Dataset Information

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

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.

SUBMITTER: Li Z

PROVIDER: S-EPMC5308722 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Li Zequn Z Guo Chun C Liu Xianglan X Zhou Chengjun C Zhu Faliang F Wang Xiaoyan X Wang Qun Q Shi Yongyu Y Wang Jianing J Zhao Wei W Zhang Lining L

Oncotarget 20160901 38

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 ...[more]

PMID: 27556698

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Project description:Non?small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer?related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor?A (VEGF?A) which plays a pivotal role in tumour angiogenesis. Anti?angiogenic therapies including VEGF?A neutralisation have significantly improved the response rates, progression?free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF?independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC?1 using serum?free culture, to which only EBC?1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC?1 cells. Among the identified proteins, interleukin?8 (IL?8), macrophage migration inhibitory factor (MIF), galectin?1, midkine (MK), IL?18, galectin?3, VEGF?A, hepatoma?derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF?A and HDGF function as angiogenic factors in EBC?1 cells. To confirm whether VEGF?A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three?dimensionally. Tube formation, neutralisation and RNA interference assays using the three?dimensional (3D) culture supernatant showed that VEGF?A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC?1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain?derived neurotrophic factor (BDNF), fibroblast growth factor?2 (FGF?2) and FGF?5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF?2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF?dependent angiogenesis and that FGF?2 is a VEGF?independent angiogenic factor in human NSCLC cells.

Project description:Macroautophagy/autophagy is an evolutionarily conserved process that involves the selective degradation of cytoplasmic components within lysosomes in response to starvation. Autophagy is an ancient defense mechanism that has been closely integrated with the immune system and has multiple effects on innate and adaptive immunity. The pro-inflammatory and anti-inflammatory cytokines can activate and inhibit autophagy, respectively. TNFAIP8L2/TIPE2 (tumor necrosis factor, alpha-induced protein 8-like 2) is a newly identified immune negative regulator of innate and adaptive immunity that plays an important role in immune homeostasis. However, whether and how TNFAIP8L2 controls autophagy is still unknown. Murine TNFAIP8L2 can directly bind to and block the RAC1 GTPase activity to regulate innate immunity. RAC1 can also bind to MTOR and regulate MTORC1 cellular localization and activity. Here, we find that TNFAIP8L2 can compete with MTOR for binding to the GTP-bound state of RAC1 and negatively regulate MTORC1 activity. Interestingly, TNFAIP8L2 overexpression fails to induce autophagy flux by the suppression of the MTOR activity under glutamine and serum starvation. Instead, TNFAIP8L2 appears to impair autophagic lysosome reformation (ALR) during prolonged starvation. Finally, we demonstrate that TNFAIP8L2 overexpression leads to a defect in MTOR reactivation and disrupts autophagy flux, thereby leading to cell death. Furthermore, TNFAIP8L2 deficiency can exacerbate the inflammatory response and lung injury by controlling the MTOR activity in an LPS-induced mouse endotoxemia model. Our study reveals a novel role of TNFAIP8L2 in autophagy by regulating the RAC1-MTORC1 axis that supports its potential as a target for therapeutic treatment.Abbreviations: ALR: autophagic lysosome reformation; BafA1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; Co-IP: Co-Immunoprecipitation; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; RAPA: rapamycin; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; Starv: Starvation; TNFAIP8L2/TIPE2: tumor necrosis factor-alpha-induced protein-8 like-2.

Dataset Information

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

Publications

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

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