Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells
Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells
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DOI：
10.1038/onc.2009.478
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发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Takahashi, K.
中科院分区：
文献类型：
--
作者：
Tajima, K.;Ohashi, R.;Takahashi, K.
恶性胸膜间皮瘤（MPM）对化疗有抵抗力，因此预后很差。骨桥蛋白（OPN）是一种分泌型非胶原蛋白和磷蛋白，被认为参与了MPM的发病机制。然而，OPN的确切作用，特别是在MPM的多药耐药中的作用，仍有待阐明。因此，我们建立了稳定的转染子（ACC-MESO-1/OPN），组成型表达OPN，以确定其在MPM中观察到的化学抗性中的作用。OPN基因的引入通过增强透明质酸（HA）结合的机制为MPM细胞提供了上调的多药耐药性。与对照转染子相比，ACC-MESO-1/OPN细胞中抑制HA结合的CD 44变体同种型的表达显著降低。有趣的是，HA-CD 44相互作用的抑制消除了ACC-MESO-1/OPN中的多药耐药性，从而表明HA-CD 44相互作用发出的存活信号的参与。在ACCMESO-1/OPN细胞中观察到p-Akt水平的增加，并且通过CD 44 siRNA减少。抑制Akt磷酸化可增加NVB、VP-16和GEM诱导的凋亡细胞数。总的来说，这些结果表明OPN通过增强CD 44与HA的结合而强烈参与多药耐药性。Oncogene（2010）29，1941-1951; doi：10.1038/onc.2009.478; 2010年1月18日在线发表
Malignant pleural mesothelioma (MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin (OPN), a secreted noncollagenous and phosphoprotein, is suggested to be involved in the pathogenesis of MPM. However, the precise role of OPN, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants (ACC-MESO-1/OPN), which constitutively express OPN, to determine its role in the chemoresistance observed in MPM. The introduction of the OPN gene provides MPM cells with upregulated multidrug resistance through the mechanism of enhanced hyaluronate (HA) binding. The expression of CD44 variant isoforms, which inhibit HA binding, significantly decreased in ACC-MESO-1/OPN cells in comparison to control transfectants. Interestingly, the inhibition of the HA-CD44 interaction abrogated multidrug resistance in the ACC-MESO-1/OPN, thus suggesting the involvement of the surviving signal emanating from the HA-CD44 interaction. An enhanced level of the p-Akt in ACCMESO-1/OPN cells was observed, and was diminished by CD44 siRNA. Inhibition of the Akt phosphorylation increased in number of the cells underwent apoptosis induced by NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA. Oncogene (2010) 29, 1941-1951; doi:10.1038/onc.2009.478; published online 18 January 2010