肝细胞癌Wnt信号通路差异表达基因筛选及意义
发布时间：2018-10-04 19:42
【摘要】：目的:肝细胞癌(Hepatocellular carcinoma,HCC)是全球常见恶性肿瘤,位列我国恶性肿瘤死因第2位。Wnt信号通路(Wnt signaling pathway)是一条在进化上极其保守的信号传导途径,在胚胎发育、组织再生、造血、细胞增殖分化与迁移等生物学过程和功能中均发挥了十分重要的作用。此外,有研究显示Wnt信号通路在许多组织和器官的干细胞更新和分化中起介导作用。Wnt信号通路的异常激活已被证实与包括HCC在内多种肿瘤发生发展密切相关。HCC是我国特色肿瘤,但我们目前对国人HCC中Wnt信号通路基因表达情况仍不明了。本研究旨在筛选国人HCC中Wnt信号通路差异表达基因,探讨Wnt信号传导通路差异表达基因在国人HCC发生发展过程中的作用,为寻找HCC潜在分子治疗靶点提供依据。方法:本研究应用Affymetrix U133 Plus2.0基因芯片检测93例HCC及其配对癌旁正常肝组织中78个Wnt信号传导通路相关基因的mRNA表达水平,筛选差异表达基因。HCC与配对癌旁正常肝组织间各基因表达水平比较采用配对t检验。差异表达基因筛选标准:t检验P0.001,且癌较癌旁肝组织基因表达上调2倍(表达上调者)或下调50%(表达下调者)。癌组织中差异基因表达水平间的相关性采用Spearman相关检验。差异表达基因的表达水平与临床病理学参数的相关性分析采用χ2检验。采用Stata 13.0软件进行统计分析。结果:1.与癌旁正常肝组织相比,HCC中TCF19、MMP12、DKK1、BCL9、SFRP4、MMP1、PYGO2、FZD6、MMP9、WNT6等10个基因表达上调,而SFRP1、TCF21、SFRP5、FZD1、WNT2等5个基因表达下调。其中,TCF19表达上调倍数最多,达9.61倍(P=1.07×10-26);2.15个HCC差异表达基因的表达水平间存在广泛相关性。TCF19表达与WNT6、FZD1、FZD6、MMP1、MMP12和BCL9表达水平均呈显著正相关(均P0.05)。Wnt拮抗家族SFRPs和DKK中差异表达基因间的相关性:DKK1与SFRP4、SFRP4与SFRP1、SFRP1与SFRP5以及SFRP4与SFRP5的表达水平间均呈显著正相关(均P0.05)。而DKK1与SFRP1及SFRP5的表达水平间均无显著相关性(均P0.05);3.TCF19高表达(≥中位表达水平)与HCC多发(P=0.017)和低分化(P=0.046)显著相关;DKK1高表达(≥中位表达水平)与高AFP(20μg/L,P=0.026)、血管侵犯(P0.001)及低分化(P0.001)显著相关;SFRP4高表达(≥中位表达水平)与高AFP(P=0.008)和低分化(P=0.046)显著相关;SFRP1高表达与肝硬化(P=0.036)和TNM分期(P=0.033)显著相关;SFRP5高表达与AFP(P=0.009)、血管侵犯(P=0.011)、Edmondson-Steiner分级(P=0.022)及TNM分期(P=0.024)显著相关。结论:Wnt信号传导通路中多个基因异常表达参与了HCC的演进,研究结果支持Wnt信号传导通路异常在我国HCC演进过程中发挥重要作用,为Wnt信号通路在国人HCC中的作用机制研究提供了基础。核内转录因子TCF19是其中表达上调倍数最多的基因,可能体现了Wnt信号通路激活的关键终末效应,因而可能成为HCC分子治疗的潜在靶点,故其在HCC中的生物学及病理学意义有待进一步研究。
[Abstract]:Objective: hepatocellular carcinoma (Hepatocellular carcinoma,HCC) is a common malignant tumor in the world. It ranks second in the cause of death of malignant tumors in China. Wnt signaling pathway (Wnt signaling pathway) is an evolutionarily conserved signal transduction pathway, which can be used in embryonic development, tissue regeneration and hematopoiesis. Cell proliferation, differentiation, migration and other biological processes and functions play a very important role. In addition, some studies have shown that Wnt signaling pathway mediates the regeneration and differentiation of stem cells in many tissues and organs. The abnormal activation of Wnt signaling pathway has been proved to be closely related to the occurrence and development of many tumors, including HCC. However, we still do not understand the gene expression of Wnt signaling pathway in Chinese HCC. The purpose of this study was to screen differentially expressed genes of Wnt signaling pathway in Chinese HCC and to explore the role of differential expression genes of Wnt signal transduction pathway in the pathogenesis and development of Chinese HCC. Methods: Affymetrix U133 Plus2.0 gene chip was used to detect the mRNA expression of 78 Wnt signal transduction pathway related genes in 93 cases of HCC and their matched normal liver tissues. The gene expression levels of HCC and matched normal liver tissues were compared by paired t test. The differential expression gene screening criteria were: P0.001, and the gene expression of cancer was increased by 2 times (the expression was up-regulated) or by 50% (the expression was down-regulated) than that of the adjacent liver tissue. The correlation of differentially expressed genes in cancer tissues was examined by Spearman correlation test. The correlation between the expression level of differentially expressed genes and clinicopathological parameters was analyzed by 蠂 2 test. Stata 13.0 software was used for statistical analysis. The result is 1: 1. Compared with the adjacent normal liver tissues, 10 TCF19,MMP12,DKK1,BCL9,SFRP4,MMP1,PYGO2,FZD6,MMP9,WNT6 genes were up-regulated and 5 SFRP1,TCF21,SFRP5,FZD1,WNT2 genes were down-regulated. The upregulation of TCF19 expression was the most. 2.15 HCC differentially expressed genes were widely correlated. TCF19 expression was significantly positively correlated with WNT6,FZD1,FZD6,MMP1,MMP12 and BCL9 expression levels (P0.05). Wnt antagonistic family SFRPs and DKK differentially expressed genes in the correlation between DKK1 and SFRP4,SFRP4 and SFRP1,SFRP1 There was a significant positive correlation with the expression of SFRP5, SFRP4 and SFRP5 (P 0.05). However, there was no significant correlation between the expression level of DKK1 and SFRP1 and SFRP5 (P0.05). 3. The high expression of TCF19 (鈮，
本文编号：2251632
[Abstract]:Objective: hepatocellular carcinoma (Hepatocellular carcinoma,HCC) is a common malignant tumor in the world. It ranks second in the cause of death of malignant tumors in China. Wnt signaling pathway (Wnt signaling pathway) is an evolutionarily conserved signal transduction pathway, which can be used in embryonic development, tissue regeneration and hematopoiesis. Cell proliferation, differentiation, migration and other biological processes and functions play a very important role. In addition, some studies have shown that Wnt signaling pathway mediates the regeneration and differentiation of stem cells in many tissues and organs. The abnormal activation of Wnt signaling pathway has been proved to be closely related to the occurrence and development of many tumors, including HCC. However, we still do not understand the gene expression of Wnt signaling pathway in Chinese HCC. The purpose of this study was to screen differentially expressed genes of Wnt signaling pathway in Chinese HCC and to explore the role of differential expression genes of Wnt signal transduction pathway in the pathogenesis and development of Chinese HCC. Methods: Affymetrix U133 Plus2.0 gene chip was used to detect the mRNA expression of 78 Wnt signal transduction pathway related genes in 93 cases of HCC and their matched normal liver tissues. The gene expression levels of HCC and matched normal liver tissues were compared by paired t test. The differential expression gene screening criteria were: P0.001, and the gene expression of cancer was increased by 2 times (the expression was up-regulated) or by 50% (the expression was down-regulated) than that of the adjacent liver tissue. The correlation of differentially expressed genes in cancer tissues was examined by Spearman correlation test. The correlation between the expression level of differentially expressed genes and clinicopathological parameters was analyzed by 蠂 2 test. Stata 13.0 software was used for statistical analysis. The result is 1: 1. Compared with the adjacent normal liver tissues, 10 TCF19,MMP12,DKK1,BCL9,SFRP4,MMP1,PYGO2,FZD6,MMP9,WNT6 genes were up-regulated and 5 SFRP1,TCF21,SFRP5,FZD1,WNT2 genes were down-regulated. The upregulation of TCF19 expression was the most. 2.15 HCC differentially expressed genes were widely correlated. TCF19 expression was significantly positively correlated with WNT6,FZD1,FZD6,MMP1,MMP12 and BCL9 expression levels (P0.05). Wnt antagonistic family SFRPs and DKK differentially expressed genes in the correlation between DKK1 and SFRP4,SFRP4 and SFRP1,SFRP1 There was a significant positive correlation with the expression of SFRP5, SFRP4 and SFRP5 (P 0.05). However, there was no significant correlation between the expression level of DKK1 and SFRP1 and SFRP5 (P0.05). 3. The high expression of TCF19 (鈮，
本文编号：2251632
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