血管生成素样蛋白4在消化系统肿瘤中的作用机制

doi:10.3760/cma.j.issn.1673-422X.2018.06.013

摘要/Abstract

摘要： 血管生成素样蛋白（ANGPTL）4参与多条肿瘤生长代谢的调节途径，在肿瘤发生的许多方面如生长、转移、凋亡、血管生成、肿瘤微环境中发挥多种作用。ANGPTL4是ANGPTL家族成员之一，近年来研究证实它对消化系统肿瘤兼具促癌和抑癌的作用，这种双重作用可能与其参与调节不同肿瘤信号通路有关。ANGPTL4有望成为消化系统肿瘤诊断及治疗的新靶点。

关键词: 消化系统肿瘤, 血管生成素样蛋白4, 机制

Abstract: Angiopoietinlike protein (ANGPTL) 4 is involved in the regulation of multiple tumor growth and metabolism pathways and plays a multifunctional role in many aspects of tumorigenesis such as growth, metastasis, apoptosis, angiogenesis and tumor microenvironment. As one of the members of ANGPTL family, it is confirmed that ANGPTL4 both has a tumorpromoting and tumorinhibiting effect on digestive system neoplasms in recent years. This dual role may be related to its involvement in regulating different tumor signaling pathways. ANGPTL4 is expected to be a new target for diagnosis and treatment of digestive system neoplasms.

Key words: Digestive system neoplasms, Angiopoietin like protein 4, Mechanism

周帅阳，龚卫娟，肖炜明. 血管生成素样蛋白4在消化系统肿瘤中的作用机制[J]. 国际肿瘤学杂志, 2018, 45(6): 371-374.

Zhou Shuaiyang, Gong Weijuan, Xiao Weiming. Mechanism of angiopoietinlike protein 4 in digestive system neoplasms[J]. Journal of International Oncology, 2018, 45(6): 371-374.

参考文献

［1］ Ye Q, Tian GP, Cheng HP, et al. MicroRNA-134 promotes the development of atherosclerosis via the ANGPTL4/LPL pathway in apolipoprotein E knockout mice［J］. J Atheroscler Thromb, 2018, 25(3): 244-253. DOI: 10.5551/jat.40212. ［2］ Chen TC, Benjamin DI, Kuo T, et al. The glucocorticoidAngptl4ceramide axis induces insulin resistance through PP2A and PKCζ［J］. Sci Signal, 2017, 10(489), pii: eaai7905. DOI: 10.1126/scisignal.aai7905. ［3］ Okamoto H, Cavino K, Na E, et al. Angptl4 does not control hyperglucagonemia or αcell hyperplasia following glucagon receptor inhibition［J］. Proc Natl Acad Sci U S A, 2017, 114(10): 2747-2752. DOI: 10.1073/pnas.1620989114. ［4］ Carbone C, Piro G, Merz V, et al. Angiopoietinlike proteins in angiogenesis, inflammation and cancer［J］. Int J Mol Sci, 2018, 19(2), pii: E431. DOI: 10.3390/ijms19020431. ［5］ Guo L, Li SY, Ji FY, et al. Role of Angptl4 in vascular permeability and inflammation［J］. Inflamm Res, 2014, 63(1): 13-22. DOI: 10.1007/s00011-013-0678-0. ［6］ Izraely S, BenMenachem S, SagiAssif O, et al. ANGPTL4 promotes the progression of cutaneous melanoma to brain metastasis［J］. Oncotarget, 2017, 8(44): 75778-75796. DOI: 10.18632/oncotarget.19018. ［7］ Masuko K. Angiopoietinlike 4: a molecular link between insulin resistance and rheumatoid arthritis［J］. J Orthop Res, 2017, 35(5):939-943.DOI: 10.1002/jor.23507. ［8］ La Paglia L, Listì A, Caruso S, et al. Potential role of ANGPTL4 in the cross talk between metabolism and cancer through PPAR signaling pathway［J］. PPAR Res, 2017, 8187235. DOI: 10.1155/2017/8187235. ［9］ Yi J, Pan BZ, Xiong L, et al. Clinical significance of angiopoietinlike protein 4 expression in tissue and serum of esophageal squamous cell carcinoma patients［J］. Med Oncol, 2013, 30(3): 680. DOI: 10.1007/s12032-013-0680-y. ［10］ Huang Z, Xie J, Lin S, et al. The downregulation of ANGPTL4 inhibits the migration and proliferation of tongue squamous cell carcinoma［J］. Arch Oral Biol, 2016, 71: 144-149. DOI: 10.1016/j.archoralbio.2016.07.011. ［11］ OkochiTakada E, Hattori N, Tsukamoto T, et al. ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis［J］. Oncogene, 2014, 33(17): 2273-2278. DOI: 10.1038/onc.2013.174. ［12］ Feng W, Xue T, Huang S, et al. HIF-1α promotes the migration and invasion of hepatocellular carcinoma cells via the IL-8NF-κB axis［J］. Cell Mol Biol Lett, 2018, 23: 26. DOI: 10.1186/s11658-018-0077-1. ［13］ Wang X, Luo G, Zhang K, et al. Hypoxic tumorderived exosomal miR301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis［J］. Cancer Res, 2018, In press. DOI: 10.1158/0008-5472.CAN-17-3841. ［14］ Kim SH, Park YY, Kim SW, et al. ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression［J］. Cancer Res, 2011, 71(22): 7010-7020. DOI: 10.1158/0008-5472.CAN-11-1262. ［15］ Khong TL, Thairu N, Larsen H, et al. Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer［J］. BMC Cancer, 2013, 13(1): 518. DOI: 10.1186/1471-2407-13-518. ［16］ Li X, Chen T, Shi Q, et al. Angiopoietinlike 4 enhances metastasis and inhibits apoptosis via inducing bone morphogenetic protein 7 in colorectal cancer cells［J］. Biochem Biophys Res Commun, 2015, 467(1): 128-134. DOI: 10.1016/j.bbrc.2015.09.104. ［17］ Alex S, Lange K, Amolo T, et al. Shortchain fatty acids stimulate angiopoietinlike 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferatoractivated receptor γ［J］. Mol Cell Biol, 2013, 33(7): 1303-1316. DOI: 10.1128/MCB.0085812. ［18］ Meng Q, Qin Y, Deshpande M, et al. Hypoxiainducible factordependent expression of angiopoietinlike 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia［J］. Invest Ophthalmol Vis Sci, 2017, 58(11): 4514-4523. DOI: 10.1167/iovs.17-21974. ［19］肖俊娟, 李岩, 梁婧. 乏氧微环境与肿瘤免疫应答［J］. 国际肿瘤学杂志, 2017, 44(1): 31-33. DOI: 10.3760/cma.j.issn.1673-422X.2017.01.008. ［20］ Gomez Perdiguero E, LiabotisFontugne A, Durand M, et al. ANGPTL4αvβ3 interaction counteracts hypoxiainduced vascular permeability by modulating Src signaling downstream of vascular endothelial growth factor receptor 2［J］. J Pathol, 2016, 240(4): 461-471. DOI: 10.1002/path.4805. ［21］ Hu K, BabapoorFarrokhran S, Rodrigues M, et al. Hypoxiainducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma［J］. Oncotarget, 2016, 7(7): 7816-7828. DOI: 10.18632/oncotarget.6868. ［22］ Wan J, Wen D, Dong L, et al. Establishment of monoclonal HCC cell lines with organ sitespecific tropisms［J］. BMC Cancer, 2015, 15: 678. DOI: 10.1186/s12885-015-1692-0. ［23］王宇婷, 陈陶阳, 朱健, 等. 肝癌高发区人群新生儿乙型肝炎疫苗接种对肝癌的预防效果［J］. 中华预防医学杂志, 2018, 52(4): 402408. DOI: 10.3760/cma.j.issn.02539624.2018.04.013. ［24］ EIShal AS, Zidan HE, Rashad NM, et al. Angiopoietinlike protein 3 and 4 expression 4 and their serum levels in hepatocellular carcinoma［J］. Cytokine, 2017, 96: 75-86. DOI: 10.1016/j.cyto.2017.03.006. ［25］ Ng KT, Xu A, Cheng Q, et al. Clinical relevance and therapeutic potential of angiopoietinlike protein 4 in hepatocellular carcinoma［J］. Mol Cancer, 2014, 13: 196. DOI: 10.1186/1476-4598-13-196. ［26］ Zhang H, Wei S, Ning S, et al. Evaluation of TGFβ, XPO4, elF5A2 and ANGPTL4 as biomarkers in HCC［J］. Exp Ther Med, 2013, 5(1): 119-127. DOI: 10.3892/etm.2012.750. ［27］ Baba K, Kitajima Y, Miyake S, et al. Hypoxiainduced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines［J］. Sci Rep, 2017, 7(1): 11127. DOI: 10.1038/s41598-017-11769-x. ［28］ Kubo H, Kitajima Y, Kai K, et al. Regulation and clinical significance of the hypoxiainduced expression of ANGPTL4 in gastric cancer［J］. Oncol Lett, 2016, 11(2): 1026-1034. DOI: 10.3892/ol.2015.4011. ［29］ Karakashev SV, Reginato MJ. Progress toward overcoming hypoxiainduced resistance to solid tumor therapy［J］. Cancer Manag Res, 2015, 7: 253264. DOI: 10.2147/CMAR.S58285. ［30］ Tanaka T, ImamuraT, Yoneda M, et al. Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α TNFR1NF-κB pathway and a possible involvement of angiopoietinlike 4 in lung metastasis［J］. Int J Oncol, 2016, 49(4): 1377-1384. DOI: 10.3892/ijo.2016.3653. ［31］ Li B, Qian M, Cao H, et al. TGFβ2induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone［J］. Oncotarget, 2017, 8(33): 54966-54977. DOI: 10.18632/oncotarget.18629. ［32］ Hou M, Cui J, Liu J, et al. Retraction: angiopoietinlike 4 confers resistance to hypoxia/serum deprivationinduced apoptosis through PI3K/Akt and ERK1/2 signaling pathways in mesenchymal stem cells［J］. PLoS One, 2018, 13(3): e0194448. DOI: 10.1371/journal.pone.0194448. ［33］ Shen CJ, Chan SH, Lee CT, et al. Oleic acidinduced ANGPTL4 enhances head and neck squamous cell carcinoma anoikis resistance and metastasis via upregulation of fibronectin［J］. Cancer Lett, 2017, 386: 110-122. DOI: 10.1016/j.canlet.2016.11.012. ［34］ Stone L. Bladder cancer: context is key: dual roles of ANGPTL4［J］. Nat Rev Urol, 2017, 14(12): 702. DOI: 10.1038/nrurol.2017.191. ［35］ Hsieh HY, Jou YC, Tung CL, et al. Epigenetic silencing of the dualrole signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment［J］. Oncogene, 2018, 37(5): 673-686. DOI: 10.1038/onc.2017.375.

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