关键作用。
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis and closely related to exposure to asbestos. MPM is a heterogeneous tumor with three main histological subtypes, epithelioid, sarcomatoid, and biphasic types, among which sarcomatoid type shows the poorest prognosis. The Ror-family of receptor tyrosine kinases, Ror1 and Ror2, is expressed in various types of tumor cells at higher levels and affects their aggressiveness. However, it is currently unknown whether they are expressed in and involved in aggressiveness of MPM. Here, we show that Ror1 and Ror2 are expressed in clinical specimens and cell lines of MPM with different histological features. Studies using MPM cell lines indicate that expression of Ror2 is associated tightly with high invasiveness of MPM cells, whereas Ror1 can contribute to their invasion in the absence of Ror2. However, both Ror1 and Ror2 promote proliferation of MPM cells. We also show that promoted invasion and proliferation of MPM cells by Ror signaling can be mediated by the Rho-family of small GTPases, Rac1, and Cdc42. These findings elucidate the critical role of Ror signaling in promoting invasion and proliferation of MPM cells.