基于Oncomie和Kaplan-Meier Plotter数据库分析KLF5在胃癌中的表达及其与患者预后相关性
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摘要
背景胃癌(gastric cancer, GC)为临床上常见的消化系统肿瘤,确诊时大多为晚期患者预后不良,且临床上缺乏预后预测相关因子.目的应用Oncomie和Kaplan-Meier Plotter数据库分析Kruppel样因子5(kruppel-likefactor5,KLF5)在GC中的表达及其与患者预后相关性.方法收集Oncomie和Kaplan-Meier Plotter数据库中关于KLF5基因表达的相关数据集,深入挖掘KLF5基因在GC组织与正常胃组织中的差异表达情况,根据KLF5中位表达水平分为高表达组和低表达组,绘制生存曲线并用Log-rank检验比较KLF5高、低表达组患者总生存及无疾病进展生存是否存在差异.同时回顾性分析天津市宝坻区人民医院收治并手术治疗的41例GC患者的临床资料,采用免疫组化检测41例患者癌组织中KLF5表达情况,探讨KLF5表达与患者临床病理特征的关系.结果Oncomine数据库共收录了424个关于KLF5基因表达水平的相关研究,其中在癌组织vs正常组织中差异表达的有35个,与正常组织相比, 8个数据集结果提示KLF5在癌组织中高表达, 27个数据集在癌组织中低表达.聚类分析显示, KLF5与ST14, TMEM125等20个基因存在共表达情况(在GC中共同低表达或高表达),提示这些共表达基因在功能上可能存在相关性.Oncomine数据库中10个KLF5表达芯片数据集对比分析了GC组织与正常组织中KLF5基因的差异表达情况,其中有4个芯片数据提示了GC组织中KLF5表达水平明显升高. Kaplan-Meier Plotter数据库中, 2个相关基因芯片数据分析了KLF5表达与GC患者预后的关系, Long-rank检验显示KLF5高表达患者总生存和无疾病进展生存均小于低表达组(P<0.05).免疫组化分析显示41例GC患者中, KLF5阳性表达者29例,阳性率为70.7(29/41). KLF5阳性表达与患者临床病理特征如性别、年龄、肿瘤分期、分级等无明显相关性(P>0.05).结论KLF5在GC中高表达并与患者的不良预后有关,而KLF5表达与患者临床病理特征无关.
BACKGROUND Gastric cancer(GC) is a common malignancy of the digestive system. Most patients with advanced GC havea poor prognosis and lack of prognostic predictors.AIM To analyze the expression of Kruppel-like factor 5(KLF5) in GC and its correlation with patient prognosis by using Oncomie and Kaplan-Meier Plotter databases.METHODS The data sets of KLF5 gene expression in Oncomie and Kaplan-Meier Plotter databases were collected. The differential expression of KLF5 gene in GC tissues was deeply mined. According to the median expression level of KLF5, the patients were divided into a high-expression group and low-expression group. Survival curves were drawn and log-rank test was used to compare the overall survival and disease-free survival of the two groups. Meanwhile, the clinical data of 41 patients with GC treated at our hospital were retrospectively analyzed. The expression of KLF5 in the 41 patients with GC was detected by immunohistochemistry, and the relationship between the expression of KLF5 and the clinicopathological characteristics of patients was analyzed.RESULTS A total of 424 studies on KLF5 gene expression were collected in Oncomine database, of which 35 showed differential expression of KLF5 in normal vs cancer tissues. Compared with normal tissues, 8 datasets showed that KLF5 was highly expressed in cancer tissues and 27 datasets showed low expression in cancer tissues. Cluster analysis showed that KLF5 was co-expressed with 20 genes such as ST14 and TMEM125(co-downregulated or up-regulated), suggesting that these coexpressed genes might be functionally related. The differential expression of KLF5 gene in GC tissues wasanalyzed by using 10 data sets of KLF5 expression chips from Oncomine database. Four of them indicated that the expression level of KLF5 in GC tissues was significantly increased. In the Kaplan-Meier Plotter database, two related gene chips were used to analyze the relationship between the expression of KLF5 and the prognosis of GC patients. The long-rank test showed that the overall survival and disease-free survival of patients with high expression of KLF5 were shorter than those of patients with low expression(P < 0.05). Immunohistochemical analysis showed that 29(70.7%) of 41 patients with GC were KLF5 positive. There was no significant correlation between KLF5 positive expression and clinicopathological features such as gender, age, tumor stage, or tumor grade(P > 0.05).CONCLUSION The high expression of KLF5 in GC is associated with a poor prognosis, although the expression of KLF5 is not related to the clinicopathological characteristics of GC patients.
BACKGROUND Gastric cancer(GC) is a common malignancy of the digestive system. Most patients with advanced GC havea poor prognosis and lack of prognostic predictors.AIM To analyze the expression of Kruppel-like factor 5(KLF5) in GC and its correlation with patient prognosis by using Oncomie and Kaplan-Meier Plotter databases.METHODS The data sets of KLF5 gene expression in Oncomie and Kaplan-Meier Plotter databases were collected. The differential expression of KLF5 gene in GC tissues was deeply mined. According to the median expression level of KLF5, the patients were divided into a high-expression group and low-expression group. Survival curves were drawn and log-rank test was used to compare the overall survival and disease-free survival of the two groups. Meanwhile, the clinical data of 41 patients with GC treated at our hospital were retrospectively analyzed. The expression of KLF5 in the 41 patients with GC was detected by immunohistochemistry, and the relationship between the expression of KLF5 and the clinicopathological characteristics of patients was analyzed.RESULTS A total of 424 studies on KLF5 gene expression were collected in Oncomine database, of which 35 showed differential expression of KLF5 in normal vs cancer tissues. Compared with normal tissues, 8 datasets showed that KLF5 was highly expressed in cancer tissues and 27 datasets showed low expression in cancer tissues. Cluster analysis showed that KLF5 was co-expressed with 20 genes such as ST14 and TMEM125(co-downregulated or up-regulated), suggesting that these coexpressed genes might be functionally related. The differential expression of KLF5 gene in GC tissues wasanalyzed by using 10 data sets of KLF5 expression chips from Oncomine database. Four of them indicated that the expression level of KLF5 in GC tissues was significantly increased. In the Kaplan-Meier Plotter database, two related gene chips were used to analyze the relationship between the expression of KLF5 and the prognosis of GC patients. The long-rank test showed that the overall survival and disease-free survival of patients with high expression of KLF5 were shorter than those of patients with low expression(P < 0.05). Immunohistochemical analysis showed that 29(70.7%) of 41 patients with GC were KLF5 positive. There was no significant correlation between KLF5 positive expression and clinicopathological features such as gender, age, tumor stage, or tumor grade(P > 0.05).CONCLUSION The high expression of KLF5 in GC is associated with a poor prognosis, although the expression of KLF5 is not related to the clinicopathological characteristics of GC patients.
引文
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2 Chen W.Cancer statistics:updated cancer burden in China.Chin J Cancer Res 2015;27:1[PMID:25717219 DOI:10.3978/j.issn.1000-9604.2015.02.07]
3 Wang S,Xu L,Wang Q,Li J,Bai B,Li Z,Wu X,Yu P,Li X,Yin J.Postoperative complications and prognosis after radical gastrectomy for gastric cancer:a systematic review and metaanalysis of observational studies.World J Surg Oncol 2019;17:52[PMID:30885211 DOI:10.1186/s12957-019-1593-9]
4 Machlowska J,Maciejewski R,Sitarz R.The Pattern of Signatures in Gastric Cancer Prognosis.Int J Mol Sci 2018;19[PMID:29867026 DOI:10.3390/ijms19061658]
5刘文天,焦焕利,杨玉龙,王栋,张维铭.p16基因高甲基化在胃癌发展中的作用.世界华人消化杂志2007;15:2839-2843[DOI:10.3969/j.issn.1009-3079.2007.26.016]
6胡志方,黄缘,钟琼,简捷.Pim-3异常表达在胃癌中的意义.世界华人消化杂志2008;16:3515-3518[DOI:10.3969/j.issn.1009-3079.2008.31.008]
7 Gao Y,Ding Y,Chen H,Chen H,Zhou J.Targeting Kruppellike factor 5(KLF5)for cancer therapy.Curr Top Med Chem2015;15:699-713[PMID:25732792 DOI:10.1038/nature08975]
8 Marrero-Rodriguez D,la Cruz HA,Taniguchi-Ponciano K,Gomez-Virgilio L,Huerta-Padilla V,Ponce-Navarrete G,Andonegui-Elguera S,Jimenez-Vega F,Romero-Morelos P,Rodriguez-Esquivel M,Meraz-Rios M,Figueroa-Corona MDP,Monroy A,Pérez-González O,Salcedo M.Kruppel Like Factors Family Expression in Cervical Cancer Cells.Arch Med Res 2017;48:314-322[PMID:29157672 DOI:10.1016/j.arcmed.2017.06.011]
9 Hart GT,Hogquist KA,Jameson SC.Kruppel-like factors in lymphocyte biology.J Immunol 2012;188:521-526[PMID:22223851 DOI:10.4049/jimmunol.1101530]
10 Oishi Y,Manabe I,Nagai R.[Kruppel-like family of transcription factor 5(KLF5).KLF5 is a key regulator of adipocyte differentiation].Nihon Rinsho 2011;69 Suppl 1:264-268[PMID:21766607 DOI:10.1038/onc.2015.340]
11 Oishi Y,Manabe I,Nagai R.[Krüppel-like transcription factor5(KLF5)].Nihon Rinsho 2006;64 Suppl 9:254-258[PMID:17458227 DOI:10.1038/s41598-017-00966-3]
12 Guo L,He P,No YR,Yun CC.Krüppel-like factor 5 incorporates into theβ-catenin/TCF complex in response to LPA in colon cancer cells.Cell Signal 2015;27:961-968[PMID:25683913 DOI:10.1016/j.cellsig.2015.02.005]
13 Kuo PL,Hsu YL,Huang MS,Chiang SL,Ko YC.Bronchial epithelium-derived IL-8 and RANTES increased bronchial smooth muscle cell migration and proliferation by Kruppel-like factor 5 in areca nut-mediated airway remodeling.Toxicol Sci2011;121:177-190[PMID:21297082 DOI:10.1093/toxsci/kfr030]
14 Chanchevalap S,Nandan MO,McConnell BB,Charrier L,Merlin D,Katz JP,Yang VW.Kruppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells.Nucleic Acids Res 2006;34:1216-1223[PMID:16500892 DOI:10.1093/nar/gkl014]
15 Soon MS,Hsu LS,Chen CJ,Chu PY,Liou JH,Lin SH,Hsu JD,Yeh KT.Expression of Kruppel-like factor 5 in gastric cancer and its clinical correlation in Taiwan.Virchows Arch 2011;459:161-166[PMID:21732124 DOI:10.1007/s00428-011-1111-0]
16 Bialkowska AB,Crisp M,Bannister T,He Y,Chowdhury S,Schürer S,Chase P,Spicer T,Madoux F,Tian C,Hodder P,Zaharevitz D,Yang VW.Identification of small-molecule inhibitors of the colorectal cancer oncogene Kruppel-like factor 5 expression by ultrahigh-throughput screening.Mol Cancer Ther 2011;10:2043-2051[PMID:21885866 DOI:10.1158/1535-7163.MCT-11-0550]
17 Bialkowska AB,Du Y,Fu H,Yang VW.Identification of novel small-molecule compounds that inhibit the proproliferative Kruppel-like factor 5 in colorectal cancer cells by highthroughput screening.Mol Cancer Ther 2009;8:563-570[PMID:19240162 DOI:10.1158/1535-7163.MCT-08-0767]
18 Ge F,Chen W,Qin J,Zhou Z,Liu R,Liu L,Tan J,Zou T,Li H,Ren G,Chen C.Ataxin-3 like(ATXN3L),a member of the Josephin family of deubiquitinating enzymes,promotes breast cancer proliferation by deubiquitinating Kruppel-like factor 5(KLF5).Oncotarget 2015;6:21369-21378[PMID:26079537 DOI:10.18632/oncotarget.4128]
19 Xia H,Wang C,Chen W,Zhang H,Chaudhury L,Zhou Z,Liu R,Chen C.Kruppel-like factor 5 transcription factor promotes microsomal prostaglandin E2 synthase 1 gene transcription in breast cancer.J Biol Chem 2013;288:26731-26740[PMID:23913682 DOI:10.1074/jbc.M113.483958]
20 Chen CJ,Lin SE,Lin YM,Lin SH,Chen DR,Chen CL.Association of expression of kruppel-like factor 4 and kruppellike factor 5 with the clinical manifestations of breast cancer.Pathol Oncol Res 2012;18:161-168[PMID:21674249 DOI:10.1007/s12253-011-9422-7]
21 Tong D,Czerwenka K,Heinze G,Ryffel M,Schuster E,Witt A,Leodolter S,Zeillinger R.Expression of KLF5 is a prognostic factor for disease-free survival and overall survival in patients with breast cancer.Clin Cancer Res 2006;12:2442-2448[PMID:16638850 DOI:10.1158/1078-0432.CCR-05-0964]
22张小玲,田志逢,王萍,王现国.KLF5和Survivin蛋白异常表达与胃癌预后的关系.临床与实验病理学杂志2016;32:142-145[DOI:10.13315/j.cnki.cjcep.2016.02.006]
23龚邵新,庄英帜,赵强,贺荣芳,丁慧,胡义燕,阳帅,曾庆彪.KLF4和KLF5蛋白在不同临床分期胃癌组织中的表达及意义.中国癌症杂志2010;20:756-759[DOI:10.3969/j.issn.1007-3639.2010.10.007]
2 Chen W.Cancer statistics:updated cancer burden in China.Chin J Cancer Res 2015;27:1[PMID:25717219 DOI:10.3978/j.issn.1000-9604.2015.02.07]
3 Wang S,Xu L,Wang Q,Li J,Bai B,Li Z,Wu X,Yu P,Li X,Yin J.Postoperative complications and prognosis after radical gastrectomy for gastric cancer:a systematic review and metaanalysis of observational studies.World J Surg Oncol 2019;17:52[PMID:30885211 DOI:10.1186/s12957-019-1593-9]
4 Machlowska J,Maciejewski R,Sitarz R.The Pattern of Signatures in Gastric Cancer Prognosis.Int J Mol Sci 2018;19[PMID:29867026 DOI:10.3390/ijms19061658]
5刘文天,焦焕利,杨玉龙,王栋,张维铭.p16基因高甲基化在胃癌发展中的作用.世界华人消化杂志2007;15:2839-2843[DOI:10.3969/j.issn.1009-3079.2007.26.016]
6胡志方,黄缘,钟琼,简捷.Pim-3异常表达在胃癌中的意义.世界华人消化杂志2008;16:3515-3518[DOI:10.3969/j.issn.1009-3079.2008.31.008]
7 Gao Y,Ding Y,Chen H,Chen H,Zhou J.Targeting Kruppellike factor 5(KLF5)for cancer therapy.Curr Top Med Chem2015;15:699-713[PMID:25732792 DOI:10.1038/nature08975]
8 Marrero-Rodriguez D,la Cruz HA,Taniguchi-Ponciano K,Gomez-Virgilio L,Huerta-Padilla V,Ponce-Navarrete G,Andonegui-Elguera S,Jimenez-Vega F,Romero-Morelos P,Rodriguez-Esquivel M,Meraz-Rios M,Figueroa-Corona MDP,Monroy A,Pérez-González O,Salcedo M.Kruppel Like Factors Family Expression in Cervical Cancer Cells.Arch Med Res 2017;48:314-322[PMID:29157672 DOI:10.1016/j.arcmed.2017.06.011]
9 Hart GT,Hogquist KA,Jameson SC.Kruppel-like factors in lymphocyte biology.J Immunol 2012;188:521-526[PMID:22223851 DOI:10.4049/jimmunol.1101530]
10 Oishi Y,Manabe I,Nagai R.[Kruppel-like family of transcription factor 5(KLF5).KLF5 is a key regulator of adipocyte differentiation].Nihon Rinsho 2011;69 Suppl 1:264-268[PMID:21766607 DOI:10.1038/onc.2015.340]
11 Oishi Y,Manabe I,Nagai R.[Krüppel-like transcription factor5(KLF5)].Nihon Rinsho 2006;64 Suppl 9:254-258[PMID:17458227 DOI:10.1038/s41598-017-00966-3]
12 Guo L,He P,No YR,Yun CC.Krüppel-like factor 5 incorporates into theβ-catenin/TCF complex in response to LPA in colon cancer cells.Cell Signal 2015;27:961-968[PMID:25683913 DOI:10.1016/j.cellsig.2015.02.005]
13 Kuo PL,Hsu YL,Huang MS,Chiang SL,Ko YC.Bronchial epithelium-derived IL-8 and RANTES increased bronchial smooth muscle cell migration and proliferation by Kruppel-like factor 5 in areca nut-mediated airway remodeling.Toxicol Sci2011;121:177-190[PMID:21297082 DOI:10.1093/toxsci/kfr030]
14 Chanchevalap S,Nandan MO,McConnell BB,Charrier L,Merlin D,Katz JP,Yang VW.Kruppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells.Nucleic Acids Res 2006;34:1216-1223[PMID:16500892 DOI:10.1093/nar/gkl014]
15 Soon MS,Hsu LS,Chen CJ,Chu PY,Liou JH,Lin SH,Hsu JD,Yeh KT.Expression of Kruppel-like factor 5 in gastric cancer and its clinical correlation in Taiwan.Virchows Arch 2011;459:161-166[PMID:21732124 DOI:10.1007/s00428-011-1111-0]
16 Bialkowska AB,Crisp M,Bannister T,He Y,Chowdhury S,Schürer S,Chase P,Spicer T,Madoux F,Tian C,Hodder P,Zaharevitz D,Yang VW.Identification of small-molecule inhibitors of the colorectal cancer oncogene Kruppel-like factor 5 expression by ultrahigh-throughput screening.Mol Cancer Ther 2011;10:2043-2051[PMID:21885866 DOI:10.1158/1535-7163.MCT-11-0550]
17 Bialkowska AB,Du Y,Fu H,Yang VW.Identification of novel small-molecule compounds that inhibit the proproliferative Kruppel-like factor 5 in colorectal cancer cells by highthroughput screening.Mol Cancer Ther 2009;8:563-570[PMID:19240162 DOI:10.1158/1535-7163.MCT-08-0767]
18 Ge F,Chen W,Qin J,Zhou Z,Liu R,Liu L,Tan J,Zou T,Li H,Ren G,Chen C.Ataxin-3 like(ATXN3L),a member of the Josephin family of deubiquitinating enzymes,promotes breast cancer proliferation by deubiquitinating Kruppel-like factor 5(KLF5).Oncotarget 2015;6:21369-21378[PMID:26079537 DOI:10.18632/oncotarget.4128]
19 Xia H,Wang C,Chen W,Zhang H,Chaudhury L,Zhou Z,Liu R,Chen C.Kruppel-like factor 5 transcription factor promotes microsomal prostaglandin E2 synthase 1 gene transcription in breast cancer.J Biol Chem 2013;288:26731-26740[PMID:23913682 DOI:10.1074/jbc.M113.483958]
20 Chen CJ,Lin SE,Lin YM,Lin SH,Chen DR,Chen CL.Association of expression of kruppel-like factor 4 and kruppellike factor 5 with the clinical manifestations of breast cancer.Pathol Oncol Res 2012;18:161-168[PMID:21674249 DOI:10.1007/s12253-011-9422-7]
21 Tong D,Czerwenka K,Heinze G,Ryffel M,Schuster E,Witt A,Leodolter S,Zeillinger R.Expression of KLF5 is a prognostic factor for disease-free survival and overall survival in patients with breast cancer.Clin Cancer Res 2006;12:2442-2448[PMID:16638850 DOI:10.1158/1078-0432.CCR-05-0964]
22张小玲,田志逢,王萍,王现国.KLF5和Survivin蛋白异常表达与胃癌预后的关系.临床与实验病理学杂志2016;32:142-145[DOI:10.13315/j.cnki.cjcep.2016.02.006]
23龚邵新,庄英帜,赵强,贺荣芳,丁慧,胡义燕,阳帅,曾庆彪.KLF4和KLF5蛋白在不同临床分期胃癌组织中的表达及意义.中国癌症杂志2010;20:756-759[DOI:10.3969/j.issn.1007-3639.2010.10.007]
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