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Article(id=1198558113377907229, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0934.2024.0527, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1689091200000, receivedDateStr=2023-07-12, revisedDate=null, revisedDateStr=null, acceptedDate=1702569600000, acceptedDateStr=2023-12-15, onlineDate=1763688122361, onlineDateStr=2025-11-21, pubDate=1727452800000, pubDateStr=2024-09-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763688122361, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763688122361, creator=13701087609, updateTime=1763688122361, updator=13701087609, issue=Issue{id=1198558106218230069, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='9', pageStart='977', pageEnd='1098', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763688120655, creator=13701087609, updateTime=1763689155065, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198562444915339352, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198562444915339353, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1045, endPage=1054, ext={EN=ArticleExt(id=1198558113801531954, articleId=1198558113377907229, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effects of Helicobacter pylori on gastric cancer progression by upregulating ADAMTS14 and activating Hippo signaling pathway and its underlying mechanisms, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To analyze the effects and mechanisms of a disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14) gene in gastric cancer associated with Helicobacter pylori (Hp) infection and explore the potential of ADAMTS14 as a novel target for biological therapy of gastric cancer. Methods The Caner Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to analyze differentially expressed genes in gastric cancer tissues and Hp-positive gastric mucosa, and to screen potential targets. For the selected target ADAMTS14, its expression pattern in gastric cancer and Hp-positive gastric mucosa was analyzed. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed on the genes co-expressed with ADAMTS14 in gastric cancer. Kaplan-Meier Plotter database was used to analyze the correlation between high- and low-ADAMTS14 expression and prognosis of gastric cancer patients. The expression of ADAMTS14 and its relationship with clinicopathological features in 30 patients with gastric cancer were analyzed using real-time fluorescent quantitative PCR (RT-qPCR) and immunohistochemistry. The relationship between Hp infection and ADAMTS14 expression was analyzed using GEO database, and confirmed by cell line infection experiment. ADAMTS14 expression in gastric cancer cell line NCI-N87 was silenced by small interfering RNA to analyze its effect on the function of gastric cancer cells; The effect of ADAMTS14 knockdown on downstream target genes of Hippo signaling pathway was analyzed by RT-qPCR and Western blotting. Results A total of 16 genes closely related to Hp infection and gastric cancer were identified by analyzing the TCGA and GEO databases. According to TCGA database, the ADAMTS14 expression in gastric cancer tissues was higher than that in healthy gastric mucosa (P<0.0001). RT-qPCR and immunohistochemistry results also showed higher ADAMTS14 expression in gastric cancer tissues compared to adjacent tissues (P<0.01). Survival analysis demonstrated poor prognosis in patients with high ADAMTS14 expression (P<0.001). Data from GSE60427 showed that ADAMTS14 expression was upregulated in Hp-infected gastric mucosa and cell lines (P<0.001). After Hp P12 infection, the ADAMTS14 expression in NCI-N87 cells was higher than that in uninfected group. ADAMTS14 knockdown significantly inhibited the proliferation and migration of NCI-N87 cells (P<0.05), and it also significantly inhibited the expression of Hippo signaling pathway target genes, including BMP7, BMPR2, FZD4, PARD3 and SAV1 (P<0.05). Conclusion ADAMTS14 is highly expressed in Hp-positive gastric mucosa and gastric cancer tissues, which may accelerate gastric cancer progression by regulating Hippo signaling pathway, and holds potential as a new marker and therapeutic target for Hp infective gastric cancer.

, correspAuthors=Peng-Yuan Zheng, authorNote=null, correspAuthorsNote=
E-mail:
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目的 研究Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14基因(ADAMTS14)对幽门螺杆菌(Hp)感染相关胃癌进展的影响及其机制，探讨ADAMTS14作为胃癌生物治疗新靶点的可能性。方法 利用癌症基因组图谱(TCGA)及高通量基因表达数据库(GEO)分析胃癌组织及Hp阳性胃黏膜中差异表达的基因，筛选可能的靶点；对于选定的靶点ADAMTS14，分析其在胃癌及Hp阳性胃黏膜中的表达模式；对胃癌中与ADAMTS14共表达的基因进行京都基因与基因组百科全书(KEGG)数据库分析；利用Kaplan-Meier Plotter数据库分析ADAMTS14高低表达与胃癌患者预后的相关性；利用实时荧光定量PCR(RT-qPCR)和免疫组化方法分析30例胃癌患者的ADAMTS14表达水平，采用χ2检验分析ADAMTS14蛋白表达与临床病理特征之间的关系；利用GEO数据库分析Hp感染与ADAMTS14表达的关系，并通过细胞系感染实验验证；利用小干扰RNA沉默胃癌细胞系NCI-N87中ADAMTS14的表达，分析其对胃癌细胞功能的影响；利用RT-qPCR和Western blotting分析敲低ADAMTS14对Hippo信号通路下游靶基因表达的影响。结果 通过分析TCGA和GEO数据库，共得到16个与Hp感染及胃癌密切相关的基因；在TCGA数据库中，ADAMTS14在胃癌组织中的表达水平高于健康人胃黏膜(P<0.001)；RT-qPCR及免疫组化结果也显示，ADAMTS14在胃癌组织中的表达水平高于癌旁组织(P<0.01)；生存分析显示ADAMTS14高表达患者的预后不良(P<0.001)；GSE60427的数据显示ADAMTS14在Hp感染的胃黏膜及细胞系中表达上调(P<0.001)；Hp P12菌株感染NCI-N87细胞后ADAMTS14表达高于未感染组(P<0.0001)；敲低胃癌细胞系NCI-N87中ADAMTS14明显抑制了胃癌细胞的增殖及迁移(P<0.05)，以及Hippo信号通路靶基因BMP7、BMPR2、FZD4、PARD3、SAV1的表达(P<0.05)。结论 ADAMTS14在Hp感染的胃黏膜及胃癌组织中高表达，可能通过调控Hippo信号通路促进胃癌进展，有望作为Hp感染相关胃癌的新标志物及治疗靶点。

, correspAuthors=郑鹏远, authorNote=null, correspAuthorsNote=
郑鹏远，E-mail：
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张博，硕士研究生，主要从事胃肠道肿瘤及免疫微生态方面的研究

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张博，硕士研究生，主要从事胃肠道肿瘤及免疫微生态方面的研究

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张博，硕士研究生，主要从事胃肠道肿瘤及免疫微生态方面的研究

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J Exp Clin Cancer Res, 2023, 42(1): 297., articleTitle=Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer, refAbstract=null)], funds=[Fund(id=1198558124857717545, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, awardId=2020YFC2006101, language=EN, fundingSource=National Key Research and Development Program of China(2020YFC2006101), fundOrder=null, country=null), Fund(id=1198558124954186539, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, awardId=2020YFC2006101, language=CN, fundingSource=国家重点研发计划(2020YFC2006101), fundOrder=null, country=null), Fund(id=1198558125054849838, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, awardId=XKZDJC202001, language=EN, fundingSource=Key Project for Discipline Construction of Zhengzhou University(XKZDJC202001), fundOrder=null, country=null), Fund(id=1198558125138735919, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, awardId=XKZDJC202001, language=CN, fundingSource=郑州大学学科建设重点专项(XKZDJC202001), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198558117576405658, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, xref=1, ext=[AuthorCompanyExt(id=1198558117584794268, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, companyId=1198558117576405658, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Gastroenterology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China), AuthorCompanyExt(id=1198558117597377180, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, companyId=1198558117576405658, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1郑州大学第五附属医院消化内科，河南郑州 450052)]), AuthorCompany(id=1198558117698040482, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, xref=2, ext=[AuthorCompanyExt(id=1198558117714817698, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, companyId=1198558117698040482, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450052, China), AuthorCompanyExt(id=1198558117719012003, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, companyId=1198558117698040482, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2郑州大学医学科学院，河南郑州 450052)])], figs=[ArticleFig(id=1198558121409999602, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.1, caption=Expression of ADAMTS14 mRNA in gastric cancer in TCGA and GEO datasets, figureFileSmall=9Bl7NFJO055H4dJP93YlKA==, figureFileBig=h2NovciUpxknWY5ovqzrVw==, tableContent=null), ArticleFig(id=1198558121523245813, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图1, caption=TCGA及GEO数据库中ADAMTS14 mRNA在胃癌中的表达情况

TCGA. 癌症基因组图谱；GEO. 基因表达数据库；ADAMTS14. I型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14；Hp. 幽门螺杆菌；A. 分析TCGA数据库中胃癌组织及Hp感染患者的GSE60427和GSE154127胃黏膜的RNA-seq数据，得到16个上调基因；B. 胃癌组织与健康胃黏膜间的差异表达基因；C. Hp阳性胃黏膜与Hp阴性胃黏膜的差异表达基因；D. 胃癌类器官与健康胃黏膜间的差异表达基因

, figureFileSmall=9Bl7NFJO055H4dJP93YlKA==, figureFileBig=h2NovciUpxknWY5ovqzrVw==, tableContent=null), ArticleFig(id=1198558121741349628, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.2, caption=Analysis results of ADAMTS14 in TCGA dataset (n=30), figureFileSmall=a9ITYxhzi7RvRgJFniIadQ==, figureFileBig=ZNsEBIAKdyK7nRDtnwiyNA==, tableContent=null), ArticleFig(id=1198558121829430014, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图2, caption=ADAMTS14在TCGA数据库中的分析结果(n=30)

TCGA. 癌症基因组图谱；ADAMTS14. I型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14；A. 在TCGA数据库中，胃癌组织与健康者胃黏膜组织中ADAMTS14 mRNA表达水平比较；B. 胃癌组织与癌旁组织中ADAMTS14 mRNA表达水平比较；**P<0.01；****P<0.0001

, figureFileSmall=a9ITYxhzi7RvRgJFniIadQ==, figureFileBig=ZNsEBIAKdyK7nRDtnwiyNA==, tableContent=null), ArticleFig(id=1198558121942676225, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.3, caption=Cocluster analysis of ADAMTS14 gene expression in gastric cancer tissues, figureFileSmall=aiuFHvg/INKW1+v/gTzJ0w==, figureFileBig=paXlPYDl26UNb+sX2xiRAg==, tableContent=null), ArticleFig(id=1198558122043339523, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图3, caption=胃癌组织中与ADAMTS14基因表达相关的共聚类分析, figureFileSmall=aiuFHvg/INKW1+v/gTzJ0w==, figureFileBig=paXlPYDl26UNb+sX2xiRAg==, tableContent=null), ArticleFig(id=1198558122139808516, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.4, caption=Functional enrichment analysis of ADAMTS14 expression in gastric cancer tissues, figureFileSmall=tGs4CLpQdPKrIh5Lt4eopQ==, figureFileBig=enXD7u7g0x3BnIdiOnfvhQ==, tableContent=null), ArticleFig(id=1198558122240471813, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图4, caption=胃癌组织中与ADAMTS14表达相关通路的功能富集分析

ADAMTS14. I型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14

, figureFileSmall=tGs4CLpQdPKrIh5Lt4eopQ==, figureFileBig=enXD7u7g0x3BnIdiOnfvhQ==, tableContent=null), ArticleFig(id=1198558122336940808, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.5, caption=Effection of ADAMTS14 gene expression on the function of NCI-N87 (n=3), figureFileSmall=D8MMn57uAOyvWTJkdTIAHA==, figureFileBig=4GN9agylRVUgUnBS2XUspw==, tableContent=null), ArticleFig(id=1198558122429215495, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图5, caption=ADAMTS14基因表达影响胃癌细胞NCI-N87的功能(n=3)

A. 5种胃癌细胞系中ADAMTS14 mRNA的表达水平；B. siRNA沉默对NCI-N87细胞中ADAMTS14 mRNA表达的影响；C. siRNA沉默对NCI-N87细胞活力的影响(与对照组比较，**P<0.01，***P<0.001，****P<0.0001)；D. siRNA沉默对NCI-N87细胞迁移能力的影响(结晶紫染色 ×400)；*P<0.05，**P<0.01，***P<0.001，****P<0.0001

, figureFileSmall=D8MMn57uAOyvWTJkdTIAHA==, figureFileBig=4GN9agylRVUgUnBS2XUspw==, tableContent=null), ArticleFig(id=1198558122534073098, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.6, caption=Correlation between Hp infection and ADAMTS14 mRNA expression, figureFileSmall=+H6YnTJSLkyqttQqmNvXxw==, figureFileBig=xFX6eQp3RaII3vKo7kpe9A==, tableContent=null), ArticleFig(id=1198558122609570572, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图6, caption=Hp感染与ADAMTS14 mRNA表达的相关性

Hp. 幽门螺杆菌；A. 在GSE60427公开数据集中，ADAMTS14 mRNA在Hp感染的胃黏膜中异常高表达；B. 在感染复数(MOI)=200时，NCI-N87细胞Hp感染不同时间时的ADAMTS14 mRNA表达情况(n=3)；C. Hp感染12 h时，不同MOI的NCI-N87细胞中的ADAMTS14 mRNA表达水平(n=3)；***P<0.001，****P<0.0001

, figureFileSmall=+H6YnTJSLkyqttQqmNvXxw==, figureFileBig=xFX6eQp3RaII3vKo7kpe9A==, tableContent=null), ArticleFig(id=1198558122672485135, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.7, caption=Effect of Hp infection on ADAMTS14 mRNA and protein expression in NCI-N87 cells, figureFileSmall=KV+jCttum0gH1p3rviocDw==, figureFileBig=XbpNASylijFyVH9uBt43ag==, tableContent=null), ArticleFig(id=1198558122743788306, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图7, caption=Hp感染对NCI-N87细胞中ADAMTS14 mRNA和蛋白表达的影响

Hp. 幽门螺杆菌；A. RT-qPCR检测(n=3)；B. Western blotting检测(n=3)；***P<0.001，****P<0.0001

, figureFileSmall=KV+jCttum0gH1p3rviocDw==, figureFileBig=XbpNASylijFyVH9uBt43ag==, tableContent=null), ArticleFig(id=1198558122819285779, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.8, caption=Effect of ADAMTS14 knockdown on target genes and proteins of Hippo signaling pathway (n=3), figureFileSmall=GFwYf2OJZBsEv2T/jjjNIQ==, figureFileBig=AgrfrmvIafIDLS4bxRnlWA==, tableContent=null), ArticleFig(id=1198558122940920597, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图8, caption=ADAMTS14敲低对Hippo信号通路下游靶基因及蛋白的影响(n=3)

A. RT-qPCR检测Hippo信号通路靶基因BMP7、BMPR2、SAV1、PARD3和FZD4 mRNA的表达情况；B. Western blotting检测验证Hippo信号通路靶基因SAV1、BMPR2和FZD4蛋白的表达情况；****P<0.0001

, figureFileSmall=GFwYf2OJZBsEv2T/jjjNIQ==, figureFileBig=AgrfrmvIafIDLS4bxRnlWA==, tableContent=null), ArticleFig(id=1198558123062555416, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.9, caption=ADAMTS14 expression is associated with poor prognosis in patients with gastric cancer, figureFileSmall=78Fxxt6upwTab0s2e5ICBA==, figureFileBig=gTiTCj1S+igTZzqQ3wfeRg==, tableContent=null), ArticleFig(id=1198558124140491547, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图9, caption=ADAMTS14表达与胃癌患者不良预后相关, figureFileSmall=78Fxxt6upwTab0s2e5ICBA==, figureFileBig=gTiTCj1S+igTZzqQ3wfeRg==, tableContent=null), ArticleFig(id=1198558124245349150, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Fig.10, caption=Protein expression of ADAMTS14 in paracancerous tissue and tumor tissue (Immunohistochemistry ×200, n=30), figureFileSmall=LXJjHvksaEjTr+suTbAyVQ==, figureFileBig=j9z791kGsCFuuXyw/G0oTQ==, tableContent=null), ArticleFig(id=1198558124341818144, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=图10, caption=ADAMTS14蛋白在正常胃黏膜及胃癌组织中的表达情况(免疫组化 ×200，n=30), figureFileSmall=LXJjHvksaEjTr+suTbAyVQ==, figureFileBig=j9z791kGsCFuuXyw/G0oTQ==, tableContent=null), ArticleFig(id=1198558124421509922, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Tab.1, caption=

Primer sequences of RT-qPCR analysis

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
GAPDH上游：CAGCGACACCCACTCCTC
下游：TGAGGTCCACCACCCTGT
ADAMTS14上游：CAGCACAGACTTTCGGGGAC
下游：GGAGTGTCGTGGTAGTGTGG
BMP7上游：GGAACGCTTCGACAATGAGAC
下游：GCAGGAAGAGATCCGATTCCC
BMPR2上游：GCAGACAGAGCCGATGGTAG
下游：CCATATCGACCTCGGCCAATC
FZD4上游：GTGTCACTCTGTGGGAACCAA
下游：GGCTGTATAAGCCAGCATCAT
PARD3上游：GCCTTTCAGCCTTACCAAGCA
下游：GGTCACTACTGCGTCGAACAT
SAV1上游：CTCTTGAGCGAGAAGGACTTCC
下游：GAGGTACACTAGGAGCACAGG
), ArticleFig(id=1198558124505396006, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=表1, caption=

RT-qPCR的引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
GAPDH上游：CAGCGACACCCACTCCTC
下游：TGAGGTCCACCACCCTGT
ADAMTS14上游：CAGCACAGACTTTCGGGGAC
下游：GGAGTGTCGTGGTAGTGTGG
BMP7上游：GGAACGCTTCGACAATGAGAC
下游：GCAGGAAGAGATCCGATTCCC
BMPR2上游：GCAGACAGAGCCGATGGTAG
下游：CCATATCGACCTCGGCCAATC
FZD4上游：GTGTCACTCTGTGGGAACCAA
下游：GGCTGTATAAGCCAGCATCAT
PARD3上游：GCCTTTCAGCCTTACCAAGCA
下游：GGTCACTACTGCGTCGAACAT
SAV1上游：CTCTTGAGCGAGAAGGACTTCC
下游：GAGGTACACTAGGAGCACAGG
), ArticleFig(id=1198558124601864998, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=EN, label=Tab.2, caption=

The relationship between ADAMTS14 protein expression and clinicopathological features of gastric cancer patients [n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
临床特征ADAMTS14蛋白相对表达量χ2P
低高
Lauren分型0.1330.716
胃型(n=213)108(50.7)105(49.3)
肠型(n=172)84(48.8)88(51.2)
性别1.8260.177
男(n=252)119(47.2)133(52.8)
女(n=136)74(54.4)62(45.6)
年龄(岁)5.5130.019
<65(n=168)95(56.5)73(43.5)
≥65(n=218)97(44.5)121(55.5)
T分期0.7610.383
T0-2(n=101)47(46.5)54(53.5)
T3-4(n=283)146(51.6)137(48.4)
淋巴结转移0.1430.706
有(n=262)132(50.4)130(49.6)
无(n=116)56(48.3)60(51.7)
M分期0.0230.880
M0(n=25)12(48.0)13(52.0)
M1(n=347)172(49.6)175(50.4)
肿瘤分期0.1980.656
Ⅰ或Ⅱ(n=172)85(49.4)87(50.6)
Ⅲ或Ⅳ(n=203)105(51.7)98(48.3)
Hp感染0.1470.885
阳性(n=20)10(50.0)10(50.0)
阴性(n=154)84(54.5)70(45.5)
), ArticleFig(id=1198558124731888423, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198558113377907229, language=CN, label=表2, caption=

ADAMTS14蛋白表达与胃癌患者临床病理特征之间的关系[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
临床特征ADAMTS14蛋白相对表达量χ2P
低高
Lauren分型0.1330.716
胃型(n=213)108(50.7)105(49.3)
肠型(n=172)84(48.8)88(51.2)
性别1.8260.177
男(n=252)119(47.2)133(52.8)
女(n=136)74(54.4)62(45.6)
年龄(岁)5.5130.019
<65(n=168)95(56.5)73(43.5)
≥65(n=218)97(44.5)121(55.5)
T分期0.7610.383
T0-2(n=101)47(46.5)54(53.5)
T3-4(n=283)146(51.6)137(48.4)
淋巴结转移0.1430.706
有(n=262)132(50.4)130(49.6)
无(n=116)56(48.3)60(51.7)
M分期0.0230.880
M0(n=25)12(48.0)13(52.0)
M1(n=347)172(49.6)175(50.4)
肿瘤分期0.1980.656
Ⅰ或Ⅱ(n=172)85(49.4)87(50.6)
Ⅲ或Ⅳ(n=203)105(51.7)98(48.3)
Hp感染0.1470.885
阳性(n=20)10(50.0)10(50.0)
阴性(n=154)84(54.5)70(45.5)
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幽门螺杆菌上调ADAMTS14激活Hippo信号通路对胃癌进展的影响及其机制
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张博 1 , 米阳 1 , 刘斌 1, 2 , 鲁彦文 1, 2 , 郑鹏远 1, *
解放军医学杂志 | 基础研究 2024,49(9): 1045-1054
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解放军医学杂志 | 基础研究 2024, 49(9): 1045-1054
幽门螺杆菌上调ADAMTS14激活Hippo信号通路对胃癌进展的影响及其机制
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张博1, 米阳1, 刘斌1, 2, 鲁彦文1, 2, 郑鹏远1, *
作者信息
  • 1郑州大学第五附属医院消化内科，河南郑州 450052
  • 2郑州大学医学科学院，河南郑州 450052

    • 张博，硕士研究生，主要从事胃肠道肿瘤及免疫微生态方面的研究

通讯作者:

郑鹏远，E-mail：
Effects of Helicobacter pylori on gastric cancer progression by upregulating ADAMTS14 and activating Hippo signaling pathway and its underlying mechanisms
Bo Zhang1, Yang Mi1, Bin Liu1, 2, Yan-Wen Lu1, 2, Peng-Yuan Zheng1, *
Affiliations
  • 1Department of Gastroenterology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
  • 2Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450052, China
出版时间: 2024-09-28 doi: 10.11855/j.issn.0577-7402.0934.2024.0527
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摘要
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目的 研究Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14基因(ADAMTS14)对幽门螺杆菌(Hp)感染相关胃癌进展的影响及其机制，探讨ADAMTS14作为胃癌生物治疗新靶点的可能性。方法 利用癌症基因组图谱(TCGA)及高通量基因表达数据库(GEO)分析胃癌组织及Hp阳性胃黏膜中差异表达的基因，筛选可能的靶点；对于选定的靶点ADAMTS14，分析其在胃癌及Hp阳性胃黏膜中的表达模式；对胃癌中与ADAMTS14共表达的基因进行京都基因与基因组百科全书(KEGG)数据库分析；利用Kaplan-Meier Plotter数据库分析ADAMTS14高低表达与胃癌患者预后的相关性；利用实时荧光定量PCR(RT-qPCR)和免疫组化方法分析30例胃癌患者的ADAMTS14表达水平，采用χ2检验分析ADAMTS14蛋白表达与临床病理特征之间的关系；利用GEO数据库分析Hp感染与ADAMTS14表达的关系，并通过细胞系感染实验验证；利用小干扰RNA沉默胃癌细胞系NCI-N87中ADAMTS14的表达，分析其对胃癌细胞功能的影响；利用RT-qPCR和Western blotting分析敲低ADAMTS14对Hippo信号通路下游靶基因表达的影响。结果 通过分析TCGA和GEO数据库，共得到16个与Hp感染及胃癌密切相关的基因；在TCGA数据库中，ADAMTS14在胃癌组织中的表达水平高于健康人胃黏膜(P<0.001)；RT-qPCR及免疫组化结果也显示，ADAMTS14在胃癌组织中的表达水平高于癌旁组织(P<0.01)；生存分析显示ADAMTS14高表达患者的预后不良(P<0.001)；GSE60427的数据显示ADAMTS14在Hp感染的胃黏膜及细胞系中表达上调(P<0.001)；Hp P12菌株感染NCI-N87细胞后ADAMTS14表达高于未感染组(P<0.0001)；敲低胃癌细胞系NCI-N87中ADAMTS14明显抑制了胃癌细胞的增殖及迁移(P<0.05)，以及Hippo信号通路靶基因BMP7、BMPR2、FZD4、PARD3、SAV1的表达(P<0.05)。结论 ADAMTS14在Hp感染的胃黏膜及胃癌组织中高表达，可能通过调控Hippo信号通路促进胃癌进展，有望作为Hp感染相关胃癌的新标志物及治疗靶点。

胃癌  /  幽门螺杆菌  /  Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14  /  Hippo信号通路

Objective To analyze the effects and mechanisms of a disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14) gene in gastric cancer associated with Helicobacter pylori (Hp) infection and explore the potential of ADAMTS14 as a novel target for biological therapy of gastric cancer. Methods The Caner Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to analyze differentially expressed genes in gastric cancer tissues and Hp-positive gastric mucosa, and to screen potential targets. For the selected target ADAMTS14, its expression pattern in gastric cancer and Hp-positive gastric mucosa was analyzed. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed on the genes co-expressed with ADAMTS14 in gastric cancer. Kaplan-Meier Plotter database was used to analyze the correlation between high- and low-ADAMTS14 expression and prognosis of gastric cancer patients. The expression of ADAMTS14 and its relationship with clinicopathological features in 30 patients with gastric cancer were analyzed using real-time fluorescent quantitative PCR (RT-qPCR) and immunohistochemistry. The relationship between Hp infection and ADAMTS14 expression was analyzed using GEO database, and confirmed by cell line infection experiment. ADAMTS14 expression in gastric cancer cell line NCI-N87 was silenced by small interfering RNA to analyze its effect on the function of gastric cancer cells; The effect of ADAMTS14 knockdown on downstream target genes of Hippo signaling pathway was analyzed by RT-qPCR and Western blotting. Results A total of 16 genes closely related to Hp infection and gastric cancer were identified by analyzing the TCGA and GEO databases. According to TCGA database, the ADAMTS14 expression in gastric cancer tissues was higher than that in healthy gastric mucosa (P<0.0001). RT-qPCR and immunohistochemistry results also showed higher ADAMTS14 expression in gastric cancer tissues compared to adjacent tissues (P<0.01). Survival analysis demonstrated poor prognosis in patients with high ADAMTS14 expression (P<0.001). Data from GSE60427 showed that ADAMTS14 expression was upregulated in Hp-infected gastric mucosa and cell lines (P<0.001). After Hp P12 infection, the ADAMTS14 expression in NCI-N87 cells was higher than that in uninfected group. ADAMTS14 knockdown significantly inhibited the proliferation and migration of NCI-N87 cells (P<0.05), and it also significantly inhibited the expression of Hippo signaling pathway target genes, including BMP7, BMPR2, FZD4, PARD3 and SAV1 (P<0.05). Conclusion ADAMTS14 is highly expressed in Hp-positive gastric mucosa and gastric cancer tissues, which may accelerate gastric cancer progression by regulating Hippo signaling pathway, and holds potential as a new marker and therapeutic target for Hp infective gastric cancer.

gastric cancer  /  Helicobacter pylori  /  ADAMTS14  /  Hippo signaling pathway
张博, 米阳, 刘斌, 鲁彦文, 郑鹏远. 幽门螺杆菌上调ADAMTS14激活Hippo信号通路对胃癌进展的影响及其机制. 解放军医学杂志, 2024 , 49 (9) : 1045 -1054 . DOI: 10.11855/j.issn.0577-7402.0934.2024.0527
Bo Zhang, Yang Mi, Bin Liu, Yan-Wen Lu, Peng-Yuan Zheng. Effects of Helicobacter pylori on gastric cancer progression by upregulating ADAMTS14 and activating Hippo signaling pathway and its underlying mechanisms[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (9) : 1045 -1054 . DOI: 10.11855/j.issn.0577-7402.0934.2024.0527
正文
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胃癌是一种高度恶性的肿瘤，也是全球癌症相关死亡的第三大原因[1-3]，幽门螺杆菌(Helicobacter pylori，Hp)感染是胃癌最主要的致病因素[4]。Hp感染引起胃癌的机制复杂多样，可能引起一系列信号通路的激活及分子改变[5]，如Hippo信号通路等，诱发从炎症、萎缩性胃炎、肠上皮化生甚至到胃癌的病程[6]。因此，探索Hp感染过程中的分子改变有助于治疗Hp感染导致的胃癌[7]。
Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶14(a disintegrin-like and metalloproteinase with thrombo-spondin type 1 motif 14，ADAMTS14)基因编码一种蛋白酶，在胶原蛋白的代谢及修饰中发挥重要作用，在多种肿瘤组织中表达上调，并与多种恶性肿瘤如结直肠癌、肝细胞癌等的发生、发展及预后有关[8]，但ADAMTS14在胃癌中的作用机制少有报道。Hippo信号通路在多种癌症中响应于Hp感染而激活[9]，从而促进胃癌的发生，与胃癌的预后不良有关[10-12]。本研究分析Hp感染后胃癌细胞中ADAMTS14 mRNA和蛋白表达水平的变化，进而探讨其在Hp感染及胃癌进展中的作用及其可能机制，旨在为ADAMTS14应用于胃癌的临床治疗提供理论依据。
1 材料与方法
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1.1 实验材料
1.1.1 细胞系和菌株
人正常胃上皮细胞系GES-1，以及人胃癌细胞系SGC7901、MGC803、MKN45、AGS、NCI-N87购自中科院上海细胞库，培养于含10%胎牛血清及1%青/链霉素混合液的RPMI 1640培养基(美国Gibco公司)中，置于温度37 ℃、饱和湿度的培养箱中。所有细胞均经过短串联重复序列(short tandem repeat，STR)鉴定。Hp标准菌株P12由德国柏林Max Planck感染生物研究所Thomsa F. Meyer教授馈赠，培养于巧克力琼脂培养平板，置于温度37 ℃、饱和湿度，且含有5% O2、10% CO2及70% N2的培养箱中，每3 d传代1次。
1.1.2 胃癌样本
胃癌组织样本取自2021年2月-2022年1月在郑州大学第五附属医院行胃全或次全切除术的30例胃癌患者，其中男17例，女13例，年龄(61.3±10.6)岁，所有患者术前均未接受放疗及化疗。同时取距离癌组织10 cm以上的正常胃黏膜作为癌旁组织，置于冰冷的RPMI 1640培养基中，用于后续实验。本研究获郑州大学第五附属医院伦理委员会审批(KY2020029)，所有患者均签署知情同意书。
1.2 实验方法
1.2.1 公共数据分析
通过突变分析与可视化(cBioPortal)数据库下载经过标准化处理的胃腺癌癌症基因组图谱(The Cancer Genome Atlas，TCGA)表达数据及临床信息，包含402例胃癌组织及34名健康志愿者胃黏膜的转录组测序(RNA-seq)数据。通过高通量基因表达数据库(Gene Expression Omnibus，GEO)下载GSE60427、GSE154127的表达数据，包含Hp感染患者的胃黏膜，以及Hp阴性志愿者胃黏膜和胃癌类器官的RNA-seq数据，并进行标准化处理。使用桑格助手在线平台(http://vip.sangerbox.com/)进行差异基因分析及可视化，并通过韦恩图工具进行共有差异基因的归类[13]。
1.2.2 基因集功能富集分析
使用京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes，KEGG)rest API(https://www.kegg.jp/kegg/rest/keggapi.html)获取最新的KEGG Pathway基因注释，并采用R软件包clusterProfiler(version 3.14.3)进行富集分析，以获得基因集富集的结果。设定最小基因集为5，最大基因集为5000，阈值为P<0.05及错误发现率(FDR)<0.25。
1.2.3 转染
将2×105个细胞均匀接种到6孔板中，待细胞融合达70%~80%时，更换不含抗生素的培养基；然后配置转染复合体：在200 μl jetPRIME® buffer(Polyplus，114-07/15)中加入12.5 μl si-RNA-ADAMTS14或si-NC(苏州吉玛基因股份有限公司)，使其终浓度为100 nmol/L，再加入4 μl转染试剂jetPRIME®，轻轻混匀后静置10 min，室温下将转染复合物滴加至细胞培养基，置于培养箱中48 h，然后收集细胞用于后续实验。敲低序列如下，siADAMTS14-1：5'-CUGGGAUCAACUACUCAAUTT-3'，siADAMTS14-2：5'-GCACCGACUUCUUCAUUGATT-3'，siADAMTS14-3：5'-CCUCAUGAAUAUCGUAGAUTT-3'。
1.2.4 细胞迁移
将1×105个细胞用200 μl无血清培养基重悬后，加入Transwell培养板(美国Corning公司)的上室，下室中加入600 μl完全培养基，置于培养箱孵育48 h。移除培养基，用棉签擦去上室未迁移的细胞，4%多聚甲醛溶液固定细胞30 min，用0.1%结晶紫染色液(北京索莱宝科技有限公司)染色30 min，再用PBS充分洗去染色液。置于显微镜下，任意选取5个400倍视野观察并拍照。
1.2.5 Hp菌液制备及感染细胞
将2×105个细胞均匀接种到6孔板中，待细胞生长融合至70%时更换无血清培养基，过夜以增加感染效率。准备Hp菌液，用棉签在巧乐力琼脂培养平板上刮下生长2~3 d的Hp菌落，重悬至液体培养基(BHI+10% FBS+1%抗生素)中，调整培养基用量，使细菌悬液在460 nm波长处光密度(OD)值为0.15，然后置于厌氧工作站中培养24 h。Hp感染细胞：取在厌氧工作站培养24 h后的细菌悬液，检测OD值并计算细菌数量，然后以4500 r/min离心8 min收集Hp，用RPMI 1640培养基将细菌稀释到1×108菌落形成单位(colony-forming units，CFU)/ml，按照感染复数(multiplicity of infection，MOI)=100的比例加入细胞中进行感染。在分别感染24、48、72 h后，弃上清，PBS洗3次，然后更换含200 μg/ml庆大霉素(大连美仑生物技术有限公司)的无血清RPMI 1640培养基处理1 h，以杀死未感染细胞的细菌，随后用PBS清洗，并用于后续的RNA提取及蛋白检测。
1.2.6 实时荧光定量聚合酶链反应(RT-qPCR)检测ADAMTS14及Hippo信号通路相关基因mRNA的表达量
用Trizol法提取RNA后，按反转录试剂盒说明书于37 ℃下反转录15 min，并在98 ℃下行酶失活反应5 min，得到cDNA，稀释10倍后作为模板配置荧光定量PCR体系。分别加入10 µl 2×SYBR Green PCR Master Mix(南京诺唯赞科技公司)、2.8 µl引物混合物(上、下游引物均为5 µmol/L)及5.2 µl无酶水，最后加入2 µl cDNA模板进行RT-qPCR反应。反应条件：95 ℃活化2 min；95 ℃变性5 s，60 ℃退火/延伸10 s，循环40次。采用2-ΔΔCt法计算相对表达量。引物由中国生工生物工程有限公司合成，序列见表1。
1.2.7 Western blotting检测ADAMTS14蛋白表达量
使用一步法PAGE凝胶快速制备试剂盒(10%)制备SDS-PAGE凝胶，电泳按照80 V、30 min，100 V、60 min两步法进行，结束后取出凝胶，制作转膜三明治结构，按300 mA、90 min恒流电转。取出硝酸纤维素膜，置于含5%脱脂奶粉封闭液中封闭1 h，加入鼠ADAMTS14(1:500；美国Santa Cruz Biotechnology公司)，兔兔源人同源重组蛋白1(SAV1)抗体(1:1000)、兔兔源骨形态发生蛋白7(BMP7)抗体(1:5000)、兔兔源卷曲类蛋白受体4(FZD4)抗体(1:800)、鼠GAPDH(1:10 000；英国Abcam公司)一抗，4 ℃孵育过夜。次日取出回收一抗，充分清洗后加入二抗，室温孵育1 h，结束后充分清洗，并采用Bio-Rad曝光仪曝光及拍照分析。
1.2.8 ADAMTS14表达水平与胃癌患者生存预后分析
采用Kaplan-Meier Plotter(https://kmplot.com)数据库分析ADAMTS14表达水平与胃癌患者生存预后的数据。
1.2.9 免疫组化检测ADAMTS14蛋白表达水平
收集胃癌患者的肿瘤组织及其癌旁组织，其中Hp阳性12例，阴性18例，将组织切片分别置于二甲苯、无水乙醇中脱蜡、脱苯；柠檬酸钠抗原修复15 min。3% H2O2和山羊血清依次封闭15 min，鼠ADAMTS14一抗(1:100)4 ℃孵育过夜。次日洗去一抗，依次加入50 μl生物素化二抗及辣根酶标记链霉卵白素孵育20 min；二氨基联苯胺(3,3'-diamino-benzidine，DAB)染色2 min，苏木精复染细胞核1 min，脱水、透明、中性树脂封片。采用德国半定量评分法对结果进行评分[14]。具体评分方法：视野内阳性细胞数占总细胞数的比例<5%计为0分，5%~25%计为1分，50%~75%计为3分，>75%计为4分；然后按照多数细胞的染色程度进行评分：未着色计为0分，浅黄色计为1分，棕黄色计为2分，棕褐色计为3分。综合得分为阳性细胞百分比得分与染色强度得分之积，并作为半定量差异性分析；再根据以下标准统计阳性表达例数以分析ADAMTS14蛋白表达水平与患者临床病理特征的相关性：0~2分记为阴性(-)，3~5分记为弱阳性(+)，6~8分记为阳性(++)，9~12分记为强阳性(+++)。
1.3 统计学处理
采用SPSS 25.0软件进行统计分析，采用GraphPad 9.0软件作图。计量资料采用Shapiro-Wilk检验及方差齐性检验分析，方差齐且符合正态分布时以$\bar{x}±s$表示，两组间比较采用独立样本t检验；不符合正态分布时，两组间比较采用Mann-Whitney U检验。计数资料以例(%)表示，组间比较采用χ2检验。生存率分析采用log-rank检验。P<0.05为差异有统计学意义。
2 结果
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2.1 Hp感染对胃黏膜及胃癌组织中ADAMTS14表达的影响
对TCGA数据库中胃癌组织及数据集GSE60427、GSE154127中Hp感染患者的胃黏膜行RNA-seq，得到16个共有的上调基因：ADAMTS14、NOX1、IDO1、MMP7、CXCL6、UBD、CXCL1、CXCL5、PLA2G7、CCL20、LAMP3、TNFRSF9、CXCL3、IFITM1、TLR2、ICAM1(图1A)。胃癌组织与健康胃黏膜间有2933个差异表达基因(图1B)；在Hp感染患者的胃黏膜数据集GSE60427中，Hp阳性与Hp阴性胃黏膜间有770个差异表达基因(图1C)；而胃癌类器官与健康胃黏膜间有689个差异表达基因(图1D)。
在TCGA数据集中，胃癌组织中ADAMTS14 mRNA表达水平高于健康志愿者的胃黏膜组织(P<0.001，图2A)。同一患者的胃癌组织中ADAMTS14 mRNA表达水平明显高于癌旁组织(P<0.01，图2B)。
2.2 ADAMTS14在胃癌中表达共聚类分析
在TCGA数据库的胃癌患者中，ADAMTS14与COCL18A1、INHBB、CHST15、KIAA1199、SLCO3A1等基因共表达水平较高，相关系数分别为0.57、0.44、0.44、0.42、0.40(图3)。
2.3 ADAMTS14功能富集分析
将2.2共聚类分析中获得的与ADAMTS14表达相关性最强的前300个基因进行KEGG通路富集分析，结果显示，ADAMTS14基因参与乳腺癌、胃癌、轴突导向及Hippo信号通路等(图4)。
2.4 ADAMTS14敲低对细胞功能的影响
5种胃癌细胞系AGS、MGC803、SGC7901、MKN45、NCI-N87中ADAMTS14 mRNA表达水平高于正常胃上皮细胞系GES-1(P<0.05，图5A)。选择表达水平最高的NCI-N87细胞系进行敲低实验，首先利用siRNA沉默细胞中ADAMTS14 mRNA的表达；选定的3条干扰序列中有2条(siADAMTS14-1、siADAMTS14-2，分别简写为siRNA1、siRNA2)显示出明显的敲低效果(P<0.001，图5B)。CCK-8法检测结果显示，24、48、72 h时siRNA1组、siRNA2组的NCI-N87细胞活力均低于对照组(P<0.01，图5C)。细胞迁移实验结果显示，siRNA1组、siRNA2组的细胞迁移数量均少于对照组(P<0.01，图5D)。
2.5 Hp与ADAMTS14 mRNA表达的相关性
公共数据集GSE60427显示Hp阳性组织中ADAMTS14 mRNA表达水平升高(P<0.0001，图6A)。RT-qPCR检测结果显示，在MOI=200时，Hp感染以时间依赖的方式上调NCI-N87细胞中ADAMTS14 mRNA的表达(P<0.001，图6B)；而在感染12 h时，随着MOI增加，ADAMTS14 mRNA表达水平也逐渐升高(P<0.001，图6C)。
2.6 Hp感染对ADAMTS14 mRNA和蛋白表达的影响
为证实Hp对ADAMTS14 mRNA和蛋白表达的影响，本研究对NCI-N87细胞系增加了Hp感染处理组和siRNA1+Hp处理组，Hp的处理条件是MOI 100/12 h，并分别通过RT-qPCR和Western blotting证实，Hp感染可上调NCI-N87细胞中ADAMTS14 mRNA和蛋白表达水平(P<0.0001，图7)。
2.7 ADAMTS14对Hippo信号通路的影响
RT-qPCR检测结果显示，ADAMTS14敲低可下调Hippo信号通路靶基因BMP7、BMPR2、SAV1、PARD3、FZD4 mRNA的表达水平(P<0.0001，图8A)；且Western blotting检测结果显示，SAV1、BMPR2和FZD4蛋白表达水平也明显降低(P<0.05，图8B)。
2.8 ADAMTS14表达与胃癌患者不良预后的相关性
采用Kaplan-Meier Plotter数据库分析ADAMTS14表达水平与胃癌患者预后的数据，生存曲线结果显示，ADAMTS14高表达患者的总生存期短于低表达者(P<0.05，图9)。
2.9 ADAMTS14蛋白高表达与胃癌患者临床病理特征的关系
免疫组织化学检测结果显示，ADAMTS14蛋白在胃癌组织中呈高表达，其中Hp阳性胃癌组织中ADAMTS14蛋白表达水平高于Hp阴性胃癌组织，差异有统计学意义(Z=-2.036，P<0.05，图10)。
通过临床数据库进一步分析ADAMTS14蛋白表达与胃癌患者临床病理特征之间的关系发现，ADAMTS14蛋白表达与患者年龄相关(P<0.05)，而与患者性别、浸润深度、淋巴结转移、远处转移、肿瘤分期、Hp感染状态等无相关性(P>0.05，表2)。
3 讨论
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胃癌是一种高度恶性的肿瘤，也是全球癌症相关死亡的第三大原因[1-2]，Hp感染被认为是胃癌的直接致癌因素[6]。Hp感染胃黏膜上皮细胞后，利用其cagPAI编码产物形成细菌4型分泌系统(T4SS)，这是一种大分子转运蛋白，可以结合宿主细胞表面分子(如整合素和磷脂酰丝氨酸)[15]，进而将Hp的细菌效应子CagA等易位到宿主细胞的细胞质中[16]，引起一系列的分子及表观遗传改变，从而启动肿瘤发生。因此，探索Hp感染引起的分子改变将加深对胃癌发病机制的理解，有助于胃癌的诊断和治疗。本研究通过分析TCGA和几项GSE测序数据发现，ADAMTS14在胃癌组织及Hp感染患者的胃黏膜中表达上调，是胃癌患者不良预后的标志物。
ADAMTS14属于ADAMTS家族，该家族编码一类包含特定结构域的酶蛋白。这些酶蛋白通过对细胞黏附、迁移、蛋白水解和信号传导等功能的影响，在调节细胞功能方面发挥着重要作用[17]。ADAMTS家族的部分成员在正常组织与肿瘤组织中具有不同的表达模式。其中ADAMTS4、ADAMTS6及ADAMTS14在肿瘤中的表达明显上调[8]。近来许多研究表明，ADAMTS14与恶性肿瘤发生、发展及预后有关。例如，ADAMTS14在肾透明细胞癌发生过程中起到了致癌作用[18]。其还是口腔肿瘤发生的危险因素，且与口腔鳞状细胞癌患者的不良预后有关[19]。ADAMTS14的表达受启动子DNA甲基化调节，与结直肠癌预后不良有关[20]。ADAMTS14表达下调可对肝细胞癌起到抑制作用[21]，但在胃癌中ADAMTS14的作用及其机制尚未报道。
Hippo通路是一种在生物体中保守的信号通路，通过传递来自上游的各种信号以调节细胞行为、生长、增殖及组织稳态[22]。Hippo信号通路失调会导致细胞及器官不受控制地过度生长[23]，进而可能促进肿瘤的发生[24]。大量研究表明，Hippo通路靶基因的过表达会导致癌细胞增殖、侵袭、转移，以及癌症干细胞特性出现及耐药性增加[25-26]。有研究发现，在小鼠中敲除Hippo上游调节因子或过表达Yes相关蛋白(Yes-associated protein，YAP)会导致肝组织过度生长，肝脏肿大，进而发展为肝癌[27]。还有大量研究表明，Hippo通路在非小细胞肺癌、乳腺癌、结直肠癌、前列腺癌等的进展中发挥重要作用。如Hippo通路在Hp介导的胃癌发生中发挥作用，并与胃癌的预后不良有关[10-12]。Hp感染可激活Hippo通路，这一过程在Hp感染的胃上皮细胞转录组学分析中得到证实[6]。几乎所有的Hippo靶基因均与胃癌的淋巴转移及肿瘤TNM分期密切相关[28]。因此靶向Hippo通路的药物对治疗胃癌具有重要意义[29]。
本研究发现了与Hp感染相关的关键基因ADAMTS14，并探究了其在胃癌中的意义。通过TCGA数据库分析结果，结合RT-qPCR及免疫组化验证，证实在胃癌组织中ADAMTS14 mRNA及蛋白表达水平明显高于癌旁组织。GSE60427的数据显示，ADAMTS14在Hp感染的胃黏膜及细胞系中表达上调；Hp P12菌株感染NCI-N87细胞后，ADAMTS14表达也高于未感染组。本研究发现，Hp感染可上调ADAMTS14的表达，推测ADAMTS14可能是胃癌的驱动因子，在Hp感染及胃癌进展中发挥重要作用。在TCGA数据库的胃癌患者中，ADAMTS14与COCL18A1、INHBB、CHST15、KIAA1199、SLCO3A1等20个基因共表达水平较高，提示ADAMTS14可能与这些基因在功能上具有相似性。ADAMTS14的功能富集结果提示ADAMTS14参与了Hippo信号通路。通过敲低胃癌细胞系NCI-N87中的ADAMTS14，增殖及迁移实验结果证实，ADAMTS14低表达能明显抑制胃癌细胞的增殖及迁移，这种作用可能是由于ADAMTS14对Hippo信号通路的调控作用实现的。本研究还发现，敲低胃癌细胞系NCI-N87中ADAMTS14后，Hippo信号通路靶基因BMP7、BMPR2、FZD4、PARD3、SAV1表达水平也降低，提示ADAMTS14的存在对Hippo信号通路的激活起着关键作用。
结合临床数据，生存分析显示ADAMTS14高表达患者的预后不良，提示ADAMTS14与胃癌不良预后相关。本研究通过数据库分析ADAMTS14表达与Hp感染状态的相关性，但由于该数据库中大量样本缺乏Hp感染的信息，因而仅分析了少量Hp阳性样本，这可能是造成本研究统计结果无相关性的原因。因此，ADAMTS14可能是Hp感染相关胃癌的潜在治疗靶点，但该结论仍需要更多的理论依据支持。未来应着眼于寻找调控ADAMTS14的小分子药物，收集更多的基础实验数据，以提高ADAMTS14作为胃癌治疗靶点的可靠性。
综上所述，本研究证实，Hp感染能够上调ADAMTS14的表达，且可促进胃癌细胞的增殖与迁移，进而促进胃癌的进展，并导致患者的预后不良，因此ADAMTS14有希望成为Hp感染相关胃癌的新的治疗靶点。但目前尚缺少体内实验数据的支持，后续拟进行体内实验，以进一步为ADAMTS14应用于Hp感染相关胃癌的临床治疗提供更多的理论依据。
基金
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  • 国家重点研发计划(2020YFC2006101)
  • 郑州大学学科建设重点专项(XKZDJC202001)
文献
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参考文献 引证文献
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2024年第49卷第9期
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doi: 10.11855/j.issn.0577-7402.0934.2024.0527
  • 接收时间：2023-07-12
  • 首发时间：2025-11-21
  • 出版时间：2024-09-28
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  • 收稿日期：2023-07-12
  • 录用日期：2023-12-15
基金
National Key Research and Development Program of China(2020YFC2006101)
国家重点研发计划(2020YFC2006101)
Key Project for Discipline Construction of Zhengzhou University(XKZDJC202001)
郑州大学学科建设重点专项(XKZDJC202001)
作者信息
    1郑州大学第五附属医院消化内科，河南郑州 450052
    2郑州大学医学科学院，河南郑州 450052

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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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