Hsu Ya-Ling, Hung Jen-Yu, Liang Yung-Yu, Lin Yi-Shiuan, Tsai Ming-Ju, Chou Shah-Hwa, Lu Chi-Yu, Kuo Po-Lin
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Oncotarget. 2015 Oct 6;6(30):29585-98. doi: 10.18632/oncotarget.4987.
S100P, a Ca2+ binding protein, has been shown to be overexpressed in various cancers. However, its functional character in lung cancer remains largely unknown. In this study, we show that S100P increases cancer migration, invasion and metastasis in lung cancer cells. Ectopic expression of S100P increases migration, invasion and EMT in less invasive CL1-0 lung cancer cells. Conversely, knockdown of S100P suppressed migration and invasion, and caused a reversion of EMT in highly invasive lung cancer cells. These effects were transduced by increasing the interaction of S100P with integrin α7, which activated focal adhesion kinase (FAK) and AKT. Blocking FAK significantly decreased S100P-induced migration by decreasing Src and AKT activation, whereas inhibiting AKT reduced S100P upregulation on ZEB1 expression. Further study has indicated that S100P knockdown prevents the spread of highly metastatic human lung cancer in animal models. This study therefore suggests that S100P represents a critical activator of lung cancer metastasis. Detection and targeted treatment of S100P-expressing cancer is an attractive therapeutic strategy in treating lung cancer.
S100P是一种钙结合蛋白，已被证明在多种癌症中过度表达。然而，其在肺癌中的功能特性仍 largely未知。在本研究中，我们表明S100P增加肺癌细胞的迁移、侵袭和转移。S100P的异位表达增加了侵袭性较低的CL1-0肺癌细胞的迁移、侵袭和上皮-间质转化（EMT）。相反，敲低S100P可抑制迁移和侵袭，并导致高侵袭性肺癌细胞中EMT的逆转。这些效应是通过增加S100P与整合素α7的相互作用来传导的，这激活了粘着斑激酶（FAK）和AKT。阻断FAK通过降低Src和AKT的激活显著降低S100P诱导的迁移，而抑制AKT则降低S100P对ZEB1表达的上调。进一步的研究表明，敲低S100P可防止高转移性人肺癌在动物模型中的扩散。因此，本研究表明S100P是肺癌转移的关键激活因子。检测和靶向治疗表达S100P的癌症是治疗肺癌的一种有吸引力的治疗策略。
