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Article(id=1211268931541668723, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211268928383348982, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.02.03, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1591027200000, receivedDateStr=2020-06-02, revisedDate=1610380800000, revisedDateStr=2021-01-12, acceptedDate=null, acceptedDateStr=null, onlineDate=1766718617567, onlineDateStr=2025-12-26, pubDate=1614441600000, pubDateStr=2021-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766718617567, onlineIssueDateStr=2025-12-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766718617567, creator=13701087609, updateTime=1766718617567, updator=13701087609, issue=Issue{id=1211268928383348982, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='2', pageStart='107', pageEnd='211', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766718616815, creator=13701087609, updateTime=1766718805938, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1211269721685627740, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211268928383348982, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1211269721685627741, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211268928383348982, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=122, endPage=128, ext={EN=ArticleExt(id=1211268933525574554, articleId=1211268931541668723, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effect and mechanism of B7-H4 expression on the prognosis of gastric cancer patients, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the effect and mechanism of B7-H4 expression on the prognosis of patients with gastric cancer. Methods The databases of Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN and Kaplan-Meier Plotter were used to analyze the expression of B7-H4 in gastric cancer tissues and its relationship with the prognosis of gastric cancer patients. Immunohistochemistry staining was performed to observe the expression of B7-H4 protein in gastric cancer tissues and analyze its correlation with clinicopathological characteristics, cell cycle regulatory proteins, microvessel density (MVD), stemness-related proteins, and PI3K/Akt/NF-κB signaling pathway proteins. Immunofluorescence and Western blotting were used to detect the expressions of B7-H4 and stemness-related proteins in gastric cancer cells. Oncomine database was employed to analyze the correlation between B7-H4 and the expressions of PI3K and Akt mRNA in gastric cancer tissues. Results The expression level of B7-H4 was higher in gastric cancer tissues than in normal tissues, and its expression was significantly related to tumor differentiation, pT staging, lymph node metastasis, distant metastasis and clinical staging (P<0.05), and indicated a poor prognosis in gastric cancer. The expression of B7-H4 was positively correlated with the expressions of cell cycle regulatory protein p16 (r=0.250, P<0.001) and stemness-related proteins LSD1 (r=0.331, P<0.001), SOX9 (r=0.176, P=0.018) and CD133 (r=0.434, P<0.001). The MVD was significantly higher in B7-H4 positive tissue than in B7-H4 negative tissue (P=0.019). Furthermore, B7-H4 was co-expressed with stemness-related proteins LSD1, SOX9, and CD133 in gastric cancer cell lines, and the expression of B7-H4 was positively correlated with the expressions of p-PI3K-p85 (r=0.269, P<0.001), p-Akt-Ser473 (r=0.282, P<0.01), p-Akt-Thr308 (r=0.214, P=0.005) and NF-κB p65 (r=0.157, P=0.034). The expression of B7-H4 in gastric cancer tissue was positively correlated with the expressions of PI3K mRNA (r=0.403, P<0.001) and Akt mRNA (r=0.351, P<0.001). Conclusion B7-H4 can promote gastric cancer progression and is closely related to poor prognosis, and the mechanism may be related to the regulation of gastric cancer stemness via PI3K/Akt/NF-κB.

, correspAuthors=Yan-Hua Xuan, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Nan Che, Wen-Bo Qi, Zhao-Ting Yang, Yan-Hua Xuan), CN=ArticleExt(id=1211268935069078516, articleId=1211268931541668723, tenantId=1146029695717560320, journalId=1189873630562394117, language=CN, title=B7-H4表达对胃癌患者预后的影响及机制, columnId=1190310109164180259, journalTitle=解放军医学杂志, columnName=临床研究, runingTitle=null, highlight=null, articleAbstract=

目的 探讨B7-H4表达对胃癌患者预后的影响及其可能机制。方法 利用UALCAN、Kaplan-Meier Plotter数据库及GEPIA在线分析工具分析胃癌组织中B7-H4的表达及其与患者预后的关系。采用免疫组化染色检测胃癌组织中B7-H4的表达，分析其与临床病理特征、细胞周期调控蛋白、微血管密度(MVD)、干性相关蛋白及PI3K/Akt/NF-κB信号通路蛋白的关系。采用免疫荧光和Western blotting检测胃癌细胞中B7-H4及干性相关蛋白的表达。采用Oncomine数据库分析胃癌组织中B7-H4与PI3K、Akt mRNA表达的相关性。结果 B7-H4在胃癌组织中的表达水平高于正常组织(P<0.001)，其表达与肿瘤分化程度、pT分期、淋巴结转移、远处转移和临床分期明显相关(P<0.05)，并预示胃癌患者预后不良。胃癌组织中B7-H4与细胞周期调控蛋白p16及干性相关蛋白LSD1、SOX9、CD133的表达呈正相关(r=0.250，P<0.001；r=0.331，P<0.001；r=0.176，P=0.018；r=0.434，P<0.001)。B7-H4阳性组织标本的MVD明显高于B7-H4阴性组织标本(P=0.019)。在胃癌细胞系中B7-H4与干性相关蛋白LSD1、SOX9、CD133共表达。B7-H4在胃癌组织中与p-PI3K-p85、p-Akt-Thr308、p-Akt-Ser473和NF-κB p65的表达呈正相关(r=0.269，P<0.001；r=0.282，P<0.01；r=0.214，P=0.005；r=0.157，P=0.034)。胃癌组织中B7-H4与PI3K、Akt mRNA的表达呈正相关(r=0.403，P<0.001；r=0.351，P<0.001)。结论 B7-H4能够促进胃癌进展且与患者的预后不良密切相关，其机制可能与B7-H4通过PI3K/Akt/NF-κB通路调节胃癌干性特征相关。

, correspAuthors=玄延花, authorNote=null, correspAuthorsNote=
玄延花，E-mail：
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车楠，博士研究生，主要从事肿瘤分子病理学研究。E-mail：

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车楠，博士研究生，主要从事肿瘤分子病理学研究。E-mail：

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车楠，博士研究生，主要从事肿瘤分子病理学研究。E-mail：

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Life Sci, 2016, 162: 77-86., articleTitle=The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-kappa B signaling, refAbstract=null)], funds=[Fund(id=1211268943537377604, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, awardId=81760531, language=EN, fundingSource=National Natural Science Foundation of China(81760531), fundOrder=null, country=null), Fund(id=1211268943621263689, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, awardId=81760531, language=CN, fundingSource=国家自然科学基金(81760531), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1211268935312347142, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, xref=1, ext=[AuthorCompanyExt(id=1211268935320735751, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, companyId=1211268935312347142, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Institute for Regenerative Medicine, College of Medicine, Yanbian University, Yanji, Jilin 133002, China), AuthorCompanyExt(id=1211268935324930056, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, companyId=1211268935312347142, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1延边大学医学院再生医学研究所，吉林 延吉 133002)]), AuthorCompany(id=1211268935421399057, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, xref=2, ext=[AuthorCompanyExt(id=1211268935425593362, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, companyId=1211268935421399057, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Pathology, College of Medicine, Yanbian University, Yanji, Jilin 133002, China), AuthorCompanyExt(id=1211268935433981971, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, companyId=1211268935421399057, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2延边大学医学院病理教研室，吉林 延吉 133002)])], figs=[ArticleFig(id=1211268939083026665, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Fig.1, caption=The expression of B7-H4 in gastric cancer tissues, figureFileSmall=hnfXvS0gpwU/muLcYX6r5A==, figureFileBig=zconw2EehsqkM9fnk+z/kw==, tableContent=null), ArticleFig(id=1211268939175301360, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=图1, caption=胃癌组织中B7-H4的表达

A. 正常胃黏膜组织和胃癌组织中B7-H4 mRNA的表达；B. B7-H4蛋白在人胚胎胃组织中的表达；C. B7-H4蛋白在正常胃黏膜组织、肠上皮化生及胃癌组织中的表达

, figureFileSmall=hnfXvS0gpwU/muLcYX6r5A==, figureFileBig=zconw2EehsqkM9fnk+z/kw==, tableContent=null), ArticleFig(id=1211268939368239359, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Fig.2, caption=Effect of B7-H4 expression on the prognosis of patients with gastric cancer, figureFileSmall=COOciPRXdCvs2oOtPjXBdQ==, figureFileBig=huSu3Wp5z61HZQ3uG5o0HA==, tableContent=null), ArticleFig(id=1211268939452125446, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=图2, caption=B7-H4对胃癌患者预后的影响

A. B7-H4阳性和阴性表达胃癌患者的总体生存曲线；B. B7-H4阳性和阴性表达胃癌患者的无进展生存曲线；C. 胃癌患者总体生存预后的单因素Cox回归分析；D. 胃癌患者总体生存预后的多因素Cox回归分析

, figureFileSmall=COOciPRXdCvs2oOtPjXBdQ==, figureFileBig=huSu3Wp5z61HZQ3uG5o0HA==, tableContent=null), ArticleFig(id=1211268939586343183, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Fig.3, caption=The relationships of B7-H4 expression to the cell cycle regulatory proteins and MVD, figureFileSmall=xiVgmS5hSpehlhGCUJ5YBg==, figureFileBig=DSOkXFPAK+f8GFyqLV6yrg==, tableContent=null), ArticleFig(id=1211268939661840660, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=图3, caption=胃癌组织B7-H4表达与细胞周期调控蛋白及MVD的关系

TPM. RNA测序标准化方法；MVD. 微血管密度；A. 胃癌组织中B7-H4、p16蛋白的表达；B. 胃癌组织中B7-H4与p16蛋白表达的相关性；C. 胃癌组织中B7-H4 mRNA与p16 mRNA表达的关系；D. B7-H4阴性和阳性表达胃癌组织中CD105蛋白的表达；E. B7-H4阴性和阳性表达胃癌组织的MVD分析

, figureFileSmall=xiVgmS5hSpehlhGCUJ5YBg==, figureFileBig=DSOkXFPAK+f8GFyqLV6yrg==, tableContent=null), ArticleFig(id=1211268942765625625, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Fig.4, caption=Relationship of the B7-H4 expressions to the stemness-related proteins in gastric cancer, figureFileSmall=Pyv5Icw1NrNTjGj2vfDziQ==, figureFileBig=beThqErjatoNN8B4wkBZzw==, tableContent=null), ArticleFig(id=1211268942887260448, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=图4, caption=胃癌中B7-H4表达与肿瘤干性相关蛋白的关系

A. B7-H4阳性表达胃癌组织中干性相关蛋白的表达；B. 胃癌组织中B7-H4与干性相关蛋白表达的相关性；C. 免疫荧光检测胃癌细胞中B7-H4和干性相关蛋白的表达；D. Western blotting检测胃癌细胞中B7-H4和干性相关蛋白的表达

, figureFileSmall=Pyv5Icw1NrNTjGj2vfDziQ==, figureFileBig=beThqErjatoNN8B4wkBZzw==, tableContent=null), ArticleFig(id=1211268942979535139, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Fig.5, caption=Relationship between B7-H4 and the expressions of PI3K/Akt/NF-κB signal pathway protein, figureFileSmall=ohWKAnfC2e/rWok0AQKiUg==, figureFileBig=2RHaPcSMTWKvwvcfUyMMcQ==, tableContent=null), ArticleFig(id=1211268943071809832, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=图5, caption=B7-H4与PI3K/Akt/NF-κB信号通路蛋白表达的关系

A、B. B7-H4阳性胃癌组织中p-PI3K-p85、p-Akt-Thr308、p-Akt-Ser473和NF-κB p65的表达；C、D. 胃癌组织中B7-H4与PI3K/Akt mRNA表达的相关性

, figureFileSmall=ohWKAnfC2e/rWok0AQKiUg==, figureFileBig=2RHaPcSMTWKvwvcfUyMMcQ==, tableContent=null), ArticleFig(id=1211268943155695919, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Tab.1, caption=

Judgment method of immunohistochemical staining results

, figureFileSmall=null, figureFileBig=null, tableContent=
分数着色细胞/计数细胞×100%(A)着色强度(B)
0≤5%未着色
15%~25%淡黄色
225%~50%棕色
350%~75%
4>75% 
), ArticleFig(id=1211268943264747828, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=表1, caption=

免疫组化染色结果判定方法

, figureFileSmall=null, figureFileBig=null, tableContent=
分数着色细胞/计数细胞×100%(A)着色强度(B)
0≤5%未着色
15%~25%淡黄色
225%~50%棕色
350%~75%
4>75% 
), ArticleFig(id=1211268943336051002, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=EN, label=Tab.2, caption=

The relationship of B7-H4 expression to clinicopathologic characteristics of gastric cancer [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
变量B7-H4阴性(n=64)B7-H4阳性(n=119)χ2P
年龄(岁)  0.0260.724
 <6541(64.1)79(66.4)
 ≥6523(35.9)40(33.6)
性别  0.1240.094
 男34(53.1)78(65.5)
 女30(46.9)41(34.5)
肿瘤直径(cm)  0.1110.125
 <4.529(45.3)40(33.6)
 ≥4.535(54.7)79(66.4)
肿瘤位置  0.1740.123
 胃窦30(46.9)68(57.1)
 贲门03(2.5)
 胃体31(48.4)39(32.8)
 混合3(4.7)9(7.6)
肿瘤分化程度  0.2540.005
 高分化11(17.2)21(17.6)
 中分化15(23.4)52(43.7)
 低分化18(28.1)31(26.1)
 印戒细胞样20(31.3)15(12.6)
pT分期  0.2170.028
 Ⅰ15(23.4)21(17.6)
 Ⅱ22(34.4)23(19.3)
 Ⅲ27(42.2)71(59.7)
 Ⅳ04(3.4)
淋巴结转移  0.1720.017
 无60(93.4)96(80.7)
 有4(6.3)23(19.3)
远处转移  0.1630.025
 无62(96.9)103(86.6)
 有2(3.1)16(13.4)
临床分期  0.2180.028
 Ⅰ23(35.9)25(21.0)
 Ⅱ15(23.4)23(19.3)
 Ⅲ24(37.5)55(46.2)
 Ⅳ2(3.1)16(13.4)
大体分型  0.8500.356
 进展期48(75.0)96(80.7)
 早期16(25.0)23(19.3)
组织学类型  0.1560.128
 肠型28(43.8)66(55.5)
 弥漫型35(54.7)46(38.7)
 混合型1(1.6)7(5.9)  
), ArticleFig(id=1211268943415742782, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268931541668723, language=CN, label=表2, caption=

B7-H4表达与胃癌临床病理特征的关系[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
变量B7-H4阴性(n=64)B7-H4阳性(n=119)χ2P
年龄(岁)  0.0260.724
 <6541(64.1)79(66.4)
 ≥6523(35.9)40(33.6)
性别  0.1240.094
 男34(53.1)78(65.5)
 女30(46.9)41(34.5)
肿瘤直径(cm)  0.1110.125
 <4.529(45.3)40(33.6)
 ≥4.535(54.7)79(66.4)
肿瘤位置  0.1740.123
 胃窦30(46.9)68(57.1)
 贲门03(2.5)
 胃体31(48.4)39(32.8)
 混合3(4.7)9(7.6)
肿瘤分化程度  0.2540.005
 高分化11(17.2)21(17.6)
 中分化15(23.4)52(43.7)
 低分化18(28.1)31(26.1)
 印戒细胞样20(31.3)15(12.6)
pT分期  0.2170.028
 Ⅰ15(23.4)21(17.6)
 Ⅱ22(34.4)23(19.3)
 Ⅲ27(42.2)71(59.7)
 Ⅳ04(3.4)
淋巴结转移  0.1720.017
 无60(93.4)96(80.7)
 有4(6.3)23(19.3)
远处转移  0.1630.025
 无62(96.9)103(86.6)
 有2(3.1)16(13.4)
临床分期  0.2180.028
 Ⅰ23(35.9)25(21.0)
 Ⅱ15(23.4)23(19.3)
 Ⅲ24(37.5)55(46.2)
 Ⅳ2(3.1)16(13.4)
大体分型  0.8500.356
 进展期48(75.0)96(80.7)
 早期16(25.0)23(19.3)
组织学类型  0.1560.128
 肠型28(43.8)66(55.5)
 弥漫型35(54.7)46(38.7)
 混合型1(1.6)7(5.9)  
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B7-H4表达对胃癌患者预后的影响及机制
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车楠 1, 2 , 齐文博 1 , 杨昭婷 1 , 玄延花 1, 2, *
解放军医学杂志 | 临床研究 2021,46(2): 122-128
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解放军医学杂志 | 临床研究 2021, 46(2): 122-128
B7-H4表达对胃癌患者预后的影响及机制
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车楠1, 2 , 齐文博1, 杨昭婷1, 玄延花1, 2, *
作者信息
  • 1延边大学医学院再生医学研究所，吉林 延吉 133002
  • 2延边大学医学院病理教研室，吉林 延吉 133002

    • 车楠，博士研究生，主要从事肿瘤分子病理学研究。E-mail：

通讯作者:

玄延花，E-mail：
Effect and mechanism of B7-H4 expression on the prognosis of gastric cancer patients
Nan Che1, 2 , Wen-Bo Qi1, Zhao-Ting Yang1, Yan-Hua Xuan1, 2, *
Affiliations
  • 1Institute for Regenerative Medicine, College of Medicine, Yanbian University, Yanji, Jilin 133002, China
  • 2Department of Pathology, College of Medicine, Yanbian University, Yanji, Jilin 133002, China
出版时间: 2021-02-28 doi: 10.11855/j.issn.0577-7402.2021.02.03
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摘要
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目的 探讨B7-H4表达对胃癌患者预后的影响及其可能机制。方法 利用UALCAN、Kaplan-Meier Plotter数据库及GEPIA在线分析工具分析胃癌组织中B7-H4的表达及其与患者预后的关系。采用免疫组化染色检测胃癌组织中B7-H4的表达，分析其与临床病理特征、细胞周期调控蛋白、微血管密度(MVD)、干性相关蛋白及PI3K/Akt/NF-κB信号通路蛋白的关系。采用免疫荧光和Western blotting检测胃癌细胞中B7-H4及干性相关蛋白的表达。采用Oncomine数据库分析胃癌组织中B7-H4与PI3K、Akt mRNA表达的相关性。结果 B7-H4在胃癌组织中的表达水平高于正常组织(P<0.001)，其表达与肿瘤分化程度、pT分期、淋巴结转移、远处转移和临床分期明显相关(P<0.05)，并预示胃癌患者预后不良。胃癌组织中B7-H4与细胞周期调控蛋白p16及干性相关蛋白LSD1、SOX9、CD133的表达呈正相关(r=0.250，P<0.001；r=0.331，P<0.001；r=0.176，P=0.018；r=0.434，P<0.001)。B7-H4阳性组织标本的MVD明显高于B7-H4阴性组织标本(P=0.019)。在胃癌细胞系中B7-H4与干性相关蛋白LSD1、SOX9、CD133共表达。B7-H4在胃癌组织中与p-PI3K-p85、p-Akt-Thr308、p-Akt-Ser473和NF-κB p65的表达呈正相关(r=0.269，P<0.001；r=0.282，P<0.01；r=0.214，P=0.005；r=0.157，P=0.034)。胃癌组织中B7-H4与PI3K、Akt mRNA的表达呈正相关(r=0.403，P<0.001；r=0.351，P<0.001)。结论 B7-H4能够促进胃癌进展且与患者的预后不良密切相关，其机制可能与B7-H4通过PI3K/Akt/NF-κB通路调节胃癌干性特征相关。

B7-H4  /  胃癌  /  预后  /  干性  /  PI3K/Akt/NF-κB

Objective To investigate the effect and mechanism of B7-H4 expression on the prognosis of patients with gastric cancer. Methods The databases of Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN and Kaplan-Meier Plotter were used to analyze the expression of B7-H4 in gastric cancer tissues and its relationship with the prognosis of gastric cancer patients. Immunohistochemistry staining was performed to observe the expression of B7-H4 protein in gastric cancer tissues and analyze its correlation with clinicopathological characteristics, cell cycle regulatory proteins, microvessel density (MVD), stemness-related proteins, and PI3K/Akt/NF-κB signaling pathway proteins. Immunofluorescence and Western blotting were used to detect the expressions of B7-H4 and stemness-related proteins in gastric cancer cells. Oncomine database was employed to analyze the correlation between B7-H4 and the expressions of PI3K and Akt mRNA in gastric cancer tissues. Results The expression level of B7-H4 was higher in gastric cancer tissues than in normal tissues, and its expression was significantly related to tumor differentiation, pT staging, lymph node metastasis, distant metastasis and clinical staging (P<0.05), and indicated a poor prognosis in gastric cancer. The expression of B7-H4 was positively correlated with the expressions of cell cycle regulatory protein p16 (r=0.250, P<0.001) and stemness-related proteins LSD1 (r=0.331, P<0.001), SOX9 (r=0.176, P=0.018) and CD133 (r=0.434, P<0.001). The MVD was significantly higher in B7-H4 positive tissue than in B7-H4 negative tissue (P=0.019). Furthermore, B7-H4 was co-expressed with stemness-related proteins LSD1, SOX9, and CD133 in gastric cancer cell lines, and the expression of B7-H4 was positively correlated with the expressions of p-PI3K-p85 (r=0.269, P<0.001), p-Akt-Ser473 (r=0.282, P<0.01), p-Akt-Thr308 (r=0.214, P=0.005) and NF-κB p65 (r=0.157, P=0.034). The expression of B7-H4 in gastric cancer tissue was positively correlated with the expressions of PI3K mRNA (r=0.403, P<0.001) and Akt mRNA (r=0.351, P<0.001). Conclusion B7-H4 can promote gastric cancer progression and is closely related to poor prognosis, and the mechanism may be related to the regulation of gastric cancer stemness via PI3K/Akt/NF-κB.

B7-H4  /  gastric cancer  /  prognosis  /  stemness  /  PI3K/Akt/NF-κB
车楠, 齐文博, 杨昭婷, 玄延花. B7-H4表达对胃癌患者预后的影响及机制. 解放军医学杂志, 2021 , 46 (2) : 122 -128 . DOI: 10.11855/j.issn.0577-7402.2021.02.03
Nan Che, Wen-Bo Qi, Zhao-Ting Yang, Yan-Hua Xuan. Effect and mechanism of B7-H4 expression on the prognosis of gastric cancer patients[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (2) : 122 -128 . DOI: 10.11855/j.issn.0577-7402.2021.02.03
正文
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胃癌是全球范围内最为常见的恶性肿瘤之一，也是我国癌症相关死亡的第二大疾病。据报道，2018年全球胃癌新发病例超过10万，死亡约7.8万例[1]。尽管胃癌的治疗手段在不断更新[2-3]，但由于原发性或获得性耐药，晚期胃癌患者5年生存率低于20%[4]。因此，探索新的分子生物标志物以预测胃癌进展并辅助靶向治疗成为主要的研究方向。肿瘤干细胞(cancer stem cells，CSCs)是具有自我更新和分化潜能的细胞亚群，参与肿瘤的起始、侵袭、转移和化疗耐药，是肿瘤治疗的新靶点。作为B7家族成员之一，B7-H4是T细胞免疫应答的负性调控因子，但在多种癌症(如肺癌、胰腺癌、乳腺癌、卵巢癌)中高表达，且与癌症进展及患者预后密切相关[5-7]。目前，关于B7-H4表达与胃癌临床病理特征及干性特征关系的研究报道较少。本研究旨在结合生物信息学分析方法，利用胃癌标本和胃癌细胞，探讨B7-H4在胃癌中的临床意义及其可能的作用机制。
1 材料与方法
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1.1 临床组织标本
附有随访信息的183份胃癌组织样本来源于上海芯超生物科技有限公司。胃癌病例中男112例，女71例，术前未接受任何治疗，随访期2~136个月。3份人胚胎组织样本来源于延边大学医学院。本研究通过延边大学医学院伦理委员会审批(BS-13-35)。
1.2 细胞及主要试剂、仪器
人胃癌细胞AGS、SNU484、MKN74、MKN28购自美国ATCC(American Type Culture Collection)细胞库。B7-H4、CD105、SOX9、LSD1、CD133和β-actin抗体购自英国Abcam公司；p16、p-PI3K-p85、p-Akt(Ser473和Thr308)及NF-κB p65抗体购自美国Millipore公司；免疫组化试剂盒、BCA蛋白检测试剂盒购自上海碧云天生物技术有限公司。Western blotting电泳系统和凝胶成像仪购自美国Bio-Rad公司；激光共聚焦显微镜购自日本尼康株式会社；流式细胞仪购自美国BD公司。
1.3 免疫组化染色检测B7-H4、细胞周期调控蛋白、干性相关蛋白及PI3K/Akt/NF-κB信号通路蛋白的表达
石蜡切片经二甲苯脱蜡后，梯度乙醇脱水，置于TE(1 mmol/L EDTA和10 mmol/L Tris，pH 9.2)缓冲液中煮沸15 min进行抗原修复；TBST洗涤，3% H2O2封闭，清除内源性过氧化物酶干扰；分别加入B7-H4 (1:100)、p16 (1:100)、CD105 (1:50)、LSD1 (1:100)、SOX9 (1:100)、CD133 (1:150)、p-PI3K-p85 (1:100)、p-Akt-Ser473(1:100)、p-Akt-Thr308 (1:100)和NF-κB p65 (1:100)蛋白抗体，4 ℃孵育过夜；TBST洗涤3次，加入生物素标记的山羊抗小鼠/兔IgG聚合物二抗(1:1000)，室温孵育1 h。DAB或AEC显色剂孵育10 min，自来水冲洗，苏木精复染，自来水返蓝10 min，脱水，中性树脂封片，显微镜下观察B7-H4、p16、CD105、LSD1、SOX9、CD133、p-PI3K-p85、p-Akt-Ser473、p-Akt-Thr308和NF-κB p65蛋白的表达情况。所有切片的免疫组化染色均由2名实验员在相同条件下完成，结果判定方法如表1所示，A×B≥3计为阳性。
1.4 Western blotting检测胃癌细胞中B7-H4及干性相关蛋白的表达
收集并裂解胃癌细胞，用BCA法检测总蛋白浓度，然后行10% SDS-PAGE凝胶电泳，上样30 μg蛋白，转膜、封闭。加入B7-H4(1:500)、LSD1 (1:1000)、CD133 (1:1000)和SOX9(1:500)一抗，4 ℃孵育过夜，加入HRP标记的羊抗兔和羊抗鼠二抗(1:8000)杂交2 h，Gel Doc凝胶成像仪成像后，以β-actin为内参，利用ImageJ软件进行灰度值分析。
1.5 免疫荧光染色检测胃癌细胞中B7-H4及干性相关蛋白的表达
将MKN28细胞以5×104个/孔的密度接种于6孔板中，当生长密度达70%时，每孔加入4%多聚甲醛固定10 min，加入0.2% Triton X-100对细胞进行破膜，封闭后，加入B7-H4 (1:100)、SOX9 (1:100)和LSD1 (1:100)一抗4 ℃下孵育过夜，PBS洗涤3次，加入FITC标记的羊抗兔和PE标记的羊抗鼠二抗(1:150)，避光孵育2 h，加入含DAPI的抗荧光淬灭封片剂进行封片，荧光显微镜下观察B7-H4、SOX9和LSD1蛋白的表达情况。
1.6 生物信息分析
利用UALCAN数据库(http://ualcan.path.uab.edu/)分析胃癌组织中B7-H4 mRNA的表达，GEPIA在线分析工具(http://gepia.cancer-pku.cn/)分析胃癌组织中B7-H4与p16的关系，Kaplan-Meier Plotter数据库(http://kmplot.com/analysis/)分析B7-H4表达与胃癌患者无进展生存期的关系，Oncomine数据库(https://www.oncomine.org)分析胃癌组织中B7-H4与PI3K、Akt mRNA的表达情况。
1.7 统计学处理
应用SPSS 17.0软件(注册号1975-01566-C)进行统计分析。阳性率比较采用McNemer χ2检验，相关性采用Spearman相关性分析。生存分析采用Kaplan-Meier法，并使用Log-rank检验进行比较。采用Cox比例风险模型分析患者预后的影响因素。计量数据以$\bar{x}±s$表示，组间比较采用t检验。P<0.05为差异有统计学意义。实验重复3次。
2 结果
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2.1 胃癌组织中B7-H4的表达情况
UALCAN数据库分析结果显示，与正常组织相比，胃癌组织中B7-H4 mRNA的表达水平明显升高(P<0.001，图1A)。免疫组化染色结果显示，B7-H4在人胚胎胃组织中几乎不表达(图1B)，在胃癌组织中的表达明显多于癌旁非肿瘤性胃黏膜组织(图1C)。
2.2 B7-H4表达与胃癌临床病理特征的关系
如表2所示，B7-H4的表达与肿瘤分化程度、pT分期、淋巴结转移、远处转移和临床分期明显相关(P<0.05)，与年龄、性别、肿瘤位置、肿瘤大小、大体分型和组织学类型无关(P>0.05)。
2.3 B7-H4对胃癌患者预后的影响
Kaplan-Meier生存分析结果显示，B7-H4阳性表达患者的总体生存率、无进展生存率明显低于B7-H4阴性表达患者(P<0.001，P=0.021，图2A、B)。单因素Cox回归分析结果显示，肿瘤大小、淋巴结转移、远处转移、B7-H4表达是胃癌患者预后不良的重要因素(P<0.05，图2C)。多因素Cox回归分析结果显示，淋巴结转移、远处转移、B7-H4表达是影响胃癌患者总体生存率的独立预后因素(P<0.05，图2D)。
2.4 胃癌组织中B7-H4表达与细胞周期调控蛋白及微血管密度(microvessel density，MVD)的关系
免疫组化染色结果显示，胃癌组织中B7-H4与细胞周期调控蛋白p16的表达呈正相关(r=0.250，P<0.001，图3A、B)。GEPIA分析结果显示，胃癌组织中B7-H4与p16的表达呈正相关(r=0.20，P<0.01，图3C)。免疫组化双重染色结果显示，CD105在胃癌细胞周围新生毛细血管中呈高表达(图3D，红色)。B7-H4阳性组织标本的MVD明显高于B7-H4阴性组织标本[(121.00±29.00)个/视野vs.(56.00±6.56)个/视野，P=0.019，图3E]。
2.5 B7-H4表达与胃癌干性相关蛋白的关系
如图4A所示，B7-H4和CD133主要表达于胃癌细胞的细胞质，而SOX9和LSD1主要定位于胃癌细胞的细胞核。B7-H4与LSD1、SOX9、CD133在胃癌组织中共表达，且呈正相关(r=0.331，P<0.001；r=0.176，P=0.018；r=0.434，P<0.001；图4B)。免疫荧光和Western blotting检测结果显示，胃癌细胞中B7-H4与CD133、LSD1、SOX9共表达(图4C、D)。
2.6 B7-H4与PI3K/Akt/NF-κB信号通路蛋白表达的关系
免疫组化多重染色结果显示，B7-H4在胃癌组织中与p-PI3K-p85、p-Akt-Thr308、p-Akt-Ser473和NF-κB p65蛋白共表达，且呈正相关(r=0.269，P<0.001；r=0.282，P<0.01；r=0.214，P=0.005；r=0.157，P=0.034；图5A、B)。Oncomine数据库分析结果显示，胃癌组织中B7-H4与PI3K、Akt mRNA的表达呈正相关(r=0.403，P<0.001；r=0.351，P<0.001；图5C、D)。
3 讨论
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B7-H4又称B7x或B7S1，在活化的抗原提呈细胞上表达，能够抑制T细胞介导的免疫应答。有研究发现，B7-H4在多种癌症患者血清或肿瘤组织中高表达，其表达高低与肿瘤进展密切相关，如B7-H4在肾癌患者血清中的表达水平明显高于健康者[5]。胆管癌组织中B7-H4的表达水平高于正常组织，可作为肿瘤转移的生物标志物[8]。然而，B7-H4在胃癌组织中的表达及其与胃癌患者临床病理特征的关系研究较少。
B7-H4高表达与多种预后因素相关，如肿瘤分级、分期、转移、复发等[6,8]。有研究发现，B7-H4在胃癌组织中呈高表达，且与肿瘤大小、临床分期等病理特征密切相关[10-12]。本研究通过生存分析和Cox回归分析发现，胃癌组织中B7-H4高表达与患者预后不良明显相关，可作为胃癌预后的独立预测因素。由此，B7-H4可能是预测胃癌患者预后及肿瘤进展的有价值的生物标志物。
B7-H4在食管鳞状细胞癌组织中呈高表达，且可通过激活IL-6/STAT3信号转导通路促进肿瘤细胞增殖[13]。Zhang等[14]发现，B7-H4可通过核移位促进肾癌细胞增殖和细胞周期进展。血管生成能够促进肿瘤的生长、侵袭和转移，与多种实体肿瘤的进展密切相关[15]。本研究发现，B7-H4与细胞周期调控蛋白p16的表达及MVD密切相关，提示B7-H4可能通过调控细胞周期和血管生成促进胃癌进展。
CSCs可通过操纵遗传因子和非遗传因子转移及抵抗治疗而维持肿瘤细胞生存、促进肿瘤进展[16]。由于CSCs持续存在，针对癌症的化疗常随着肿瘤复发而失败。靶向调控肿瘤细胞干性能够有效抑制胃癌的进展[17]。有研究发现，作为食管鳞状细胞癌和前列腺癌细胞干性的调节因子，B7-H4在肿瘤组织与细胞系中与SOX2、CD44及LSD1等CSCs标志物的表达密切相关[18-19]。本研究发现，胃癌组织中B7-H4与CD133、LSD1和SOX9的表达呈正相关，且B7-H4在胃癌细胞中与CSCs标志物共表达，表明B7-H4参与了胃癌细胞干性特征的调控，胃癌中B7-H4高表达可促进癌细胞获得干性特征，从而促进癌症进展。
多项遗传和癌症生物学研究发现，PI3K/Akt/NF-κB信号通路的异常激活可促进肿瘤进展，并对化疗产生耐药性[20]。靶向抑制PI3K/Akt/NF-κB信号通路能够降低CD44+前列腺癌干细胞的生存和转移能力[22]。因此，PI3K/Akt/NF-κB信号通路是调控肿瘤干性的重要机制之一。本研究发现，胃癌组织中B7-H4与p-PI3K-p85、p-Akt-Ser473、p-Akt-Thr308和NF-κB p65的表达存在明显的正相关关系，此外，Oncomine数据库分析结果表明，胃癌组织中B7-H4与PI3K、Akt mRNA的表达呈正相关，提示B7-H4可能参与调控PI3K/Akt/NF-κB信号通路。
综上所述，本研究结果显示，B7-H4在胃癌组织中呈高表达，可促进胃癌进展且与患者预后不良相关，这一作用可能与其通过PI3K/Akt/NF-κB信号通路调节胃癌的干性特征有关。
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  • 国家自然科学基金(81760531)
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2021年第46卷第2期
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doi: 10.11855/j.issn.0577-7402.2021.02.03
  • 接收时间：2020-06-02
  • 首发时间：2025-12-26
  • 出版时间：2021-02-28
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  • 收稿日期：2020-06-02
  • 修回日期：2021-01-12
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National Natural Science Foundation of China(81760531)
国家自然科学基金(81760531)
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    1延边大学医学院再生医学研究所，吉林 延吉 133002
    2延边大学医学院病理教研室，吉林 延吉 133002

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