Department of Respiratory Medicine, Juntendo University, School of Medicine, Bunkyo-Ku, Tokyo, Japan.
Oncogene. 2010 Apr 1;29(13):1941-51. doi: 10.1038/onc.2009.478. Epub 2010 Jan 18.
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 ACC-MESO-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.
恶性胸膜间皮瘤 (MPM) 对化疗具有耐药性，因此预后不佳。骨桥蛋白 (OPN) 是一种分泌型非胶原磷蛋白，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 的多药耐药性方面，仍有待阐明。因此，我们建立了稳定转染体 (ACC-MESO-1/OPN)，该转染体持续表达 OPN，以确定其在 MPM 中观察到的化疗耐药性中的作用。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。与对照转染体相比，ACC-MESO-1/OPN 细胞中 CD44 变体同工型的表达显著降低，这些同工型抑制 HA 结合。有趣的是，抑制 HA-CD44 相互作用可消除 ACC-MESO-1/OPN 中的多药耐药性，这表明存活信号源自 HA-CD44 相互作用。在 ACC-MESO-1/OPN 细胞中观察到 p-Akt 的水平增强，并且通过 CD44 siRNA 减少。Akt 磷酸化的抑制作用增加了 NVB、VP-16 和 GEM 诱导的细胞凋亡数量。总之，这些结果表明 OPN 通过增强 CD44 与 HA 的结合强烈参与多药耐药性。
