Guo Xiaobin, Zhu Xiaoming, Zhao Limin, Li Xiao, Cheng Dongjun, Feng Keqing
1 Department of Respiratory Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China.
2 Department of Thoracic Surgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China.
Tumour Biol. 2017 Mar;39(3):1010428317694324. doi: 10.1177/1010428317694324.
Lung cancer, especially the non-small-cell lung cancer, is a highly aggressive vascular cancer with excessively activated signaling pathways. Tumor-associated calcium signal transducer 2, also known as trop2, was identified to be correlated with tumor proliferation and invasion of non-small-cell lung cancer; however, the biological role of trop2 in neovascularization of non-small-cell lung cancer remained elusive. In this study, we first verified that trop2 was overexpressed in non-small-cell lung cancer tissues as well as cell lines and that the increased expression of trop2 promoted non-small-cell lung cancer cell proliferation and invasion. Then, we expanded the biological role of trop2 by in vitro and in vivo angiogenesis assay. The tubular formation analysis revealed that trop2 promoted non-small-cell lung cancer angiogenesis in vitro, and the immunohistochemistry staining of vascular markers (CD31 and CD34) provided evidences that trop2 promoted in vivo neovascularization. The results of polymerase chain reaction array revealed that trop2 promoted the expression level of two well-known angiogenesis factors MMP13 and PECAM1. By screening the trop2-related signaling pathways, we observed that excessive angiogenesis was correlated with activation of ERK1/2 signaling pathway, and ERK1/2 inhibitor (U0126) could suppress the tubular formation ability induced by trop2 expression. These results suggested that trop2 facilitated neovascularization of non-small-cell lung cancer via activating ERK1/2 signaling pathway. Targeting trop2 might provide novel anti-angiogenesis strategy for non-small-cell lung cancer treatment.
肺癌，尤其是非小细胞肺癌，是一种具有高度侵袭性的血管性癌症，其信号通路过度激活。肿瘤相关钙信号转导蛋白2，也称为trop2，已被确定与非小细胞肺癌的肿瘤增殖和侵袭相关；然而，trop2在非小细胞肺癌新生血管形成中的生物学作用仍不清楚。在本研究中，我们首先证实trop2在非小细胞肺癌组织以及细胞系中过表达，并且trop2表达的增加促进了非小细胞肺癌细胞的增殖和侵袭。然后，我们通过体外和体内血管生成试验扩展了trop2的生物学作用。管状形成分析显示trop2在体外促进非小细胞肺癌血管生成，血管标志物（CD31和CD34）的免疫组织化学染色提供了trop2在体内促进新生血管形成的证据。聚合酶链反应阵列结果显示trop2促进了两种著名的血管生成因子MMP13和PECAM1的表达水平。通过筛选与trop2相关的信号通路，我们观察到过度的血管生成与ERK1/2信号通路的激活相关，并且ERK1/2抑制剂（U0126）可以抑制trop2表达诱导的管状形成能力。这些结果表明trop2通过激活ERK1/2信号通路促进非小细胞肺癌的新生血管形成。靶向trop2可能为非小细胞肺癌治疗提供新的抗血管生成策略。
