赖氨酰氧化酶样蛋白2在肝细胞癌发生发展中的作用研究进展

摘要/Abstract

摘要： 赖氨酰氧化酶样蛋白2（lysyl oxidase-like 2,LOXL2）是赖氨酰氧化酶（lysyl oxidase,LOX）家族成员之一,可催化细胞外基质中胶原蛋白与弹性蛋白共价交联,在肝细胞癌（hepatocellular carcinoma,HCC）中过表达可促进肝癌细胞生长、肿瘤侵袭及转移。近年来,越来越多的证据表明LOXL2在HCC的发生、发展中发挥着关键作用,较高水平的LOXL2是影响HCC患者预后的独立因素,提示其有作为治疗靶点的巨大潜力。

关键词: 赖氨酰氧化酶样蛋白2, 肝细胞癌, 肿瘤微环境, 血管生成拟态, 上皮细胞-间充质细胞转化

Abstract: Lysyl oxidase-like 2 (LOXL2), one of the members of the lysyl oxidase (LOX) family, can catalyze the covalent cross-linking of collagen and elastin in the extracellular matrix. It is found overexpressed in hepatocellular carcinoma (HCC) and can promote cell growth, tumor invasion and metastasis. In recent years, more and more evidences has showed that LOXL2 plays a key role in the occurrence and development of HCC. High level of LOXL2 is an independent factor affecting the prognosis of HCC, suggesting that it has great potential as therapeutic targets.

Key words: Lysyl oxidase-like 2, Hepatocellular carcinoma, Tumor microenvironment, Vasculogenic mimicry, Epithelia-mesenchymal transition

申亚琼, 李皎, 李兴欣, 徐敬, 金焰. 赖氨酰氧化酶样蛋白2在肝细胞癌发生发展中的作用研究进展[J]. 肝癌电子杂志, 2023, 10(2): 41-44.

Shen Yaqiong, Li Jiao, Li Xingxin, Xu Jing, Jin Yan. Research progress on the role of lysyl oxidase-like 2 in the development of hepatocellular carcinoma[J]. Electronic Journal of Liver Tumor, 2023, 10(2): 41-44.

参考文献

[1] WANG W, WEI C.Advances in the early diagnosis of hepatocellular carcinoma[J]. Genes Dis, 2020, 7(3): 308-319.
[2] 覃小宾, 李祖隆, 曾胜澜, 等. 赖氨酰氧化酶家族在肝细胞癌发生发展中的作用[J]. 临床肝胆病杂志, 2022, 38(3): 682-687.
[3] ZHOU M, WANG H, ZENG X, et al.Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet, 2019, 394(10204): 1145-1158.
[4] BRAY F, FERLAY J, SOERJOMATARAM I, et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[5] BAGHBAN R, ROSHANGAR L, JAHANBAN-ESFAHLAN R, et al.Tumor microenvironment complexity and therapeutic implications at a glance[J]. Cell Commun Signal, 2020, 18(1): 59.
[6] ARNETH B.Tumor Microenvironment[J]. Medicina (Kaunas), 2019, 56(1): 15.
[7] NINOMIYA G, YAMADA S, HAYASHI M, et al.Significance of Lysyl oxidaselike 2 gene expression on the epithelialmesenchymal status of hepatocellular carcinoma[J]. Oncol Rep, 2018, 39(6): 2664-2672.
[8] DE JONG O G, VAN DER WAALS L M, KOOLS F R W, et al. Lysyl oxidase-like 2 is a regulator of angiogenesis through modulation of endothelial-to-mesenchymal transition[J]. J Cell Physiol, 2019, 234(7): 10260-10269.
[9] HUTCHINSON J H, ROWBOTTOM M W, LONERGAN D, et al.Small Molecule Lysyl Oxidase-like 2 (LOXL2) Inhibitors: The Identification of an Inhibitor Selective for LOXL2 over LOX[J]. ACS Med Chem Lett, 2017, 8(4): 423-427.
[10] CHEN W, YANG A, JIA J, et al.Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis[J]. Hepatology, 2020, 72(2): 729-741.
[11] CSISZAR K.Lysyl oxidases: a novel multifunctional amine oxidase family[J]. Prog Nucleic Acid Res Mol Biol, 2001, 70: 1-32.
[12] MOLNAR J, FONG K S, HE Q P, et al.Structural and functional diversity of lysyl oxidase and the LOX-like proteins[J]. Biochim Biophys Acta, 2003, 1647(1-2): 220-224.
[13] MAKI J M, RASANEN J, TIKKANEN H, et al.Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice[J]. Circulation, 2002, 106(19): 2503-2509.
[14] WANG Y, ZHANG X, WANG W, et al.Integrin alphaVbeta5/Akt/Sp1 pathway participates in matrix stiffness-mediated effects on VEGFR2 upregulation in vascular endothelial cells[J]. Am J Cancer Res, 2020, 10(8): 2635-2648.
[15] CHOI S E, JEON N, CHOI H Y, et al.Lysyl oxidaselike 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis[J]. Mol Med Rep, 2017, 16(3): 2477-2482.
[16] PEINADO H, DEL CARMEN IGLESIAS-DE LA CRUZ M, OLMEDA D, et al. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression[J]. EMBO J, 2005, 24(19): 3446-3458.
[17] JAHANBAN-ESFAHLAN R, SEIDI K, BANIMOHAMAD-SHOTORBANI B, et al.Combination of nanotechnology with vascular targeting agents for effective cancer therapy[J]. J Cell Physiol, 2018, 233(4): 2982-2992.
[18] JAHANBAN-ESFAHLAN R, SEIDI K, ZARGHAMI N.Tumor vascular infarction: prospects and challenges[J]. Int J Hematol, 2017, 105(3): 244-256.
[19] WU L, ZHANG Y, ZHU Y, et al.The effect of LOXL2 in hepatocellular carcinoma[J]. Mol Med Rep, 2016, 14(3): 1923-1932.
[20] WANG M, ZHAO X, ZHU D, et al.HIF-1alpha promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment[J]. J Exp Clin Cancer Res, 2017, 36(1): 60.
[21] TAKI M, ABIKO K, UKITA M, et al.Tumor Immune Microenvironment during Epithelial-Mesenchymal Transition[J]. Clin Cancer Res, 2021, 27(17): 4669-4679.
[22] PEZ F, DAYAN F, DURIVAULT J, et al.The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth[J]. Cancer Res, 2011, 71(5): 1647-1657.
[23] SONG G, XU S, ZHANG H, et al.TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway[J]. J Exp Clin Cancer Res, 2016, 35(1): 148.
[24] LEE S W, KWAK H S, KANG M H, et al.Fibroblast-associated tumour microenvironment induces vascular structure-networked tumouroid[J]. Sci Rep, 2018, 8(1): 2365.
[25] YOSHII S, HAYASHI Y, IIJIMA H, et al.Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression[J]. Cancer Sci, 2019, 110(8): 2396-2407.
[26] ISHII T, SUZUKI A, KUWATA T, et al.Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy[J]. Gastric Cancer, 2021, 24(4): 810-822.
[27] DWYER B J, JARMAN E J, GOGOI-TIWARI J, et al.TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression[J]. J Hepatol, 2021, 74(4): 860-872.
[28] NURMIK M, ULLMANN P, RODRIGUEZ F, et al.In search of definitions: Cancer-associated fibroblasts and their markers[J]. Int J Cancer, 2020, 146(4): 895-905.
[29] NISHISHITA R, MOROHASHI S, SEINO H, et al.Expression of cancer-associated fibroblast markers in advanced colorectal cancer[J]. Oncol Lett, 2018, 15(5): 6195-6202.
[30] BARKER H E, BIRD D, LANG G, et al.Tumor-secreted LOXL2 activates fibroblasts through FAK signaling[J]. Mol Cancer Res, 2013, 11(11): 1425-1436.
[31] DUAN Z, LIN X, WANG L, et al.Specificity of TGF-beta1 signal designated by LRRC33 and integrin alpha(V)beta(8)[J]. Nat Commun, 2022, 13(1): 4988.
[32] BAKER A M, COX T R, BIRD D, et al.The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer[J]. J Natl Cancer Inst, 2011, 103(5): 407-424.
[33] LI R K, ZHAO W Y, FANG F, et al.Lysyl oxidase-like 4 (LOXL4) promotes proliferation and metastasis of gastric cancer via FAK/Src pathway[J]. J Cancer Res Clin Oncol, 2015, 141(2): 269-281.
[34] LEIGHT J L, WOZNIAK M A, CHEN S, et al.Matrix rigidity regulates a switch between TGF-beta1-induced apoptosis and epithelial-mesenchymal transition[J]. Mol Biol Cell, 2012, 23(5): 781-791.
[35] TADDEI M L, GIANNONI E, COMITO G, et al.Microenvironment and tumor cell plasticity: an easy way out[J]. Cancer Lett, 2013, 341(1): 80-96.
[36] XING X, WANG Y, ZHANG X, et al.Matrix stiffness-mediated effects on macrophages polarization and their LOXL2 expression[J]. FEBS J, 2021, 288(11): 3465-3477.
[37] 秦瑜, 郑浩呈, 林雅思, 等. 靶向肿瘤相关巨噬细胞在肿瘤细胞治疗应用的研究进展[J]. 中国医药导刊, 2022, 24(11): 1068-1072.
[38] QIU Y, CHEN T, HU R, et al.Next frontier in tumor immunotherapy: macrophage-mediated immune evasion[J]. Biomark Res, 2021, 9(1): 72.
[39] WU S, ZHENG Q, XING X, et al.Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation[J]. J Exp Clin Cancer Res, 2018, 37(1): 99.
[40] BIGNON M, PICHOL-THIEVEND C, HARDOUIN J, et al.Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane[J]. Blood, 2011, 118(14): 3979-3989.
[41] FAN Z, ZHENG W, LI H, et al.LOXL2 upregulates hypoxiainducible factor1alpha signaling through SnailFBP1 axis in hepatocellular carcinoma cells[J]. Oncol Rep, 2020, 43(5): 1641-1649.
[42] SESTITO R, CIANFROCCA R, ROSANO L, et al.Macitentan blocks endothelin-1 receptor activation required for chemoresistant ovarian cancer cell plasticity and metastasis[J]. Life Sci, 2016, 159: 43-48.
[43] FOLBERG R, MANIOTIS A J.Vasculogenic mimicry[J]. APMIS, 2004, 112(7-8): 508-525.
[44] SAITO S, LIN Y C, TSAI M H, et al.Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells[J]. Kaohsiung J Med Sci, 2015, 31(6): 279-286.
[45] JU R J, LI X T, SHI J F, et al.Liposomes, modified with PTD (HIV-1) peptide, containing epirubicin and celecoxib, to target vasculogenic mimicry channels in invasive breast cancer[J]. Biomaterials, 2014, 35(26): 7610-7621.
[46] YANG J, ANTIN P, BERX G, et al.Guidelines and definitions for research on epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2020, 21(6): 341-352.
[47] GOOSSENS S, VANDAMME N, VAN VLIERBERGHE P, et al.EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET[J]. Biochim Biophys Acta Rev Cancer, 2017, 1868(2): 584-591.
[48] TENTI P, VANNUCCI L.Lysyl oxidases: linking structures and immunity in the tumor microenvironment[J]. Cancer Immunol Immunother, 2020, 69(2): 223-235.