| 167 | 0 | 61 |
| 下载次数 | 被引频次 | 阅读次数 |
本研究运用生物信息学方法筛选宫颈癌中高表达的蛋白激酶及其抑制剂，为宫颈癌的分子靶向治疗提供参考。从基因表达数据库(Gene Expression Omnibus, GEO)下载宫颈癌表达谱芯片数据GSE63514,筛选高表达激酶基因；使用clusterProfiler软件包进行GO富集分析和KEGG通路分析；从激酶-激酶抑制剂相互作用图谱中筛选高表达激酶对应的最具选择性的抑制剂，并通过文献挖掘技术进行评估。筛选得到差异表达基因1 167个，其中高表达激酶基因33个。GO分析结果显示，高表达激酶基因主要富集在蛋白磷酸化、细胞周期和DNA损伤等生物学过程。KEGG通路分析表明，这些激酶基因主要富集在细胞周期、p53信号通路、卵母细胞减数分裂和人乳头状瘤病毒(human papilloma virus, HPV)感染等通路。通过激酶-激酶抑制剂相互作用图谱，得到最具潜力的8个高表达激酶，对应最具选择性激酶抑制剂16个。文献挖掘的结果显示这16个激酶抑制剂在肿瘤中均有研究，但有8种抑制剂与宫颈癌没有关联文献，具有成为抗宫颈癌新药物的潜力，可为宫颈癌的靶向治疗提供新的参考。
Abstract：This study used bioinformatics methods to screen highly expressed protein kinases and their inhibitors, which may provide references for molecular targeted therapy in cervical cancer. Expression profile dataset GSE63514 was downloaded from GEO database, and the highly expressed protein kinase genes were identified. GO enrichment and KEGG pathway analysis were conducted with clusterProfiler package. The most selectivity inhibitors of highly expressed kinases were selected based on kinase-kinase inhibitor interaction map and eva-luated them with literature mining. A total of 1 167 differentially expressed genes were identified from the expression profile dataset, of which 33 were highly expressed kinase genes. GO analysis showed that these genes were mainly enriched in protein phosphorylation, cell cycle, DNA damage and other biological processes. KEGG pathway analysis indicated that these genes were enriched in cell cycle, p53 signaling pathway, oocyte meiosis and human papilloma virus(HPV) infection pathways. Based on the kinase-kinase inhibitor interaction map, the most potent 8 highly expressed kinases correspond to 16 most selective kinase inhibitors were identified. The results of the literature mining showed that the 16 inhibitors have been studied in tumors, but 8 of them have no literature associations with cervical cancer and have potential to become new drugs against cervical cancer, which might provide new references for cervical cancer targeted therapy.
Chen G.,Zhang B.,Xu H.,Sun Y.,Shi Y.,Luo Y.,Jia H.and Wang F.,2017,Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis,Oncogene,36(50):6863-6872
Chen W.Q.,Zheng R.S.,Baade P.D.,Zhang S.W.,Zeng H.M.,Bray F.,Jemal A.,Yu X.Q.,and He J.,2016,Cancer statistics in China,2015,CA Cancer J.Clin.,66(2):115-132.
den Boon J.A.,Pyeon D.,Wang S.S.,Horswill M.,Schiffman M.,Sherman M.,Zuna R.E.,Wang Z.S.,Hewitt S.M.,Pearson R.,Schott M.,Chung L.,He Q.L.,Lambert P.,Walker J.,Newton M.A.,Wentzensen N.,and Ahlquist P.,2015,Molecular transitions from papillomavirus infection to cervical precancer and cancer:role of stromal estrogen receptor signaling,Proc.Natl.Acad.Sci.USA,112(25):E3255-E3264.
de Foucher T.,Bendifallah S.,Ouldamer L.,Bricou A.,Lavoue V.,Varinot J.,Canlorbe G.,Carcopino X.,Raimond E.,Monnier L.,Graesslin O.,Touboul C.,Collinet P.,Neveu M.E.,Huchon C.,Dara? E.and Ballester M.,2019,Patterns of recurrence and prognosis in locally advanced FIGO stage IB2 to IIB cervical cancer:retrospective multicentre study from the FRANCOGYN group,Eur.J.Surg.Oncol.,45(4):659-665
DePinto W.,Chu X.J.,Yin X.F.,Smith M.,Packman K.,Goelzer P.,Lovey A.,Chen Y.S.,Qian H.,Hamid R.,Xiang Q.,Tovar C.,Blain R.,Nevins T.,Higgins B.,Luistro L.,Kolinsky K.,Felix B.,Hussain S.,and Heimbrook D.,2006,In vitro and in vivo activity of R547:a potent and selective cyclin-depen-dent kinase inhibitor currently in phase I clinical trials,Mol.Cancer Ther.,5(11):2644-2658.
Dickson M.A.,Mahoney M.R.,Tap W.D.,D′Angelo S.P.,Keohan M.L.,van Tine B.A.,Agulnik M.,Horvath L.E.,Nair J.S.,and Schwartz G.K.,2016,Phase Ⅱ study of MLN8237 (Alisertib) in advanced/metastatic sarcoma,Ann.Oncol.,27(10):1855-1860.
Do T.V.,Xiao F.,Bickel L.E.,Klein-Szanto A.J.,Pathak H.B.,Hua X.,Howe C.,O′Brien S.W.,Maglaty M.,Ecsedy J.A.,Litwin S.,Golemis E.A.,Schilder R.J.,Godwin A.K.,and Connolly D.C.,2014,Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion,Oncogene,33(5):539-549.
Endicott J.A.,Noble M.E.M.,and Johnson L.N.,2012,The structural basis for control of eukaryotic protein kinases,Annu.Rev.Biochem.,81:587-613.
Fathi A.T.,Wander S.A.,Blonquist T.M.,Brunner A.M.,Amrein P.C.,Supko J.,Hermance N.M.,Manning A.L.,Sadrzadeh H.,Ballen K.K.,Attar E.C.,Grau-bert T.A.,Hobbs G.,Joseph C.,Perry A.M.,Burke M.,Silver R.,Foster J.,Bergeron M.,Ramos A.Y.,Som T.T.,Fishman K.M.,McGregor K.L.,Connolly C.,Neuberg D.S.,and Chen Y.B.,2017,Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia,Haematologica,102(4):719-727.
Gabrielli B.,Bokhari F.,Ranall M.V.,Oo Z.Y.,Stevenson A.J.,Wang W.L.,Murrell M.,Shaikh M.,Fallaha S.,Clarke D.,Kelly M.,Sedelies K.,Christensen M.,McKee S.,Leggatt G.,Leo P.,Skalamera D.,Soyer H.P.,Gonda T.J.,and McMillan N.A.J.,2015,Aurora A is critical for survival in HPV-transformed cervical cancer,Mol.Cancer Ther.,14(12):2753-2761.
Gautier L.,Cope L.,Bolstad B.M.,and Irizarry R.A.,2004,Affy—analysis of Affymetrix GeneChip data at the probe level,Bioinformatics,20(3):307-315.
Guo Y.N.,Kenney S.R.,Muller C.Y.,Adams S.,Rutledge T.,Romero E.,Murray-Krezan C.,Prekeris R.,Sklar L.A.,Hudson L.G.,and Wandinger-Ness A.,2015,R-ketorolac targets Cdc42 and Rac1 and alters ovarian cancer cell behaviors critical for invasion and metastasis,Mol.Cancer Ther.,14(10):2215-2227.
Hao S.,Luo C.L.,Abukiwan A.,Wang G.X.,He J.J.,Huang L.Y.,Weber C.E.M.,Lv N.,Xiao X.Y.,Eichmüller S.B.,and He D.C.,2015,miR-137 inhibits proliferation of melanoma cells by targeting PAK2,Exp.Dermatol.,24(12):947-952.
Jiao Q.L.,Bi L.,Ren Y.D.,Song S.L.,Wang Q.,and Wang Y.S.,2018,Advances in studies of tyrosine kinase inhibitors and their acquired resistance,Mol.Cancer,17(1):36.
Jin X.,Mo Q.Q.,Zhang Y.,Gao Y.,Wu Y.,Li J.,Hao X.,Ma D.,Gao Q.L.,and Chen P.B.,2016,The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer,Cancer Biol.Ther.,17(5):566-576.
Kivinummi K.,Urbanucci A.,Leinonen K.,Tammela T.L.J.,Annala M.,Isaacs W.B.,Bova G.S.,Nykter M.,and Visakorpi T.,2017,The expression of AURKA is androgen regulated in castration-resistant prostate cancer,Sci.Rep.,7(1):17978.
Klaeger S.,Heinzlmeir S.,Wilhelm M.,Polzer H.,Vick B.,Koenig P.A.,Reinecke M.,Ruprecht B.,Petzoldt S.,Meng C.,Zecha J.,Reiter K.,Qiao H.,Helm D.,Koch H.,Schoof M.,Canevari G.,Casale E.,Depaolini S.R.,Feuchtinger A.,Wu Z.,Schmidt T.,Rueckert L.,Becker W.,Huenges J.,Garz A.K.,Gohlke B.O.,Zolg D.P.,Kayser G.,Vooder T.,Presi-sner R.,Hahne H.,T?nisson N.,Kramer K.,G?tze K.,Bassermann F.,Schlegl J.,Ehrlich H.C.,Aiche S.,Walch A.,Greif P.A.,Schneider S.,Felder E.R.,Ruland J.,Médard G.,Jeremias I.,Spiekermann K.and Kuster B.,2017,The target landscape of clinical kinase drugs,Science,358(6367):eaan4368
Lee K.S.,Park J.E.,Ahn J.I.,Wei Z.,and Zhang L.,2020,A self-assembled cylindrical platform for Plk4-induced centriole biogenesis,Open Biol.,10(8):200102.
Leijen S.,van Geel R.M.J.M.,Sonke G.S.,de Jong D.,Rosenberg E.H.,Marchetti S.,Pluim D.,van Werkhoven E.,Rose S.,Lee M.A.,Freshwater T.,Beijnen J.H.,and Schellens J.H.M.,2016,Phase Ⅱ study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resis-tant to first-line therapy within 3 months,J.Clin.Oncol.,34(36):4354-4361.
Li X.,Wen W.H.,Liu K.D.,Zhu F.,Malakhova M.,Peng C.,Li T.T.,Kim H.G.,Ma W.Y.,Cho Y.Y.,Bode A.M.,Dong Z.M.,and Dong Z.G.,2011,Phosphorylation of caspase-7 by p21-activated protein kinase (PAK) 2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines,J.Biol.Chem.,286(25):22291-22299.
Marina M.,and Saavedra H.I.,2014,Nek2 and Plk4:Prognostic markers,drivers of breast tumorigenesis and drug resistance,Front.Biosci.:Landmark Ed.,19(2):352-365.
Martin D.,Fallaha S.,Proctor M.,Stevenson A.,Perrin L.,McMillan N.,and Gabrielli B.,2017,Inhibition of aurora A and aurora B is required for the sensitivity of HPV-driven cervical cancers to aurora kinase inhi-bitors,Mol.Cancer Ther.,16(9):1934-1941.
Mine K.L.,Shulzhenko N.,Yambartsev A.,Rochman M.,Sanson G.F.O.,Lando M.,Varma S.,Skinner J.,Volfovsky N.,Deng T.,Brenna S.M.F.,Carvalho C.R.N.,Ribalta J.C.L.,Bustin M.,Matzinger P.,Silva I.D.C.G.,Lyng H.,Gerbase-Delima M.,and Morgun A.,2013,Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer,Nat.Commun.,4:1806.
Nogueira-Rodrigues A.,Moralez G.,Grazziotin R.,Carmo C.C.,Small I.A.,Alves F.V.G.,Mamede M.,Erlich F.,Viegas C.,Triginelli S.A.,and Ferreira C.G.,2014,Phase 2 trial of erlotinib combined with cisplatin and radiotherapy in patients with locally advanced cervical cancer,Cancer,120(8):1187-1193.
Reggi E.,and Diviani D.,2017,The role of A-kinase anchoring proteins in cancer development,Cell.Signal.,40:143-155.
Ritchie M.E.,Phipson B.,Wu D.,Hu Y.F.,Law C.W.,Shi W.,and Smyth G.K.,2015,Limma powers differential expression analyses for RNA-sequencing and microarray studies,Nucleic.Acids Res.,43(7):e47.
Samaras P.,Schmidt T.,Frejno M.,Gessulat S.,Reinecke M.,Jarzab A.,Zecha J.,Mergner J.,Giansanti P.,Ehrlich H.C.,Aiche S.,Rank J.,Kienegger H.,Krcmar H.,Kuster B.,and Wilhelm M.,2020,ProteomicsDB:a multi-omics and multi-organism resource for life science research,Nucleic Acids Res.,48(D1):D1153-D1163.
Sohal D.P.S.,Mangu P.B.,Khorana A.A.,Shah M.A.,Philip P.A.,O′Reilly E.M.,Uronis H.E.,Ramanathan R.K.,Crane C.H.,Engebretson A.,Rug-giero J.T.,Copur M.S.,Lau M.,Urba S.,and Laheru D.,2016,Metastatic pancreatic cancer:American society of clinical oncology clinical practice guideline,J.Clin.Oncol.,34(23):2784-2796.
Tewari K.S.,and Monk B.J.,2014,New strategies in advanced cervical cancer:from angiogenesis blockade to immunotherapy,Clin.Cancer Res.,20(21):5349-5358.
The UniProt Consortium,2021,UniProt:the universal protein knowledgebase in 2021,Nucleic Acids Res.,49(D1):D480-D489
Venkatakrishnan K.,Kim T.M.,Lin C.C.,Thye L.S.,Chng W.J.,Ma B.,Chen M.H.,Zhou X.F.,Liu H.,Kelly V.,and Kim W.S.,2015,Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients:pharmacokinetics and recommended phase 2 dose,Invest.New Drugs,33(4):942-953.
Wang Y.S.,Schmid-Bindert G.,and Zhou C.C.,2012,Erlotinib in the treatment of advanced non-small cell lung cancer:an update for clinicians,Ther.Adv.Med.Oncol.,4(1):19-29.
Wu T.Z.,Hu E.Q.,Xu S.B.,Chen M.J.,Guo P.F.,Dai Z.H.,Feng T.Z.,Zhou L.,Tang W.L.,Zhan L.,Fu X.C.,Liu S.S.,Bo X.C.,and Yu G.C.,2021,clusterProfiler 4.0:a universal enrichment tool for interpreting omics data,Innovation:Camb.,2(3):100141.
Zhang X.Y.,Wei C.,Liang H.,and Han L.,2021,Polo-like kinase 4′s critical role in cancer development and strategies for Plk4-targeted therapy,Front.Oncol.,11:587554.
基本信息:
DOI：10.13417/j.gab.041.001112
中图分类号:R737.33
引用信息:
[1]唐欣,赵洪波.宫颈癌中高表达蛋白激酶及其抑制剂的生物信息学筛选[J].基因组学与应用生物学,2022,41(05):1112-1119.DOI:10.13417/j.gab.041.001112.
基金信息:
国家自然科学基金项目(81360336); 云南省科技厅-昆明医科大学联合专项项目(202101AY070001-075)共同资助
2022-05-25
2022-05-25