TIPE2 suppresses angiogenesis and non-small cell lung cancer (NSCLC) invasiveness via inhibiting Rac1 activation and VEGF expression.

// Zequn Li 1 , Chun Guo 1 , Xianglan Liu 1 , Chengjun Zhou 2 , Faliang Zhu 1 , Xiaoyan Wang 1 , Qun Wang 1 , Yongyu Shi 1 , Jianing Wang 1 , Wei Zhao 1 , Lining Zhang 1 1 Department of Immunology, Shandong University School of Medicine, Jinan, China 2 Department of Pathology, The Second Hospital of Shandong University, Jinan, China Correspondence to: Lining Zhang, email: zhanglining@sdu.edu.cn Keywords: TIPE2, NSCLC, angiogenesis, invasiveness, Rac1 Received: September 22, 2015     Accepted: August 08, 2016     Published: August 19, 2016 ABSTRACT Non-small cell lung cancer (NSCLC) is one of the leading causes of all cancer-related deaths worldwide. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a newly introduced negative immune regulator, which also controls tumorigenesis. However, the role of TIPE2 in angiogenesis is unknown. In the present study, we investigated the expression and roles of TIPE2 in NSCLC. TIPE2 upregulation in human NSCLC tissues was negatively associated with the primary tumor size, lymph node metastasis, and advanced clinical stage, which can be used to predict lymph node metastasis. Moreover, overexpression of TIPE2 not only inhibited the colony formation, migration, and invasion of NSCLC cells but also indirectly suppressed the proliferation, migration, and tube formation of vascular endothelial cells. Furthermore, TIPE2 suppressed tumor invasiveness and angiogenesis via inhibiting the activation of Rac1 and subsequently weakening its downstream effects, including F-actin polymerization and VEGF expression. Collectively, these results indicate that TIPE2 plays a key role in NSCLC metastasis, suggesting that forced TIPE2 expression might be a novel strategy for the treatment of NSCLC.