Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis
Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis
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DOI：
10.1038/onc.2015.520
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发表时间：
2016-08-01
期刊：
影响因子：
8
通讯作者：
Lee, S.
中科院分区：
文献类型：
--
作者：
Park, C. S.;Kim, T-K;Lee, S.
上皮性卵巢癌（EOC）的侵袭和转移是一种复杂的现象，是许多转移调节因子协同作用的结果，必须加以克服，以改善这些癌症患者的临床结局。新的治疗靶点的确定是至关重要的，因为目前的治疗方案的成功有限，特别是在晚期卵巢癌。在这项研究中，我们发现四跨膜蛋白8（tetraspanin 8，TSPAN 8）在约52%（14/27）的EOC组织中过表达，并且与较差的存活率相关。使用小干扰RNA介导的TSPAN 8敲低和与纯化的TSPAN 8大细胞外环（TSPAN 8-LEL）蛋白的竞争测定，我们鉴定TSPAN 8-LEL为EOC细胞侵袭的关键调节因子。此外，我们开发的用TSPAN 8阻断抗体的单一疗法显示TSPAN 8-LEL的基于抗体的调节可以显著降低EOC转移的发生率，而没有严重的体内毒性。最后，我们证明了TSPAN 8阻断抗体促进细胞表面TSPAN 8的内化和伴随的下调。总的来说，我们的数据表明TSPAN 8是EOCs中潜在的新型治疗靶点，并且TSPAN 8的抗体靶向是抑制表达TSPAN 8的EOCs的侵袭和转移的有效策略。
Epithelial ovarian cancer (EOC) invasion and metastasis are complex phenomena that result from the coordinated action of many metastatic regulators and must be overcome to improve clinical outcomes for patients with these cancers. The identification of novel therapeutic targets is critical because of the limited success of current treatment regimens, particularly in advanced-stage ovarian cancers. In this study, we found that tetraspanin 8 (TSPAN8) is overexpressed in about 52% (14/27) of EOC tissues and correlates with poor survival. Using small interfering RNA-mediated TSPAN8 knockdown and a competition assay with purified TSPAN8 large extracellular loop (TSPAN8-LEL) protein, we identified TSPAN8-LEL as a key regulator of EOC cell invasion. Furthermore, monotherapy with TSPAN8-blocking antibody we developed shows that antibody-based modulation of TSPAN8-LEL can significantly reduce the incidence of EOC metastasis without severe toxicity in vivo. Finally, we demonstrated that the TSPAN8-blocking antibody promotes the internalization and concomitant downregulation of cell surface TSPAN8. Collectively, our data suggest TSPAN8 as a potential novel therapeutic target in EOCs and antibody targeting of TSPAN8 as an effective strategy for inhibiting invasion and metastasis of TSPAN8-expressing EOCs.