CAJ | 학술논문

目的寻找胰腺导管腺癌（PDAC）预后相关基因并探讨其分子调控机制。方法从美国国立生物技术信息中心基因表达数据库中选取102例包含完整临床生存资料的 PDAC 患者的基因表达谱数据。从 Transfac 数据库中收集到106个转录因子调控基因集合。使用 PicTar 和 TargetScanS 算法收集到715个 miRNA 靶向调控基因集合。生物学通路数据来源于京都基因与基因组百科全书（KEGG）。已知癌基因数据来自癌基因普查（CGC）数据库。使用单因素 Cox 比例风险模型分析基因表达谱数据与生存时间的相关性，得到全基因组范围内的与生存相关的候选基因。使用超几何分布算法分析3种数据集的基因富集情况。使用 BH-FDR 算法进行多重矫正检验（要求假阳性率＜0．05）。采用 Kaplan-Meier 法对 PDAC 患者进行生存曲线分析。结果单因素 Cox 比例风险模型分析102例PDAC 患者数据后显示，有273个基因与患者的生存时间显著相关（P ＜0．0001）。将273个生存基因针对106个转录因子调控基因集合进行富集分析，得到12个富集生存基因的转录因子靶基因集合。将273个生存基因针对715个 miRNA 靶向调控基因集合进行富集分析，得到11个富集生存基因的miRNA 靶向调控基因集合。将273个生存基因针对 KEGG 通路数据进行富集分析，得到15个富集生存基因的生物学通路。生物钟周期基因2可能在转录水平受到转录因子 CCAAT 框/增强子蛋白（CEBPA）的调控，同时在转录后水平受到 miRNA-32的调控，进而通过昼夜节律通路影响 PDAC 的预后。102例 PDAC 患者按生物钟周期基因2表达量从高到低排序，前51例归为生物钟周期基因2高表达组，其余归为生物钟周期基因2低表达组，行 Kaplan-Meier 生存分析后显示，生物钟周期基因2与PDAC 的预后显著相关（P ＜0．01）。结论CEBPA/miRNA-32/生物钟周期基因2及其相关的生物钟节律通路可能是干预 PDAC 发展的靶通路，与 PDAC 预后相关。目的尋找胰腺導管腺癌（PDAC）預後相關基因併探討其分子調控機製。方法從美國國立生物技術信息中心基因錶達數據庫中選取102例包含完整臨床生存資料的 PDAC 患者的基因錶達譜數據。從 Transfac 數據庫中收集到106箇轉錄因子調控基因集閤。使用 PicTar 和 TargetScanS 算法收集到715箇 miRNA 靶嚮調控基因集閤。生物學通路數據來源于京都基因與基因組百科全書（KEGG）。已知癌基因數據來自癌基因普查（CGC）數據庫。使用單因素 Cox 比例風險模型分析基因錶達譜數據與生存時間的相關性，得到全基因組範圍內的與生存相關的候選基因。使用超幾何分佈算法分析3種數據集的基因富集情況。使用 BH-FDR 算法進行多重矯正檢驗（要求假暘性率＜0．05）。採用 Kaplan-Meier 法對 PDAC 患者進行生存麯線分析。結果單因素 Cox 比例風險模型分析102例PDAC 患者數據後顯示，有273箇基因與患者的生存時間顯著相關（P ＜0．0001）。將273箇生存基因針對106箇轉錄因子調控基因集閤進行富集分析，得到12箇富集生存基因的轉錄因子靶基因集閤。將273箇生存基因針對715箇 miRNA 靶嚮調控基因集閤進行富集分析，得到11箇富集生存基因的miRNA 靶嚮調控基因集閤。將273箇生存基因針對 KEGG 通路數據進行富集分析，得到15箇富集生存基因的生物學通路。生物鐘週期基因2可能在轉錄水平受到轉錄因子 CCAAT 框/增彊子蛋白（CEBPA）的調控，同時在轉錄後水平受到 miRNA-32的調控，進而通過晝夜節律通路影響 PDAC 的預後。102例 PDAC 患者按生物鐘週期基因2錶達量從高到低排序，前51例歸為生物鐘週期基因2高錶達組，其餘歸為生物鐘週期基因2低錶達組，行 Kaplan-Meier 生存分析後顯示，生物鐘週期基因2與PDAC 的預後顯著相關（P ＜0．01）。結論CEBPA/miRNA-32/生物鐘週期基因2及其相關的生物鐘節律通路可能是榦預 PDAC 髮展的靶通路，與 PDAC 預後相關。
목적심조이선도관선암（PDAC）예후상관기인병탐토기분자조공궤제。방법종미국국립생물기술신식중심기인표체수거고중선취102례포함완정림상생존자료적 PDAC 환자적기인표체보수거。종 Transfac 수거고중수집도106개전록인자조공기인집합。사용 PicTar 화 TargetScanS 산법수집도715개 miRNA 파향조공기인집합。생물학통로수거래원우경도기인여기인조백과전서（KEGG）。이지암기인수거래자암기인보사（CGC）수거고。사용단인소 Cox 비례풍험모형분석기인표체보수거여생존시간적상관성，득도전기인조범위내적여생존상관적후선기인。사용초궤하분포산법분석3충수거집적기인부집정황。사용 BH-FDR 산법진행다중교정검험（요구가양성솔＜0．05）。채용 Kaplan-Meier 법대 PDAC 환자진행생존곡선분석。결과단인소 Cox 비례풍험모형분석102례PDAC 환자수거후현시，유273개기인여환자적생존시간현저상관（P ＜0．0001）。장273개생존기인침대106개전록인자조공기인집합진행부집분석，득도12개부집생존기인적전록인자파기인집합。장273개생존기인침대715개 miRNA 파향조공기인집합진행부집분석，득도11개부집생존기인적miRNA 파향조공기인집합。장273개생존기인침대 KEGG 통로수거진행부집분석，득도15개부집생존기인적생물학통로。생물종주기기인2가능재전록수평수도전록인자 CCAAT 광/증강자단백（CEBPA）적조공，동시재전록후수평수도 miRNA-32적조공，진이통과주야절률통로영향 PDAC 적예후。102례 PDAC 환자안생물종주기기인2표체량종고도저배서，전51례귀위생물종주기기인2고표체조，기여귀위생물종주기기인2저표체조，행 Kaplan-Meier 생존분석후현시，생물종주기기인2여PDAC 적예후현저상관（P ＜0．01）。결론CEBPA/miRNA-32/생물종주기기인2급기상관적생물종절률통로가능시간예 PDAC 발전적파통로，여 PDAC 예후상관。
Objective To explore the prognosis related genes of pancreatic ductal adenocarcinoma (PDAC)and investigate the molecular regulation mechanism.Methods Gene expression data of 102 PDAC patients with complete clinical survival data were selected from gene expression database of National Center for Biotechnology Information.The 106 transcription regulation gene collection was collected from Transfac database.The 715 microRNA (miRNA)target regulation gene collection was selected according to PicTar and TargetScanS method.Biological pathway data obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG).The known cancer genes were collected from the cancer gene census (CGC) database.Univariate Cox proportional hazards model was used to analyze the correlation between gene expression data and survival time,then obtained survival related candidate genes from the whole genome. Then the enriched genes were analyzed by hypergeometric distribution algorithm from three databases. Multiple correction testing was performed by BH-FDR method (FDR < 0.05 ).Kaplan-Meier was performed for survival curve analysis of PDAC.Results The results of data of 102 PDAC patients analyzed by univariate Cox proportional hazards model indicated that 273 genes were significantly related to the survival time of patients (P <0.000 1 ).After 273 survival genes were enrichment analyzed in 106 transcription factor regulation gene collection,12 survival genes enriched transcription factor target gene sets were found.After 273 survival genes were enrichment analyzed in 715 miRNA target regulation gene collection,11 survival genes enriched miRNAs target sets were discovered.After 273 survival genes were enrichment analyzed in pathway data of KEGG,15 survival genes enriched pathways were obtained. Period circadian clock 2 (PER2 )was regulated by CCAAT/enhancer binding protein (CEBPA)at transcription level and regulated by miRNA-32 after transcription.The prognosis of PDAC was affected by circadian rhythm pathway.The 102 patients with PDAC were ranked according to the expression of PER2 from high to low,the first 51 cases were included in PER2 higher expression group and the left were included in PER2 lower expression group.Kaplan-Meier survival analysis indicated that PER2 was significantly correlated with prognosis of PDAC (P <0.01 ).Conclusion CEBPA/miRNA-32/PER2 and its related circadian clock pathway may be the target pathway in interfering the development of PDAC,and is correlated with the prognosis of PDAC.