Abstract：【Objective】The Dedicator of Cytokinesis (DOCKs) family, containing 11 members, is a class of proteins with guanine nucleotide exchange factor activity and plays an important role in the processes of life. However, the expressions and clinical values of DOCKs in cervical squamous cells remain unknown. Based on bioinformatics analysis, this article aims to fully reveal the expression pattern and clinical significance of DOCKs in cervical squamous cell carcinoma.【Methods】UACLAN, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER online databases were used to analyze the expression levels, gene mutations, prognostic value of DOCKs genes in cervical squamous cell carcinoma and their correlation with immune cell infiltration.【Results】Compared with normal tissues, the expression of DOCK5 was significantly upregulated and the expression of DOCK3/11 was downregulated in cervical squamous cell carcinoma (P<0.05), respectively. The expression of DOCK5 was significantly different among distinct tissue types of cervical squamous cell carcinoma. DOCK5 expression was significantly negatively correlated with overall survival (OS) and relapse free survival (RFS) in patients with cervical squamous cell carcinoma (P<0.05). The gene mutation rate of DOCK5 was 6%, and the OS and RFS time of patients with DOCK5 mutation were notably shorter (P<0.05). DOCK5 expression was negatively correlated with B cell and macrophage infiltration (P<0.05), positively associated with B cell marker CD19, neutrophil marker KIR2DL1, helper Th2 cell marker STAT6, helper Th17 cell marker STAT3 and the expression level of NK cell marker NCR1 (P<0.05).【Conclusion】DOCK5 expression was upregulated in cervical squamous cell carcinoma, which was positively correlated with poor prognosis of patients, and was related to the regulation of tumor immune microenvironment in patients with cervical squamous cell carcinoma, suggesting that DOCK5 is involved and plays vital roles in the occurrence, development and prognosis of cervical squamous cell carcinoma.
肖郁蓁, 赵礼蕴, 夏晓梦. 基于生物信息学分析DOCK5在子宫颈癌中的表达及其临床意义[J]. 医学临床研究, 2021, 38(6): 811-816.
XIAO Yu-zhen, ZHAO Li-yun, XIA Xiao-meng. Expression and Clinical Significance of DOCK5 in Cervical Cancer Based on Bioinformatics Analysis. JOURNAL OF CLINICAL RESEARCH, 2021, 38(6): 811-816.
[1] C T J, VUORI K.Identification of an evolutionarily conserved superfamily of dock180-related proteins with guanine nucleotide exchange activity[J].J Cell Sci,2002, 1154901-4913. [2] DOBBS K, DOM?NGUEZ CONDE C, ZHANG S, et al.Inherited dock2 deficiency in patients with early-onset invasive infections[J].N Engl J Med,2015, 372(25):2409-2422. [3] SANDERS M, AMPASALA D, BASSON M.Dock5 and dock1 regulate caco-2 intestinal epithelial cell spreading and migration on collagen iv[J].J Biol Chem,2009, 284(1):27-35. [4] HELBIG K, MROSKE C, MOORTHY D, et al.Biallelic loss-of-function variants in dock3 cause muscle hypotonia, ataxia, and intellectual disability[J].Clin Genet,2017, 92(4):430-433. [5] CHEN Q, YOSHIDA H, SCHUBERT D, et al.Presenilin binding protein is associated with neurofibrillary alterations in alzheimer's disease and stimulates tau phosphorylation[J].Am J Pathol, 2001, 159(5):1597-1602. [6] XU X, HAN L, ZHAO G, et al.Lrch1 interferes with dock8-cdc42-induced t cell migration and ameliorates experimental autoimmune encephalomyelitis[J].J Exp Med,2017, 214(1):209-226. [7] 张曦, Mir-20a通过作用于dock4影响宫颈癌细胞的侵袭能力[D].太原:山西医科大学, 2020. [8] CARPINO N, WISNIEWSKI D, STRIFE A, et al.P62(dok):A constitutively tyrosine-phosphorylated, gap-associated protein in chronic myelogenous leukemia progenitor cells[J].Cell,1997, 88(2):197-204. [9] CHANDRASHEKAR D, BASHEL B, BALASUBRAMANYA S, et al.Ualcan:A portal for facilitating tumor subgroup gene expression and survival analyses[J].Neoplasia (New York, N.Y.),2017, 19(8):649-658. [10] GYO″RFFY B, SUROWIAK P, BUDCZIES J, et al.Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer[J].PLoS One,2013, 8(12):e82241. [11] CERAMI E, GAO J, DOGRUSOZ U, et al.The cbio cancer genomics portal:An open platform for exploring multidimensional cancer genomics data[J].Cancer discov,2012, 2(5):401-404. [12] GAO J, AKSOY B, DOGRUSOZ U, et al.Integrative analysis of complex cancer genomics and clinical profiles using the cbioportal[J].Sci Signal,2013, 6(269):pl1. [13] LI T, FAN J, WANG B, et al.Timer:A web server for comprehensive analysis of tumor-infiltrating immune cells[J].Cancer Res,2017, 77(21):e108-e110. [14] TANG Z, LI C, KANG B, et al.Gepia:A web server for cancer and normal gene expression profiling and interactive analyses[J].Nucleic Acids Res,2017, 45W98-W102. [15] GRIMSLEY C, KINCHEN J, TOSELLO-TRAMPONT A, et al.Dock180 and elmo1 proteins cooperate to promote evolutionarily conserved rac-dependent cell migration[J].J Biol Chem,2004, 279(7):6087-6097. [16] LAURIN M, FRADET N, BLANGY A, et al.The atypical rac activator dock180 (dock1) regulates myoblast fusion in vivo[J].Proc Natl Acad Sci USA,2008, 105(40):15446-15451. [17] LI X, GAO X, LIU G, et al.Netrin signal transduction and the guanine nucleotide exchange factor dock180 in attractive signaling[J].Nat Neurosci,2008, 11(1):28-35. [18] MELLER N, MERLOT S, GUDA C.CZH proteins:A new family of rho-gefs[J].J Cell Sci,2005, 118(Pt21):4937-4946. [19] SANEMATSU F, HIRASHIMA M, LAURIN M, et al.Dock180 is a rac activator that regulates cardiovascular development by acting downstream of cxcr4[J].Circ Res,2010, 107(9):1102-1105. [20] CHIANG S, CHANG W, CHEN S, et al.Dock1 regulates growth and motility through the rrp1b-claudin-1 pathway in claudin-low breast cancer cells[J].Cancers,2019, 11(11):1762. [21] ZHANG B, LI H, YIN C, et al.Dock1 promotes the mesenchymal transition of glioma and is modulated by mir-31[J].Neuropathol Appl Neurobiol,2017, 43(5):419-432. [22] FUKUI Y, HASHIMOTO O, SANUI T, et al.Haematopoietic cell-specific cdm family protein dock2 is essential for lymphocyte migration[J].Nature,2001, 412(6849):826-831. [23] WU M, HAMAKER M, LI L, et al.Dock2 interacts with flt3 and modulates the survival of flt3-expressing leukemia cells[J].Leukemia,2017, 31(3):688-696. [24] BJERRE M, STRAND S, NØRGAARD M, et al.Aberrant DOCK2, GRASP, HIF3A and PKFP hypermethylation has potential as a prognostic biomarker for prostate cancer[J].Int J Mol Sci,2019, 20(5):1173. [25] DE SILVA M, ELLIOTT K, DAHL H, et al.Disruption of a novel member of a sodium/hydrogen exchanger family and dock3 is associated with an attention deficit hyperactivity disorder-like phenotype[J].J Med Genet,2003, 40(10):733-740. [26] CHEN Q, PETO C, SHELTON G, et al.Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration[J].J Neurosci,2009, 29(1):118-130. [27] ZHU X, GAO G, CHU K, et al.Inhibition of rac1-gef dock3 by mir-512-3p contributes to suppression of metastasis in non-small cell lung cancer[J].Int J Biochem Cell Biol,2015, 61:103-114. [28] LU M, KINCHEN J, ROSSMAN K, et al.A steric-inhibition model for regulation of nucleotide exchange via the dock180 family of gefs[J].Curr Biol,2005, 15(4):371-377. [29] YAJNIK V, PAULDING C, SORDELLA R, et al.Dock4, a gtpase activator, is disrupted during tumorigenesis[J].Cell,2003, 112(5):673-684. [30] MIYAMOTO Y, YAMAUCHI J.Cellular signaling of dock family proteins in neural function[J].Cell Signal,2010, 22(2):175-182. [31] WESTBROOK J, WOOD S, CAIRNS D, et al.Identification and validation of dock4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer[J].J Pathol,2019, 247(3):381-391. [32] VIVES V, LAURIN M, CRES G, et al.The rac1 exchange factor dock5 is essential for bone resorption by osteoclasts[J].J Bone Miner Res,2011, 26(5):1099-1110. [33] MOORE C, PARKIN C, BIDET Y, et al.A role for the myoblast city homologues dock1 and dock5 and the adaptor proteins crk and crk-like in zebrafish myoblast fusion[J].Development (Cambridge, England),2007, 134(17):3145-3153. [34] LAI Y, ZHAO A, TAN M, et al.Dock5 regulates energy balance and hepatic insulin sensitivity by targeting mtorc1 signaling[J].EMBO Rep,2020, 21(2):e49473. [35] CHEN A, YANG D, XUAN X, et al.Dock5 controls the peripheral b cell differentiation via regulating bcr signaling and actin reorganization[J].Cell Immunol,2019, 337:15-21. [36] LIU C, GUO T, XU G, et al.Characterization of alternative splicing events in hpv-negative head and neck squamous cell carcinoma identifies an oncogenic dock5 variant[J].Clin Cancer Res,2018, 24(20):5123-5132. [37] MIYAMOTO Y, TORII T, YAMAMORI N, et al.Akt and pp2a reciprocally regulate the guanine nucleotide exchange factor dock6 to control axon growth of sensory neurons[J].Sci Signal,2013, 6(265):ra15. [38] CHI H, TSAI C, WANG C, et al.Dock6 promotes chemo- and radioresistance of gastric cancer by modulating wnt/β-catenin signaling and cancer stem cell traits[J].Oncogene,2020, 39(37):5933-5949. [39] MURRAY D, DIDIER S, CHAN A, et al.Guanine nucleotide exchange factor dock7 mediates hgf-induced glioblastoma cell invasion via rac activation[J].Br J Cancer,2014, 110(5):1307-1315. [40] SU H, JING H, ANGELUS P, et al.Insights into immunity from clinical and basic science studies of dock8 immunodeficiency syndrome[J].Immunol Rev,2019, 287(1):9-19. [41] DAI W, JIN X, HAN L, et al.Exosomal lncrna dock9-as2 derived from cancer stem cell-like cells activated wnt/β-catenin pathway to aggravate stemness, proliferation, migration, and invasion in papillary thyroid carcinoma[J].Cell Death Dis,2020, 11(9):743. [42] NISHIKIMI A, MELLER N, UEKAWA N, et al.Zizimin2:A novel, dock180-related cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes[J].FEBS Lett,2005, 579(5):1039-1046. [43] SAKABE I, ASAI A, IIJIMA J, et al.Age-related guanine nucleotide exchange factor, mouse zizimin2, induces filopodia in bone marrow-derived dendritic cells[J].Immun Ageing,2012, 9:2 [44] KUNIMURA K, URUNO T, FUKUI Y.Dock family proteins:Key players in immune surveillance mechanisms[J].Int Immunol,2020, 32(1):5-15. [45] GADEA G, BLANGY A.Dock-family exchange factors in cell migration and disease[J].Eur J Cell Biol,2014, 93(10-12):466-477.
2021, Vol. 38 
