Cui Ri, Takahashi Fumiyuki, Ohashi Rina, Yoshioka Masakata, Gu Tao, Tajima Ken, Unnoura Takeshi, Iwakami Shinichiro, Hirama Michihiro, Ishiwata Toshiji, Iwase Akihiko, Takahashi Kazuhisa
Department of Respiratory Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
Lung Cancer. 2009 Mar;63(3):368-74. doi: 10.1016/j.lungcan.2008.06.020. Epub 2008 Aug 26.
Malignant pleural effusion (MPE) is associated with advanced-stage lung cancer and is a poor prognostic sign for these patients. Osteopontin (OPN) is a multifunctional cytokine that is involved in the tumor progression and angiogenesis of lung cancer cells. The purpose of this study is to investigate and provide evidence for the role of OPN in the formation of MPE associated with lung cancer. In this study, we established an OPN knockdown murine lung cancer cell line, 3LL cells, utilizing the small interfering RNA (siRNA) technique. To reveal the effect of OPN on the formation of MPE associated with lung cancer, we directly injected OPN knockdown 3LL cells, 3LL/OPN siRNA, or control cells, 3LL/control siRNA, into the pleural space of C57BL/6 mice. OPN knockdown significantly reduced the formation of MPE, but did not inhibit in vivo tumor growth of 3LL cells in mice. Vascular endothelial growth factor (VEGF) concentration in MPE was markedly decreased in the 3LL/OPN siRNA in comparison with that of the 3LL/control siRNA. In vitro, recombinant OPN protein enhanced VEGF secretion from human umbilical vein endothelial cell (HUVEC) or human mesothelial cell line, Met5A cells, in a concentration-dependent manner. These results suggest that OPN is positively involved in the formation of MPE of lung cancer presumably by promoting VEGF secretion from vascular endothelial cells or mesothelial cells. OPN could be an effective target molecule for reducing MPE in lung cancer patients.
恶性胸腔积液（MPE）与晚期肺癌相关，是这些患者预后不良的标志。骨桥蛋白（OPN）是一种多功能细胞因子，参与肺癌细胞的肿瘤进展和血管生成。本研究的目的是调查并提供证据证明OPN在与肺癌相关的MPE形成中的作用。在本研究中，我们利用小干扰RNA（siRNA）技术建立了一种OPN敲低的小鼠肺癌细胞系，即3LL细胞。为了揭示OPN对与肺癌相关的MPE形成的影响，我们将OPN敲低的3LL细胞（3LL/OPN siRNA）或对照细胞（3LL/对照siRNA）直接注射到C57BL/6小鼠的胸腔内。OPN敲低显著减少了MPE的形成，但并未抑制3LL细胞在小鼠体内的肿瘤生长。与3LL/对照siRNA相比，3LL/OPN siRNA中MPE的血管内皮生长因子（VEGF）浓度明显降低。在体外，重组OPN蛋白以浓度依赖的方式增强了人脐静脉内皮细胞（HUVEC）或人间皮细胞系Met5A细胞的VEGF分泌。这些结果表明，OPN可能通过促进血管内皮细胞或间皮细胞分泌VEGF而积极参与肺癌MPE的形成。OPN可能是降低肺癌患者MPE的有效靶分子。
