Microvesicles releasing by oral cancer cells enhance endothelial cell angiogenesis via Shh/RhoA signaling pathway
Microvesicles releasing by oral cancer cells enhance endothelial cell angiogenesis via Shh/RhoA signaling pathway
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DOI：
10.1080/15384047.2017.1373213
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发表时间：
2017-09
影响因子：
3.6
通讯作者：
Xiao Huaitong;Feng Yuanyong;Tao Yueqin;Z. Peng;S. Wei;S. Kai
中科院分区：
文献类型：
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作者：
Xiao Huaitong;Feng Yuanyong;Tao Yueqin;Z. Peng;S. Wei;S. Kai
本研究旨在探讨与口腔鳞状细胞癌（OSCC）临床病理参数相关的刺猬信号通路的意义及其对血管生成的影响。采用免疫组化方法检测80例OSCC原发肿瘤和转移淋巴结中Sonic Hh （Shh）和Gli1的表达。western blot检测Shh在OSCC细胞系和OSCC源性微泡（mv）中的表达。通过基质电泳进一步研究了Shh在诱导内皮细胞血管生成中的作用。结果表明，Shh的表达与微血管口腔（MVD）、TNM分期、肿瘤复发和淋巴结转移呈正相关。此外，Shh和Gli1在配对转移淋巴结中的表达高于原发肿瘤的表达。Shh在Cal27中表达丰富，在SCC4、SCC9中也存在，并且靶向mv的Cal27中Shh蛋白的量比Cal27细胞组显著增加，高达5倍。Cal27衍生的MVs可显著促进HUVECs体外血管生成，其作用可通过抑制RhoA的表达和激活而被C3转移酶（C3）和靶向RhoA的shRNA阻断。这些数据表明，由mv携带的OSCC衍生Shh可能促进肿瘤生长并调节原发肿瘤和/或转移前生态位血管网络的制备。
ABSTRACT The present study aimed to investigate the significance of hedgehog signaling pathway in association with clinicopathology parameters and its effect on angiogenesis in oral squamous cell carcinoma (OSCC). The expression of Sonic Hh (Shh) and Gli1 were done on primary tumors and metastatic lymph nodes in OSCC samples from 80 patients by immunohistochemical analysis. The western blot was used to examine the expression of Shh in OSCC cell lines and OSCC-derived microvesicles (MVs). The role of Shh carried by MVs to induce endothelial cell angiogenesis was further investigated by matrigel assay. Our results indicated that the expression of Shh was positive associated with microvesseldentisty(MVD), TNM stage, tumor recurrence and lymph node metastasis. Moreover, Shh and Gli1 expression were higher in paired metastatic lymph nodes compared with expression of their primary tumors. The expression of Shh was abundant in Cal27, and present in SCC4, SCC9, and the amount of Shh protein in Cal27 targeting MVs was increased significantly than Cal27 cell group, up to ∼ fifth-fold. The Cal27 derived MVs increased significantly angiogenesis of HUVECs in vitro, and this effect was blocked with exoenzyme C3 transferase (C3) and shRNA targeting RhoA by suppressing RhoA expression and activation. The data suggested that OSCC derived Shh carried by MVs may facilitate the tumor growth and modulate the preparation of a vascular network in primary tumor and/or premetastatic niche.