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

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          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.

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          Most cited references41

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          Molecular basis of metastasis.

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            Regulation of cancer cell motility through actin reorganization.

            Cell migration is a critical step in tumor invasion and metastasis, and regulation of this process will lead to appropriate therapies for treating cancer. Cancer cells migrate in various ways, according to cell type and degree of differentiation. The different types of cell migration are regulated by different mechanisms. Reorganization of the actin cytoskeleton is the primary mechanism of cell motility and is essential for most types of cell migration. Actin reorganization is regulated by Rho family small GTPases such as Rho, Rac, and Cdc42. These small GTPases transmit extracellular chemotactic signals to downstream effectors. Of these downstream effectors, Wiskott-Aldrich syndrome protein (WASP) family proteins are key regulators of cell migration. Activated WASP family proteins induce the formation of protrusive membrane structures involved in cell migration and degradation of the extracellular matrix. Inhibition of Rho family small GTPase signaling suppresses the migration and invasion of cancer cells. Thus, control of cell migration via the actin cytoskeleton provides the possibility of regulating cancer cell invasion and metastasis.
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              Lung cancer in China: challenges and interventions.

              In 2008, lung cancer replaced liver cancer as the number one cause of death among people with malignant tumors in China. The registered lung cancer mortality rate increased by 464.84% in the past 3 decades, which imposes an enormous burden on patients, health-care professionals, and society. We performed a systematic review of the published data on lung cancer in China between 1990 and 2011 to analyze the incidence and mortality rates, economic burden, and risk factors of cancer and the effectiveness of interventions. Lung cancer incidence varies within China. People in eastern China, especially women, likely have a higher risk of developing lung cancer than those in western China. The crude mortality rates from lung cancer in 2008 were 47.51 per 100,000 men and 22.69 per 100,000 women. The crude mortality rate was highest in Shanghai (76.49 per 100,000 men and 35.82 per 100,000 women) and lowest in Tibet (25.14 per 100,000 men) and Ningxia (12.09 per 100,000 women). Smoking and environmental pollution are major risk factors for lung cancer in China. Continuous efforts should be concentrated on education of the general public regarding lung cancer to increase prevention and early detection. Specific interventions need to be implemented to reduce smoking rates and environmental risk factors. Standardized treatment protocols should be adapted in China.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                20 September 2016
                19 August 2016
                : 7
                : 38
                : 62224-62239
                Affiliations
                1 Department of Immunology, Shandong University School of Medicine, Jinan, China
                2 Department of Pathology, The Second Hospital of Shandong University, Jinan, China
                Author notes
                Correspondence to: Lining Zhang, zhanglining@ 123456sdu.edu.cn
                Article
                11406
                10.18632/oncotarget.11406
                5308722
                27556698
                ec697d85-8e33-41fa-8af3-ae00d8488e88
                Copyright: © 2016 Li et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 September 2015
                : 8 August 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                tipe2,nsclc,angiogenesis,invasiveness,rac1
                Oncology & Radiotherapy
                tipe2, nsclc, angiogenesis, invasiveness, rac1

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