MMP家族基因与宫颈癌的关系研究
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摘要
目的利用癌症基因组图谱(TCGA)数据库中宫颈癌的相关数据,研究人乳头瘤病毒(HPV)阳性宫颈癌人群与HPV阴性宫颈癌人群的基质金属蛋白酶(MMP)家族相关免疫基因的变化。方法从TCGA数据库中收集宫颈癌患者137例及相关数据信息,分为HPV阴性宫颈癌组和HPV阳性宫颈癌组。利用Edge R计算分析所有样本的转录组测序(RNA-Seq)数据,寻找两组之间差异表达的基因;并利用基因本体(GO)对表达差异的基因进行生物功能富集分析;利用RNA-Seq及拷贝数变异等数据,对MMP家族相关免疫基因进行分析;利用Kaplan-Meier分析评估MMP家族免疫特征基因对患者总生存期和无进展生存期的影响。结果通过Edge R计算分析发现,两组之间有2 368个基因的表达差异有统计学意义(P<0.01);其中有823个基因表达上调,1 545个基因表达下调。通过GO进行功能富集分析发现,表达上调的差异基因主要富集在免疫反应通路上。MMP家族3个免疫基因的变化在拷贝数变异和mRNA表达上相关联,当基因的拷贝数扩增时,mRNA表达相应上调,反之亦然。MMP-1、MMP-3、MMP-13基因对HPV宫颈癌患者的总生存期和无进展生存期均无明显影响。结论与HPV阴性宫颈癌患者相比,HPV阳性宫颈癌患者中有大量差异表达的基因,表达上调的基因主要富集在免疫通路上,其中免疫基因MMP-1、MMP-3、MMP-13的mRNA表达与拷贝数变异类型相关联;有多种免疫通路上的基因都会影响MMPs家族免疫基因的改变,从而诱发癌症。
Objective To investigate the association between metalloproteinase(MMP) family-related genes and cervical cancer.Methods The data of 137 patients with cervical cancer were collected from the Cancer Genome Atlas(TCGA) database, including 7HPV-negative cases and 130 HPV-positive cases. The RNA-Seq data of all samples were analyzed by edgeR calculation, the differential expression genes were selected and the gene ontology(GO) was used for functional enrichment analysis. CNV and other data of the MMP family genes were explored and demonstrated further. Kaplan-Meier analysis was used to assess the impact of MMP family immune signature genes on overall survival and progression-free survival in patients. Results Using edgeR analysis, 2 368 differentially expressed genes were found in two group(P<0.01). Functional enrichment analysis by GO revealed that genes with differential expression were significantly enriched in immune response pathways. According to comprehensive analysis, we found that the three core MMP family immune genes were associated with CNV and m RNA expression. When CN amplified, m RNA expression was up-regulated, and vice versa. MMP-1, MMP-3 and MMP-13 genes was not correlated with overall survival and progression-free survival of patients with HPV-positive cervical cancer. Conclusion Compared with HPV-negative cervical cancer patients, there are a large number of differentially expressed genes in HPV-positive cervical cancer patients, which mainly concentrated in the immune pathway. The expression of immune genes MMP-1, MMP-3 and MMP-13 are related to the CNV type. There are many genes on the immune pathway would influence the changes of the MMPs family genes, thus inducing the generation of cancer.
Objective To investigate the association between metalloproteinase(MMP) family-related genes and cervical cancer.Methods The data of 137 patients with cervical cancer were collected from the Cancer Genome Atlas(TCGA) database, including 7HPV-negative cases and 130 HPV-positive cases. The RNA-Seq data of all samples were analyzed by edgeR calculation, the differential expression genes were selected and the gene ontology(GO) was used for functional enrichment analysis. CNV and other data of the MMP family genes were explored and demonstrated further. Kaplan-Meier analysis was used to assess the impact of MMP family immune signature genes on overall survival and progression-free survival in patients. Results Using edgeR analysis, 2 368 differentially expressed genes were found in two group(P<0.01). Functional enrichment analysis by GO revealed that genes with differential expression were significantly enriched in immune response pathways. According to comprehensive analysis, we found that the three core MMP family immune genes were associated with CNV and m RNA expression. When CN amplified, m RNA expression was up-regulated, and vice versa. MMP-1, MMP-3 and MMP-13 genes was not correlated with overall survival and progression-free survival of patients with HPV-positive cervical cancer. Conclusion Compared with HPV-negative cervical cancer patients, there are a large number of differentially expressed genes in HPV-positive cervical cancer patients, which mainly concentrated in the immune pathway. The expression of immune genes MMP-1, MMP-3 and MMP-13 are related to the CNV type. There are many genes on the immune pathway would influence the changes of the MMPs family genes, thus inducing the generation of cancer.
引文
[1]Small JrW,Bacon MA,Bajaj A,et al.Cervical cancer:A global health crisis[J].Cancer,2017,123(13):2404-2412.
[2]Schwartz SM,Daling JR,Shera KA,et al.Human papillomavirus and prognosis of invasive cervical cancer:a population-based study[J].Journal of Clinical Oncology,2001,19(7):1906-1915.
[3]蒋桔莲,陈健,钟倩怡,等.宫颈癌及癌前病变患者HPV感染与机体免疫状态的研究[J].浙江医学,2015,37(19):1578-1581.
[4]唐田娟.基质金属蛋白酶基因多态性同宫颈癌患病风险的meta分析[D].广西医科大学,2015.
[5]Lahmann C,Young AR,Wittern KP,et al.Induction of mRNA for matrix metalloproteinase 1 and tissue inhibitor of metalloproteinases 1 in human skin in vivo by solar simulated radiation[J].Photochemistry&Photobiology,2010,73(6):657-663.
[6]罗春芳,朱润庆,王晖,等.环氧合酶-2和基质金属蛋白酶-9在宫颈癌中的表达及其临床意义[J].中华肿瘤杂志,2007,29(7):526-530.
[7]Paula Borden,Renu A.Heller.Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases[J].Critical Reviews in Eukaryotic Gene Expression,1997,7(1-2):159-178.
[8]Gomes JR,Omar NF,Neves JD,et al.Immunolocalization and activity of the MMP-9 and MMP-2 in odontogenic region of the rat incisor tooth after post shortening procedure[J].Journal of Molecular Histology,2011,42(2):153-159.
[9]Brummer O,Bo hmer G,Hollwitz B,et al.MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation--an immunohistochemical study[J].Gynecologic Oncology,2002,84(2):222-227.
[10]Greulich H.The genomics of lung adenocarcinoma:opportunities for targeted therapies[J].Genes&Cancer,2010,1(12):1200-1210.
[11]Zhang Y,Frohman MA.Cellular and physiological roles for phospholipase D1 in cancer[J].Journal of Biological Chemistry,2014,289(33):22567-22574.
[12]Kang DW,Min DS.Platelet derived growth factor increases phospholipase D1 but not phospholipase D2 expression via NFkappaBsignaling pathway and enhances invasion of breast cancer cells[J].Cancer Letters,2010,294(1):125-133.
[13]Cho JH,Hong SK,Kim EY,et al.Overexpression of phospholipase D suppresses taxotere-induced cell death in stomach cancer cells[J].Biochim Biophys Acta,2008,1783(5):912-923.
[14]Luquain C,Singh A,Wang L,et al.Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells[J].Journal of Lipid Research,2003,44(10):1963-1975.
[2]Schwartz SM,Daling JR,Shera KA,et al.Human papillomavirus and prognosis of invasive cervical cancer:a population-based study[J].Journal of Clinical Oncology,2001,19(7):1906-1915.
[3]蒋桔莲,陈健,钟倩怡,等.宫颈癌及癌前病变患者HPV感染与机体免疫状态的研究[J].浙江医学,2015,37(19):1578-1581.
[4]唐田娟.基质金属蛋白酶基因多态性同宫颈癌患病风险的meta分析[D].广西医科大学,2015.
[5]Lahmann C,Young AR,Wittern KP,et al.Induction of mRNA for matrix metalloproteinase 1 and tissue inhibitor of metalloproteinases 1 in human skin in vivo by solar simulated radiation[J].Photochemistry&Photobiology,2010,73(6):657-663.
[6]罗春芳,朱润庆,王晖,等.环氧合酶-2和基质金属蛋白酶-9在宫颈癌中的表达及其临床意义[J].中华肿瘤杂志,2007,29(7):526-530.
[7]Paula Borden,Renu A.Heller.Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases[J].Critical Reviews in Eukaryotic Gene Expression,1997,7(1-2):159-178.
[8]Gomes JR,Omar NF,Neves JD,et al.Immunolocalization and activity of the MMP-9 and MMP-2 in odontogenic region of the rat incisor tooth after post shortening procedure[J].Journal of Molecular Histology,2011,42(2):153-159.
[9]Brummer O,Bo hmer G,Hollwitz B,et al.MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation--an immunohistochemical study[J].Gynecologic Oncology,2002,84(2):222-227.
[10]Greulich H.The genomics of lung adenocarcinoma:opportunities for targeted therapies[J].Genes&Cancer,2010,1(12):1200-1210.
[11]Zhang Y,Frohman MA.Cellular and physiological roles for phospholipase D1 in cancer[J].Journal of Biological Chemistry,2014,289(33):22567-22574.
[12]Kang DW,Min DS.Platelet derived growth factor increases phospholipase D1 but not phospholipase D2 expression via NFkappaBsignaling pathway and enhances invasion of breast cancer cells[J].Cancer Letters,2010,294(1):125-133.
[13]Cho JH,Hong SK,Kim EY,et al.Overexpression of phospholipase D suppresses taxotere-induced cell death in stomach cancer cells[J].Biochim Biophys Acta,2008,1783(5):912-923.
[14]Luquain C,Singh A,Wang L,et al.Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells[J].Journal of Lipid Research,2003,44(10):1963-1975.