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摘要:目的
筛选与挖掘卵巢癌多药耐药相关基因及其生物信息。
方法基于GSE41499、GSE33482、GSE15372和GSE28739等4套来源不同的卵巢癌化疗耐药与敏感基因芯片表达谱数据集，综合运用差异基因表达分析、基因通路富集分析和文本挖掘等生物信息学方法预测卵巢癌多药耐药相关基因及通路。
结果MAPK信号通路、泛素介导的蛋白质水解、轴突导向、焦点粘连、神经营养素信号通路、癌症通路、肾细胞癌、柠檬酸循环、类萜骨干生物合成、错配修复和亨廷顿氏舞蹈病等11条基因通路是出现频率相对较高的显著性上调通路（P<0.05），甘油脂、戊醣酸途径、果糖和甘露糖代谢、谷胱甘肽代谢、蛋白酶体、p53信号通路和溶酶体等7条基因通路是出现频率相对较高的显著性下调通路（P<0.05）；进一步的文本挖掘发现，ACO1、BDNF、CXCR4、HMGCR和NRP1等5个上调表达基因（P<0.05）和CDKN2C、FAS和SKP2等3个下调表达基因（P<0.05）可能与卵巢癌多药耐药形成相关。
结论卵巢癌多药耐药机制的形成可能涉及到多种不同的通路和基因，其中ACO1、BDNF、CXCR4、HMGCR、NRP1、CDKN2C、FAS和SKP2等基因可能在其中发挥着关键作用，后续研究将对其进行实验和临床双重验证。
Abstract:ObjectiveTo screen and mine the genes related to multidrug resistance (MDR) in ovarian cancer(OC) and their biological information.
MethodsBased on four different microarray expression profiles(GSE41499, GSE33482, GSE15372 and GSE28739) between resistant samples and sensitive samples relatedto OC, we performed a comprehensive bioinformatics analysis through gene expression analysis, geneticpathway enrichment analysis and text mining to predict the pathways and their genes related to MDR inOC.
ResultsEleven significantly upregulated pathways were found frequently among four OC microarraydatasets, including MAPK signaling pathway, ubiquitin-mediated proteolysis, axon guidance, focal adhesion,neurotrophin signaling pathway, pathways in cancer, renal cell carcinoma, citrate cycle, terpenoid backbonebiosynthesis, mismatch repair and Huntington’s disease(P<0.05); and seven significantly downregulatedpathways were found frequently, including glycerolipid metabolism, pentose phosphate pathway, fructoseand mannose metabolism, glutathione metabolism, proteasome, p53 signaling pathway and lysosome(P<0.05). By further text mining methods, we found five significantly upregulated genes, including ACO1,BDNF, CXCR4, HMGCR and NRP1(P<0.05), as well as three significantly downregulated genes, includingCDKN2C, FAS and SKP2(P<0.05), might be associated with MDR in OC.
ConclusionOC MDR mightbe involved in various pathways and genes. ACO1, BDNF, CXCR4, HMGCR, NRP1, CDKN2C, FAS andSKP2 might play crucial roles in those pathways. Follow-up study would validate the roles of those genes inthe experiments and clinical practice.
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Key words:
- Ovarian cancer /
- MDR /
- Gene /
- Bioinformatics analysis /
- Screen and mine
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图 1 从文献水平上反映差异基因与一般性耐药、多药耐药和肿瘤耐药的关系图
Figure 1 Co-occurrence analysis of differentially expressedgenes to exact keyword expression ‘drug resistance’, ‘drugresistance, multiple’ and ‘drug resistance, neoplasm’
表 3 差异基因与卵巢癌的关系
Table 3 Relationship between differentially expressed genes and ovarian cancer
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[1] Rubin SC, Randall TC, Armstrong KA, et al. Ten-year followup of ovarian cancer patients after second-look laparotomy with negative findings[J]. Obstet Gynecol, 1999, 93(1): 21-4. [1] Rubin SC, Randall TC, Armstrong KA, et al. Ten-year followupof ovarian cancer patients after second-look laparotomy withnegative findings[J]. Obstet Gynecol, 1999, 93(1): 21-4.
[2] Lin H, Changchien CC. Management of relapsed/refractory epithelial ovarian cancer: current standards and novel approaches[J]. Taiwan J Obstet Gynecol, 2007, 46: 379-88. [2] Lin H, Changchien CC. Management of relapsed/refractoryepithelial ovarian cancer: current standards and novelapproaches[J]. Taiwan J Obstet Gynecol, 2007, 46: 379-88.
[3] Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010[J]. CACancer J Clin, 2010, 60: 277-300.
[3] Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010[J]. CA Cancer J Clin, 2010, 60: 277-300. [4] Elgaaen BV, Olstad OK, Sandvik L, et al. ZNF385B and VEGFAare strongly differentially expressed in serous ovarian carcinomasand correlate with survival[J]. PLoS One, 2012, 7(9): e46317.
[4] Elgaaen BV, Olstad OK, Sandvik L, et al. ZNF385B and VEGFA are strongly differentially expressed in serous ovarian carcinomas and correlate with survival[J]. PLoS One, 2012, 7(9): e46317. [5] Huang RY, Chen GB, Matsumura N, et al. Histotype-specific copynumberalterations in ovarian cancer[J]. BMC Med Genomics,2012, 5: 47.
[5] Huang RY, Chen GB, Matsumura N, et al. Histotype-specific copynumber alterations in ovarian cancer[J]. BMC Med Genomics, 20 12, 5: 47. [6] Marchion DC, Cottrill HM, Xiong Y, et al. BAD phosphorylationdetermines ovarian cancer chemosensitivity and patientsurvival[J]. Clin Cancer Res, 2011, 17: 6356-66.
[6] Marchion DC, Cottrill HM, Xiong Y, et al. BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival[J]. Clin Cancer Res, 2011, 17: 6356-66. [7] Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository[J]. Nucleic Acids Res, 2002, 30(1): 207-10. [7] Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus:NCBI gene expression and hybridization array data repository[J].Nucleic Acids Res, 2002, 30(1): 207-10.
[8] Benjamini Y, Hochberg Y. Controlling the false discovery rate-a practical and powerful approach to multiple testing[J]. J R STAT SOC B, 1995, 57(1): 289-300. [8] Benjamini Y, Hochberg Y. Controlling the false discovery rate-apractical and powerful approach to multiple testing[J]. J R STATSOC B, 1995, 57(1): 289-300.
[9] Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive forfunctional genomics data sets-update[J]. Nucleic Acids Res, 2013,41(Dataase issue): D991-5.
[9] Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets-update[J]. Nucleic Acids Res, 2013, 41 (Dataase issue): D991-5. [10] Huang DW, Sherman BT, Tan Q, et al. DAVID BioinformaticsResources: expanded annotation database and novel algorithms tobetter extract biology from large gene lists[J]. Nucleic Acids Res,2007, 35(Web Server issue): W169-75.
[10] Huang DW, Sherman BT, Tan Q, et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists[J]. Nucleic Acids Res, 20 07, 35(Web Server issue): W169-75. [11] Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes[J]. Nucleic Acids Res, 2000, 28(1): 27-30. [11] Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes andgenomes[J]. Nucleic Acids Res, 2000, 28(1): 27-30.
[12] Shannon P, Markiel A, Ozier O, et al. Cytoscape: a softwareenvironment for integrated models of biomolecular interactionnetworks[J]. Genome Res, 2003, 13(11): 2498-504.
[12] Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks[J]. Genome Res, 2003, 13(11): 2498-504. [13] Zhang F, Drabier R. IPAD: the Integrated Pathway Analysis Database for Systematic Enrichment Analysis[J]. BMC Bioinformatics, 2012, 13 Suppl 15: S7. [13] Zhang F, Drabier R. IPAD: the Integrated Pathway AnalysisDatabase for Systematic Enrichment Analysis[J]. BMCBioinformatics, 2012, 13 Suppl 15: S7.
[14] Rosanò L, Cianfrocca R, Spinella F, et al. Acquisition ofchemoresistance and EMT phenotype is linked with activation ofthe endothelin A receptor pathway in ovarian carcinoma cells[J].Clin Cancer Res, 2011, 17(8): 2350-60.
[14] Rosanò L, Cianfrocca R, Spinella F, et al. Acquisition of chemoresistance and EMT phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells[J]. Clin Cancer Res, 2011, 17(8): 2350-60. [15] Masoumi-Moghaddam S, Amini A, Wei AQ, et al. Sprouty2 protein in prediction of post-treatment ascites in epithelial ovarian cancer treated with adjuvant carbotaxol chemotherapy[J]. Am J Cancer Res, 2015, 5(8): 2498-507. [15] Masoumi-Moghaddam S, Amini A, Wei AQ, et al. Sprouty2protein in prediction of post-treatment ascites in epithelial ovariancancer treated with adjuvant carbotaxol chemotherapy[J]. Am JCancer Res, 2015, 5(8): 2498-507.
[16] Yang-Hartwich Y, Soteras MG, Lin ZP, et al. p53 proteinaggregation promotes platinum resistance in ovarian cancer[J].Oncogene, 2015, 34(27): 3605-16.
[16] Yang-Hartwich Y, Soteras MG, Lin ZP, et al. p53 protein aggregation promotes platinum resistance in ovarian cancer[J]. Oncogene, 2015, 34(27): 3605-16. [17] Woo MG, Xue K, Liu J, et al. Calpain-mediated processing ofp53-associated parkin-like cytoplasmic protein (PARC) affectschemosensitivity of human ovarian cancer cells by promoting p53subcellular trafficking[J]. J Biol Chem, 2012, 287(6): 3963-75.
[17] Woo MG, Xue K, Liu J, et al. Calpain-mediated processing of p53-associated parkin-like cytoplasmic protein (PARC) affects chemosensitivity of human ovarian cancer cells by promoting p53 subcellular trafficking[J]. J Biol Chem, 2012, 287(6): 3963-75. [18] Leung EL, Fraser M, Fiscus RR, et al. Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: involvement in p53 regulation and cisplatin resistance[J]. Br J Cancer, 2008, 98(11): 18 03-9. [18] Leung EL, Fraser M, Fiscus RR, et al. Cisplatin alters nitric oxidesynthase levels in human ovarian cancer cells: involvement in p53regulation and cisplatin resistance[J]. Br J Cancer, 2008, 98(11):1803-9.
[19] Fecher LA, Amaravadi RK, Flaherty KT. The MAPK pathway inmelanoma[J]. Curr Opin Oncol, 2008, 20(2): 183-9.
[19] Fecher LA, Amaravadi RK, Flaherty KT. The MAPK pathway in melanoma[J]. Curr Opin Oncol, 2008, 20(2): 183-9. [20] Villedieu M, Deslandes E, Duval M, et al. Acquisition ofchemoresistance following discontinuous exposures to cisplatin isassociated in ovarian carcinoma cells with progressive alterationof FAK, ERK and p38 activation in response to treatment[J].Gynecol Oncol, 2006, 101(3): 507-19.
[20] Villedieu M, Deslandes E, Duval M, et al. Acquisition of chemoresistance following discontinuous exposures to cisplatin is associated in ovarian carcinoma cells with progressive alteration of FAK, ERK and p38 activation in response to treatment[J]. Gynecol Oncol, 2006, 101(3): 507-19. [21] Vogelstein B, Lane D, Levine AJ. Surfing the p53 network[J].Nature, 2000, 408(6810): 307-10.
[21] Vogelstein B, Lane D, Levine AJ. Surfing the p53 network[J]. Nature, 2000, 408(6810): 307-10. [22] Green JA, Berns EM, Coens C, et al. Alterations in the p53pathway and prognosis in advanced ovarian cancer: a multifactorialanalysis of the EORTC Gynaecological Cancer group(study 55865)[J]. Eur J Cancer, 2006, 42(15): 2539-48.
[22] Green JA, Berns EM, Coens C, et al. Alterations in the p53 pathway and prognosis in advanced ovarian cancer: a multifactorial analysis of the EORTC Gynaecological Cancer group (study 55865)[J]. Eur J Cancer, 2006, 42(15): 2539-48. [23] Bartel F, Jung J, Böhnke A, et al. Both germ line and somaticgenetics of the p53 pathway affect ovarian cancer incidence andsurvival[J]. Clin Cancer Res, 2008, 14(1): 89-96.
[23] Bartel F, Jung J, Böhnke A, et al. Both germ line and somatic genetics of the p53 pathway affect ovarian cancer incidence and survival[J]. Clin Cancer Res, 2008, 14(1): 89-96. [24] Pani E, Stojic L, El-Shemerly M, et al. Mismatch repair status and the response of human cells to cisplatin[J]. Cell Cycle, 2007, 6( 14): 1796-802. [24] Pani E, Stojic L, El-Shemerly M, et al. Mismatch repair statusand the response of human cells to cisplatin[J]. Cell Cycle, 2007,6(14): 1796-802.
[25] Helleman J, van Staveren IL, Dinjens WN, et al. Mismatch repair andtreatment resistance in ovarian cancer[J]. BMC Cancer, 2006, 6: 201.
[25] Helleman J, van Staveren IL, Dinjens WN, et al. Mismatch repair and treatment resistance in ovarian cancer[J]. BMC Cancer, 2006, 6: 201. [26] Kwong J, Kulbe H, Wong D, et al. An antagonist of the chemokinereceptor CXCR4 induces mitotic catastrophe in ovarian cancercells[J]. Mol Cancer Ther, 2009, 8(7): 1893-905
[26] Kwong J, Kulbe H, Wong D, et al. An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells[J]. Mol Cancer Ther, 2009, 8(7): 1893-905. [27] Ray P, Lewin SA, Mihalko LA, et al. Noninvasive imaging reveals inhibition of ovarian cancer by targeting CXCL12-CXCR4[J]. Neoplasia, 2011, 13(12): 1152-61. [27] Ray P, Lewin SA, Mihalko LA, et al. Noninvasive imaging revealsinhibition of ovarian cancer by targeting CXCL12-CXCR4[J].Neoplasia, 2011, 13(12): 1152-61.
[28] Beck B, Driessens G, Goossens S, et al. A vascular niche and aVEGF-Nrp1 loop regulate the initiation and stemness of skintumours[J]. Nature, 2011, 478(7369): 399-403.
[28] Beck B, Driessens G, Goossens S, et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours[J]. Nature, 2011, 478(7369): 399-403. [29] Grandclement C, Borg C. Neuropilins: a new target for cancer therapy[J]. Cancers (Basel), 2011, 3(2): 1899-928. [29] Grandclement C, Borg C. Neuropilins: a new target for cancertherapy[J]. Cancers (Basel), 2011, 3(2): 1899-928.
[30] Siamakpour-Reihani S, Owzar K, Jiang C, et al. Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma[J]. Gynecol Oncol, 2015, 139(1): 23-9. [30] Siamakpour-Reihani S, Owzar K, Jiang C, et al. Prognosticsignificance of differential expression of angiogenic genes inwomen with high-grade serous ovarian carcinoma[J]. GynecolOncol, 2015, 139(1): 23-9.
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