脾酪氨酸激酶及其相关信号通路对头颈部肿瘤发生与发展的影响及作用机制
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摘要
脾酪氨酸激酶(Syk)对细胞的信号转导有广泛的作用,具有调节细胞应答与促进细胞激活、增殖与分化、吞噬等作用。在对颈部肿瘤的研究中,Syk的异常表达和活性降低可通过多种信号通路影响肿瘤细胞的增殖、凋亡、侵袭、转移等多个方面,Syk及其相关信号通路可能成为靶向治疗头颈部肿瘤的有效靶点,具有良好的临床应用潜力。本文旨在总结Syk及其相关信号通路对头颈部肿瘤发生、发展的影响,以及这些影响的细胞内机制,展望Syk及其相关信号通路作为靶点在临床应用中的前景。
Spleen tyrosine kinase(Syk) has a wide range of effects on cell signal transduction, regulating cellular responses and promoting cell activation, proliferation, differentiation, and phagocytosis. In the studies on head and neck tumors, the abnormal expression and the reduced activity of Syk can affect the proliferation, apoptosis, invasion and metastasis of tumor cells via various signalling pathways. Syk and its related signalling pathways can be potential targets for clinical treatment of head and neck tumors. This review aims to summarize the effects of Syk and its related signalling pathways on the development of head and neck tumors and its intracellular mechanisms, and thus to evaluate their potential application in clinic.
Spleen tyrosine kinase(Syk) has a wide range of effects on cell signal transduction, regulating cellular responses and promoting cell activation, proliferation, differentiation, and phagocytosis. In the studies on head and neck tumors, the abnormal expression and the reduced activity of Syk can affect the proliferation, apoptosis, invasion and metastasis of tumor cells via various signalling pathways. Syk and its related signalling pathways can be potential targets for clinical treatment of head and neck tumors. This review aims to summarize the effects of Syk and its related signalling pathways on the development of head and neck tumors and its intracellular mechanisms, and thus to evaluate their potential application in clinic.
引文
[1]Siegel RL,Miller KD,Jemal A.Cancer statistics,2019[J].CA Cancer J Clin,2019,69(1):7-34.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,669(2):115-132.
[3]Taniguchi T,Kobayashi T,Kondo J,et al.Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis[J].J Biol Chem,1991,266(24):15790-15796.
[4]Ku G,Malissen B,Mattei MG.Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans[J].Immunogenetics,1994,40(4):300-302.
[5]Koerber RM,Held SAE,Heine A,et al.Analysis of the anti-proliferative and the pro-apoptotic efficacy of Syk inhibition in multiple myeloma[J].Exp Hematol Oncol,2015,4:21.
[6]Larive RM,Urbach S,Poncet J,et al.Phosphoproteomic analysis of Syk kinase signaling in human cancer cells reveals its role in cell-cell adhesion[J].Oncogene,2009,28(24):2337-2347.
[7]Mócsai A,Ruland J,Tybulewicz VL.The SYK tyrosine kinase:a crucial player in diverse biological functions[J].Nat Rev Immunol,2010,10(6):387-402.
[8]Wang L,Duke L,Zhang PS,et al.Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer[J].Cancer Res,2003,63(15):4724-4730.
[9]Ni B,Hu J,Chen D,et al.Alternative splicing of spleen tyrosine kinase differentially regulates colorectal cancer progression[J].Oncol Lett,2016,12(3):1737-1744.
[10]Guo A,Lu P,Coffey G,et al.Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia:cerdulatinib,but not ibrutinib,induces apoptosis of tumor cells protected by the microenvironment[J].Oncotarget,2017,8(8):12953-12967.
[11]Spurgeon SE,Coffey G,Fletcher LB,et al.The selective SYK inhibitor P505-15(PRT062607)inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia[J].J Pharmacol Exp Ther,2013,344(2):378-387.
[12]Chen L,Monti S,Juszczynski P,et al.SYK inhibition modulates distinct PI3K/AKT-dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas[J].Cancer Cell,2013,23(6):826-838.
[13]Uckun FM,Qazi S.SYK as a new therapeutic target in B-cell precursor acute lymphoblastic leukemia[J].J Cancer Ther,2014,5(1):124-131.
[14]Coebergh van den Braak RRJ,Sieuwerts AM,Kandimalla R,et al.High mRNA expression of splice variant SYK short correlates with hepatic disease progression in chemonaive lymph node negative colon cancer patients[J].PLoS One,2017,12(9):e0185607.
[15]Li Z,Cai Z,Tao B,et al.Full-length spleen tyrosine kinase inhibits the invasion and metastasis of human laryngeal squamous cell carcinoma[J].Int J Clin Exp Pathol,2015,8(12):15786-15793.
[16]王钊,陈洁,储伟明,等.全长型脾酪氨酸激酶在口腔鳞状细胞癌组织中的表达及其与肿瘤侵袭和转移的关系[J].华西口腔医学杂志,2015,33(5):519-523.Wang Z,Chen J,Chu WM,et al.Expression of fulllength spleen tyrosine kinase in the oral squamous cell carcinoma and its relationship with tumor invasion and metastasis[J].West China J Stomatol,2015,33(5):519-523.
[17]Ogane S,Onda T,Takano N,et al.Spleen tyrosine kinase as a novel candidate tumor suppressor gene for human oral squamous cell carcinoma[J].Int JCancer,2009,124(11):2651-2657.
[18]Jin Q,Liu C,Yan C,et al.5-aza-CdR induces the demethylation of Syk promoter in nasopharyngeal carcinoma cell[J].Gene,2012,511(2):224-226.
[19]Zhou X,Matskova L,Rathje LS,et al.SYK interaction with ITGβ4 suppressed by Epstein-Barr virus LMP2A modulates migration and invasion of nasopharyngeal carcinoma cells[J].Oncogene,2015,34(34):4491-4499.
[20]Luangdilok S,Box C,Patterson L,et al.Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck[J].Cancer Res,2007,67(16):7907-7916.
[21]Chuang JY,Huang YL,Yen WL,et al.Syk/JNK/AP-1 signaling pathway mediates interleukin-6-promoted cell migration in oral squamous cell car cinoma[J].Int J Mol Sci,2014,15(1):545-559.
[22]Gao P,Qiao X,Sun H,et al.Activated spleen tyrosine kinase promotes malignant progression of oral squamous cell carcinoma via mTOR/S6 signaling pathway in an ERK1/2-independent manner[J].Oncotarget,2017,8(48):83900-83912.
[23]Fu G,Somasundaram RT,Jessa F,et al.ER maleate is a novel anticancer agent in oral cancer:implications for cancer therapy[J].Oncotarget,2016,7(13):17162-17181.
[24]Du ZM,Kou CW,Wang HY,et al.Clinical significance of elevated spleen tyrosine kinase ex pression in nasopharyngeal carcinoma[J].Head Neck,2012,34(10):1456-1464.
[25]Seda V,Mraz M.B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells[J].Eur J Haematol,2015,94(3):193-205.
[26]Balsas P,Esteve-Arenys A,Roldán J,et al.Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma[J].J Hematol Oncol,2017,10(1):80.
[27]Ma J,Xing W,Coffey G,et al.Cerdulatinib,a novel dual SYK/JAK kinase inhibitor,has broad antitumor activity in both ABC and GCB types of diffuse large B cell lymphoma[J].Oncotarget,2015,6(41):43881-43896.
[28]林洁,王淼,吉阳,等.脾络氨酸激酶-核因子κB调控口腔癌相关巨噬细胞中癌痛相关环氧化酶2的机制[J].华西口腔医学杂志,2016,34(5):454-458.Lin J,Wang M,Ji Y,et al.In vitro investigation on the mechanism of cyclooxygenase-2 upregulation induced by spleen tyrosine kinase-nuclear factor kappaB signaling in cancer pain caused by oral cancerassociated macrophage[J].West China J Sto matol,2016,34(5):454-458.
[29]Srivastava S,Pelloso D,Feng H,et al.Effects of interleukin-18 on natural killer cells:costimulation of activation through Fc receptors for immunoglobulin[J].Cancer Immunol Immunother,2013,62(6):1073-1082.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,669(2):115-132.
[3]Taniguchi T,Kobayashi T,Kondo J,et al.Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis[J].J Biol Chem,1991,266(24):15790-15796.
[4]Ku G,Malissen B,Mattei MG.Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans[J].Immunogenetics,1994,40(4):300-302.
[5]Koerber RM,Held SAE,Heine A,et al.Analysis of the anti-proliferative and the pro-apoptotic efficacy of Syk inhibition in multiple myeloma[J].Exp Hematol Oncol,2015,4:21.
[6]Larive RM,Urbach S,Poncet J,et al.Phosphoproteomic analysis of Syk kinase signaling in human cancer cells reveals its role in cell-cell adhesion[J].Oncogene,2009,28(24):2337-2347.
[7]Mócsai A,Ruland J,Tybulewicz VL.The SYK tyrosine kinase:a crucial player in diverse biological functions[J].Nat Rev Immunol,2010,10(6):387-402.
[8]Wang L,Duke L,Zhang PS,et al.Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer[J].Cancer Res,2003,63(15):4724-4730.
[9]Ni B,Hu J,Chen D,et al.Alternative splicing of spleen tyrosine kinase differentially regulates colorectal cancer progression[J].Oncol Lett,2016,12(3):1737-1744.
[10]Guo A,Lu P,Coffey G,et al.Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia:cerdulatinib,but not ibrutinib,induces apoptosis of tumor cells protected by the microenvironment[J].Oncotarget,2017,8(8):12953-12967.
[11]Spurgeon SE,Coffey G,Fletcher LB,et al.The selective SYK inhibitor P505-15(PRT062607)inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia[J].J Pharmacol Exp Ther,2013,344(2):378-387.
[12]Chen L,Monti S,Juszczynski P,et al.SYK inhibition modulates distinct PI3K/AKT-dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas[J].Cancer Cell,2013,23(6):826-838.
[13]Uckun FM,Qazi S.SYK as a new therapeutic target in B-cell precursor acute lymphoblastic leukemia[J].J Cancer Ther,2014,5(1):124-131.
[14]Coebergh van den Braak RRJ,Sieuwerts AM,Kandimalla R,et al.High mRNA expression of splice variant SYK short correlates with hepatic disease progression in chemonaive lymph node negative colon cancer patients[J].PLoS One,2017,12(9):e0185607.
[15]Li Z,Cai Z,Tao B,et al.Full-length spleen tyrosine kinase inhibits the invasion and metastasis of human laryngeal squamous cell carcinoma[J].Int J Clin Exp Pathol,2015,8(12):15786-15793.
[16]王钊,陈洁,储伟明,等.全长型脾酪氨酸激酶在口腔鳞状细胞癌组织中的表达及其与肿瘤侵袭和转移的关系[J].华西口腔医学杂志,2015,33(5):519-523.Wang Z,Chen J,Chu WM,et al.Expression of fulllength spleen tyrosine kinase in the oral squamous cell carcinoma and its relationship with tumor invasion and metastasis[J].West China J Stomatol,2015,33(5):519-523.
[17]Ogane S,Onda T,Takano N,et al.Spleen tyrosine kinase as a novel candidate tumor suppressor gene for human oral squamous cell carcinoma[J].Int JCancer,2009,124(11):2651-2657.
[18]Jin Q,Liu C,Yan C,et al.5-aza-CdR induces the demethylation of Syk promoter in nasopharyngeal carcinoma cell[J].Gene,2012,511(2):224-226.
[19]Zhou X,Matskova L,Rathje LS,et al.SYK interaction with ITGβ4 suppressed by Epstein-Barr virus LMP2A modulates migration and invasion of nasopharyngeal carcinoma cells[J].Oncogene,2015,34(34):4491-4499.
[20]Luangdilok S,Box C,Patterson L,et al.Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck[J].Cancer Res,2007,67(16):7907-7916.
[21]Chuang JY,Huang YL,Yen WL,et al.Syk/JNK/AP-1 signaling pathway mediates interleukin-6-promoted cell migration in oral squamous cell car cinoma[J].Int J Mol Sci,2014,15(1):545-559.
[22]Gao P,Qiao X,Sun H,et al.Activated spleen tyrosine kinase promotes malignant progression of oral squamous cell carcinoma via mTOR/S6 signaling pathway in an ERK1/2-independent manner[J].Oncotarget,2017,8(48):83900-83912.
[23]Fu G,Somasundaram RT,Jessa F,et al.ER maleate is a novel anticancer agent in oral cancer:implications for cancer therapy[J].Oncotarget,2016,7(13):17162-17181.
[24]Du ZM,Kou CW,Wang HY,et al.Clinical significance of elevated spleen tyrosine kinase ex pression in nasopharyngeal carcinoma[J].Head Neck,2012,34(10):1456-1464.
[25]Seda V,Mraz M.B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells[J].Eur J Haematol,2015,94(3):193-205.
[26]Balsas P,Esteve-Arenys A,Roldán J,et al.Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma[J].J Hematol Oncol,2017,10(1):80.
[27]Ma J,Xing W,Coffey G,et al.Cerdulatinib,a novel dual SYK/JAK kinase inhibitor,has broad antitumor activity in both ABC and GCB types of diffuse large B cell lymphoma[J].Oncotarget,2015,6(41):43881-43896.
[28]林洁,王淼,吉阳,等.脾络氨酸激酶-核因子κB调控口腔癌相关巨噬细胞中癌痛相关环氧化酶2的机制[J].华西口腔医学杂志,2016,34(5):454-458.Lin J,Wang M,Ji Y,et al.In vitro investigation on the mechanism of cyclooxygenase-2 upregulation induced by spleen tyrosine kinase-nuclear factor kappaB signaling in cancer pain caused by oral cancerassociated macrophage[J].West China J Sto matol,2016,34(5):454-458.
[29]Srivastava S,Pelloso D,Feng H,et al.Effects of interleukin-18 on natural killer cells:costimulation of activation through Fc receptors for immunoglobulin[J].Cancer Immunol Immunother,2013,62(6):1073-1082.