HCV NS5A及其反式激活基因NS5ATP9对肝细胞凋亡的影响及机制研究
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摘要
第一部分HCV(Ib型)NS5A真核表达载体构建及凋亡
相关基因表达谱芯片分析目的：构建HCV(Ib型)NS5A真核表达载体pcDNA3.1/myc-His(-)-HCV NS5A，研究NS5A蛋白对人肝癌细胞凋亡相关分子表达的影响。方法：以丙肝患者血清HCV RNA（Ib型）为模板，逆转录PCR法获取NS5A基因序列，再将该基因连到pGEM-T Easy载体上，经Xho I和Hind III双酶切获得NS5A粘性末端，将NS5A粘性末端与同样经Xho I和Hind III双酶切的pcDNA3.1/myc-His(-)连接从而构建成NS5A的真核表达载体。用Western blot法鉴定NS5A基因在人肝癌细胞系HepG2中的表达。将转染了pcDNA3.1/myc-His(-)-HCVNS5A的HepG2进行表达谱芯片分析。结果：构建的真核表达载体经双酶切及测序鉴定正确无误，转染HepG2细胞系后Western blot检测显示HepG2大量表达myc-his-NS5A融合蛋白。芯片分析显示11条与凋亡相关的基因出现差异表达其中5条基因表达上调，6条表达下调。结论：成功构建了Ib型HCV NS5A的真核表达载体，利用表达谱芯片分析发现NS5A对肝细胞凋亡的作用可能涉及死亡受体通路、线粒体凋亡通路、DNA修复机制。
第二部分NS5ATP9抑制血清饥饿诱导的HepG2细胞凋亡
目的：探讨HCV NS5A反式激活基因NS5ATP9对肝癌细胞系HepG2细胞凋亡的影响。方法：将NS5ATP9基因表达质粒、NS5ATP9干扰RNA质粒及各自的对照空质粒转染到HepG2细胞系，48 h后换无血清培养基培养24 h诱导凋亡，用实时荧光定量PCR验证转染后NS5ATP9 mRNA表达水平的变化，用Annexin V/7AAD流式细胞术检测细胞凋亡，JC-1检测线粒体膜电位，Western blot技术检测Bax蛋白表达，以观察NS5ATP9对HepG2细胞血清饥饿诱导凋亡的影响。结果：Annexin V/7AAD检测结果显示，NS5ATP9过表达组和对照组相比早期凋亡和总凋亡率显著减少（P<0.05）；而NS5ATP9干扰RNA组的早期凋亡、晚期凋亡和总凋亡率均显著增加（P<0.05）。JC-1检测结果显示，NS5ATP9过表达组和对照组相比线粒体膜电位保持正常形式的比例增加（P=0.053），而出现去极化电位形式的比例显著减少（P<0.05），Δψm有增高趋势(P=0.324)；而NS5ATP9干扰RNA组线粒体膜电位保持正常形式的比例显著减少（P<0.05），Δψm有降低趋势（P=0.378）。促凋亡分子Bax蛋白Western blot检测结果显示，NS5ATP9干扰RNA组Bax表达量显著上升（P<0.05），NS5ATP9过表达组Bax表达量则有下降趋势（P=0.551）。结论：NS5ATP9基因抑制血清饥饿诱导的HepG2凋亡，其机制可能是通过线粒体途径。
Part IConstruction of eukaryotic expression vector of HCV(Ib) NS5A and
analysis of apoptosis-related genes via microarrayObjective To construct a recombinant expression plasmid carrying HCV NS5A(Ib) mediated bypcDNA3.1/myc-His(-) and explore its effect on apoptosis-related genes.Methods HCV NS5AcDNA was obtained from HCV RNA by reverse transcriptase PCR ,then NS5A was connected topGEM-T Easy vector。Both pGEM-T-HCV NS5A and pcDNA3.1/myc-His(-) were cut bydouble-enzyme cleavage method using Xho I and Hind III to make sticky ends .Then,weconnected pcDNA3.1/myc-His(-) with NS5A. The pcDNA3.1/myc-His(-)-HCV NS5A plasmidwas transfected to HepG2,then NS5A protein expression was detected by Wesern blot. RestultsThe recombinant eukaryotic expression vector was verified by double-enzyme cleavage methodand DNA sequencing analysis, NS5A protein expression was also confirmed by Wesern blot. Aset of 11 genes related apoptosis(6 up-regulated, 5 down-regulated) whose expression wasmodified by at least twofold was selected from oligonucleotide microarrays.Conclusion Wesucceeded in constructing NS5A recombinant eukaryotic expression vector. NS5A may promoteapoptosis of HepG2 through many pathway,including death receptor pathway, mitochondrialapoptosis pathway,DNA repairment.
Part IINS5ATP9 expression inhibits the apoptosis of HepG2 induced byserum starvation
Objective To investigate the effect of NS5ATP9 on the apoptosis of HepG2. Methods NS5ATP9exptession plasmid (pEGFP-N1-NS5ATP9) and miR RNAi expression vector forNS5ATP9(pcDNA6.2-GW/EmGFP-miR-NS5ATP9) were transiently transfected into HepG2cells by jet PRIME. Cell apoptosis was induced by starvation.The expression of NS5ATP9 inHepG2 was detected by semiquantitative RT-PCR.Cell apoptosis was evaluated by AnnexinV/7AAD, mitochondrial membrane potentials was detected by JC-1 staining. Bax protein wassemiquantidied by Western blotting. Restults After overexpression of NS5ATP9, the percentageof early and total apoptosis decreased significantly ,detected by Annexin V/7AAD(P<0.05),when we knocked down the expression of NS5ATP9 by RNAi expression vector transfection, thepercentage of early ,late and total apoptosis increased significantly(P<0.05) .Compared tocontrol group,the percentage of cells with polarization membrane potential showed a risingtedency after overexpression of NS5ATP9(P=0.053),meanwhile cells with depolarizationmembrane potential decreased significantly(P<0.05),thenΔψm increased ,but notsignificantly(P=0.324);after knocking down of NS5ATP9 , the percentage of cells withpolarization membrane potential dereased significantly (P<0.05),meanwhileΔψm tent todecline(P=0.378).Overexpression of NS5ATP9 downregulated the expression of pro-apoptoticBax(P=0.551),and knocking down of NS5ATP9 induced upregulating of Bax significantly(P<0.05) .Conclusion Our investigation suggested that NS5ATP9 inhibits apoptosis viamitochondrial apoptosis pathway in HepG2.
相关基因表达谱芯片分析目的：构建HCV(Ib型)NS5A真核表达载体pcDNA3.1/myc-His(-)-HCV NS5A，研究NS5A蛋白对人肝癌细胞凋亡相关分子表达的影响。方法：以丙肝患者血清HCV RNA（Ib型）为模板，逆转录PCR法获取NS5A基因序列，再将该基因连到pGEM-T Easy载体上，经Xho I和Hind III双酶切获得NS5A粘性末端，将NS5A粘性末端与同样经Xho I和Hind III双酶切的pcDNA3.1/myc-His(-)连接从而构建成NS5A的真核表达载体。用Western blot法鉴定NS5A基因在人肝癌细胞系HepG2中的表达。将转染了pcDNA3.1/myc-His(-)-HCVNS5A的HepG2进行表达谱芯片分析。结果：构建的真核表达载体经双酶切及测序鉴定正确无误，转染HepG2细胞系后Western blot检测显示HepG2大量表达myc-his-NS5A融合蛋白。芯片分析显示11条与凋亡相关的基因出现差异表达其中5条基因表达上调，6条表达下调。结论：成功构建了Ib型HCV NS5A的真核表达载体，利用表达谱芯片分析发现NS5A对肝细胞凋亡的作用可能涉及死亡受体通路、线粒体凋亡通路、DNA修复机制。
第二部分NS5ATP9抑制血清饥饿诱导的HepG2细胞凋亡
目的：探讨HCV NS5A反式激活基因NS5ATP9对肝癌细胞系HepG2细胞凋亡的影响。方法：将NS5ATP9基因表达质粒、NS5ATP9干扰RNA质粒及各自的对照空质粒转染到HepG2细胞系，48 h后换无血清培养基培养24 h诱导凋亡，用实时荧光定量PCR验证转染后NS5ATP9 mRNA表达水平的变化，用Annexin V/7AAD流式细胞术检测细胞凋亡，JC-1检测线粒体膜电位，Western blot技术检测Bax蛋白表达，以观察NS5ATP9对HepG2细胞血清饥饿诱导凋亡的影响。结果：Annexin V/7AAD检测结果显示，NS5ATP9过表达组和对照组相比早期凋亡和总凋亡率显著减少（P<0.05）；而NS5ATP9干扰RNA组的早期凋亡、晚期凋亡和总凋亡率均显著增加（P<0.05）。JC-1检测结果显示，NS5ATP9过表达组和对照组相比线粒体膜电位保持正常形式的比例增加（P=0.053），而出现去极化电位形式的比例显著减少（P<0.05），Δψm有增高趋势(P=0.324)；而NS5ATP9干扰RNA组线粒体膜电位保持正常形式的比例显著减少（P<0.05），Δψm有降低趋势（P=0.378）。促凋亡分子Bax蛋白Western blot检测结果显示，NS5ATP9干扰RNA组Bax表达量显著上升（P<0.05），NS5ATP9过表达组Bax表达量则有下降趋势（P=0.551）。结论：NS5ATP9基因抑制血清饥饿诱导的HepG2凋亡，其机制可能是通过线粒体途径。
Part IConstruction of eukaryotic expression vector of HCV(Ib) NS5A and
analysis of apoptosis-related genes via microarrayObjective To construct a recombinant expression plasmid carrying HCV NS5A(Ib) mediated bypcDNA3.1/myc-His(-) and explore its effect on apoptosis-related genes.Methods HCV NS5AcDNA was obtained from HCV RNA by reverse transcriptase PCR ,then NS5A was connected topGEM-T Easy vector。Both pGEM-T-HCV NS5A and pcDNA3.1/myc-His(-) were cut bydouble-enzyme cleavage method using Xho I and Hind III to make sticky ends .Then,weconnected pcDNA3.1/myc-His(-) with NS5A. The pcDNA3.1/myc-His(-)-HCV NS5A plasmidwas transfected to HepG2,then NS5A protein expression was detected by Wesern blot. RestultsThe recombinant eukaryotic expression vector was verified by double-enzyme cleavage methodand DNA sequencing analysis, NS5A protein expression was also confirmed by Wesern blot. Aset of 11 genes related apoptosis(6 up-regulated, 5 down-regulated) whose expression wasmodified by at least twofold was selected from oligonucleotide microarrays.Conclusion Wesucceeded in constructing NS5A recombinant eukaryotic expression vector. NS5A may promoteapoptosis of HepG2 through many pathway,including death receptor pathway, mitochondrialapoptosis pathway,DNA repairment.
Part IINS5ATP9 expression inhibits the apoptosis of HepG2 induced byserum starvation
Objective To investigate the effect of NS5ATP9 on the apoptosis of HepG2. Methods NS5ATP9exptession plasmid (pEGFP-N1-NS5ATP9) and miR RNAi expression vector forNS5ATP9(pcDNA6.2-GW/EmGFP-miR-NS5ATP9) were transiently transfected into HepG2cells by jet PRIME. Cell apoptosis was induced by starvation.The expression of NS5ATP9 inHepG2 was detected by semiquantitative RT-PCR.Cell apoptosis was evaluated by AnnexinV/7AAD, mitochondrial membrane potentials was detected by JC-1 staining. Bax protein wassemiquantidied by Western blotting. Restults After overexpression of NS5ATP9, the percentageof early and total apoptosis decreased significantly ,detected by Annexin V/7AAD(P<0.05),when we knocked down the expression of NS5ATP9 by RNAi expression vector transfection, thepercentage of early ,late and total apoptosis increased significantly(P<0.05) .Compared tocontrol group,the percentage of cells with polarization membrane potential showed a risingtedency after overexpression of NS5ATP9(P=0.053),meanwhile cells with depolarizationmembrane potential decreased significantly(P<0.05),thenΔψm increased ,but notsignificantly(P=0.324);after knocking down of NS5ATP9 , the percentage of cells withpolarization membrane potential dereased significantly (P<0.05),meanwhileΔψm tent todecline(P=0.378).Overexpression of NS5ATP9 downregulated the expression of pro-apoptoticBax(P=0.551),and knocking down of NS5ATP9 induced upregulating of Bax significantly(P<0.05) .Conclusion Our investigation suggested that NS5ATP9 inhibits apoptosis viamitochondrial apoptosis pathway in HepG2.
引文
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20 Kanda T, Steele R, Ray R, et al．Inhibition of intrahepatic gamma interferon production by hepatitis Cvirus nonstructural protein 5A in transgenic mice．J Virol,2009,83(17):8463-9.
21 Lan KH, Sheu ML, Hwang SJ, et al．HCV NS5A interacts with p53 and inhibits p53-mediatedapoptosis.Oncogene,2002, 21(31):4801-11.
22 Chung YL，Sheu ML，Yen SH．Hepatitis C virus NS5A as a potential viral Bcl-2 homologue interacts withBax and inhibits apoptosis in hepatocellular carcinoma．Int J Cancer, 2003,107(1):65-73.
23 Nanda SK, Herion D, Liang TJ. The SH3 binding motif of HCV [corrected] NS5A protein interacts withBin1 and is important for apoptosis and infectivity.Gastroenterology,2006,130(3):794-809.
24 Pedersen IM, Cheng G, Wieland S, et al. Interferon modulation of cellular microRNAs as an antiviralmechanism. Nature, 2007, 449(7164):919-22.
25 Esau C, Davis S, Murray SF.miR-122 regulation of lipid metabolism revealed by in vivo antisensetargeting.Cell Metab,2006,3(2): 87-98.
26 Kojima S, Gatfield D, Esau CC, et al.MicroRNA-122 modulates the rhythmic expression profile of thecircadian deadenylase Nocturnin in mouse liver.PLoS One, 2010,5(6):e11264.
27 Jopling CL, Norman KL, Sarnow P. Positive and negative modulation of viral and cellular mRNAs byliver-specific microRNA miR-122.Cold Spring Harb Symp Quant Biol,2006,71:369-76.
1 Yu P, Huang B, Shen M, et al. p15(PAF), a novel PCNA associated factor with increased expression intumor tissues. Oncogene, 2001,20(4):484-9.
2李强,梁耀东,成军,等.丙型肝炎病毒非结构蛋白NS5A反式激活基因NS5ATP9的克隆化研究.胃肠病学和肝病学杂志, 2003,12(3):254-256.
3 Mizutani K, Onda M, Asaka S, et al. Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as anovel gene responsible for anaplastic thyroid carcinoma. Cancer, 2005,103(9):1785-90.
4 Li H, Ma WL, Zuo CQ, et al. [Functional prediction of KIAA0101 gene in human non-small cell lungcancer]. Nan Fang Yi Ke Da Xue Xue Bao, 2010,30(1):157-9.
5 Simpson F, Lammerts vBK, Butterfield N, et al. The PCNA-associated factor KIAA0101/p15(PAF) bindsthe potential tumor suppressor product p33ING1b. Exp Cell Res, 2006,312(1):73-85.
6 Guo M, Li J, Wan D, et al. KIAA0101 (OEACT-1), an expressionally down-regulated andgrowth-inhibitory gene in human hepatocellular carcinoma. BMC Cancer, 2006,6:109.
7 Novakovic B, Rakyan V, Ng HK, et al. Specific tumour-associated methylation in normal human termplacenta and first-trimester cytotrophoblasts. Mol Hum Reprod, 2008,14(9):547-54.
8 Li K, Ma Q, Shi L, et al. NS5ATP9 gene regulated by NF-kappaB signal pathway. Arch Biochem Biophys,2008,479(1):15-9.
9 Hosokawa M, Takehara A, Matsuda K, et al. Oncogenic role of KIAA0101 interacting with proliferatingcell nuclear antigen in pancreatic cancer. Cancer Res, 2007,67(6):2568-76.
10 Turchi L, Fareh M, Aberdam E, et al. ATF3 and p15PAF are novel gatekeepers of genomic integrity uponUV stress. Cell Death Differ, 2009,16(5):728-37.
11 Emanuele MJ, Ciccia A, Elia AE, et al. Proliferating cell nuclear antigen (PCNA)-associatedKIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate.Proc Natl Acad Sci U S A, 2011,108(24):9845-50.
12 Kais Z, Barsky SH, Mathsyaraja H, et al. KIAA0101 interacts with BRCA1 and regulates centrosomenumber. Mol Cancer Res, 2011,9(8):1091-9.
13 Jain M, Zhang L, Patterson EE, et al. KIAA0101 is overexpressed, and promotes growth and invasion inadrenal cancer. PLOS ONE, 2011,6(11):e26866.
14 van BKL, Bennetts JS, Fowles LF, et al. Murine embryonic expression of the gene for the UV-responsiveprotein p15(PAF). Gene Expr Patterns, 2007,7(1-2):47-50.
15 Kato T, Daigo Y, Aragaki M, et al. Overexpression of KIAA0101 predicts poor prognosis in primary lungcancer patients. Lung Cancer, 2012,75(1):110-8.
16 Bjorck E, Ek S, Landgren O, et al. High expression of cyclin B1 predicts a favorable outcome in patientswith follicular lymphoma. Blood, 2005,105(7):2908-15.
17 Nakamura T, Yana I, Kobayashi T, et al. p53 gene mutations associated with anaplastic transformation ofhuman thyroid carcinomas. Jpn J Cancer Res,1992,83(12): 1293-8.
18 Garcia-Rostan G, Tallini G, Herrero A, et al.Frequent mutation and nuclear localization of beta-catenin inanaplastic thyroid carcinoma. Cancer Res,1999,59(8): 1811-5.
19 Onda M, Nagai H, Yoshida A, et al. Up-regulation of transcriptional factor E2F1 in papillary andanaplastic thyroid cancers. J Hum Genet. 2004,49(6):312-8.
20 Yuan RH, Jeng YM, Pan HW, et al. Overexpression of KIAA0101 predicts high stage, early tumorrecurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res, 2007,13(18 Pt 1):5368-76.
21 Collado M, Garcia V, Garcia JM, et al. Genomic profiling of circulating plasma RNA for the analysis ofcancer. Clin Chem, 2007,53(10):1860-3.
22 Miller WR, Larionov A. Changes in expression of oestrogen regulated and proliferation genes withneoadjuvant treatment highlight heterogeneity of clinical resistance to the aromatase inhibitor, letrozole.Breast Cancer Res, 2010,12(4):R52.
23 Shi L, Zhang SL, Li K, et al. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett,2008,259(2):192-7.
24 Lan KH, Sheu ML, Hwang SJ, et al. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis.Oncogene,2002,21(31): 4801-11.
25 Ghosh AK, Steele R, Meyer K, Ray R, Ray RB. Hepatitis C virus NS5A protein modulates cell cycleregulatory genes and promotes cell growth. J Gen Virol. 1999,80 ( Pt 5):1179-83.
2 Grakoui A, Wychowski C, Lin C, et al.Expression and identification of hepatitis C virus polyproteincleavageproducts. Virol,1993,67(3):1385-95.
3孙树艳,郭慧,李波,等.丙型肝炎病毒NS3蛋白对血清饥饿诱导QSG7701细胞凋亡的影响中华肝脏病杂志,2007,15(7):540-541
4杨春，李昌平，陈枫，等．丙型肝炎病毒NS4B对L02肝细胞周期及cyclinD1表达的影响．实用肝脏病,2008,11(1):14-16.
5 Shi L, Zhang SL, Li K, et al. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett,2008,259(2):192-7.
6 Yu P, Huang B, Shen M, et al. p15(PAF), a novel PCNA associated factor with increased expression intumor tissues. Oncogene, 2001,20(4):484-9.
7 Mizutani K, Onda M, Asaka S, et al. Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as anovel gene responsible for anaplastic thyroid carcinoma. Cancer, 2005,103(9):1785-90.
8 Li H, Ma WL, Zuo CQ, et al. [Functional prediction of KIAA0101 gene in human non-small cell lungcancer]. Nan Fang Yi Ke Da Xue Xue Bao, 2010,30(1):157-9.
9 Simpson F, Lammerts vBK, Butterfield N, et al. The PCNA-associated factor KIAA0101/p15(PAF) bindsthe potential tumor suppressor product p33ING1b. Exp Cell Res, 2006,312(1):73-85.
1 Street A, Macdonald A, Crowder K，et al．The Hepatitis C virus NS5A protein activates aphosphoinositide 3-kinase-dependent survival signaling cascade．J Biol Chem,2004:279(13):12232-41.
2中华医学会肝病学分会，中华医学会传染病与寄生虫病学分会．丙型肝炎防治指南．中华肝脏病杂志,2004,12(4):194-198.
3 Majumder M，Ghosh AK，Steele R，et al．Hepatitis C virus NS5A protein impairs TNF-mediated hepaticapoptosis, but not by an anti-FAS antibody, in transgenic mice．Virology,2002 Mar 1;294(1):94-105.
4 Girard S，Vossman E，Misek DE，et al．Hepatitis C virus NS5A-regulated gene expression and signalingrevealed via microarray and comparative promoter analyses．Hepatology,2004,40(3):708-18.
5 Grakoui A，Wychowski C，Lin C，et al．Expression and identification of hepatitis C virus polyproteincleavageproducts．Virol,1993,67(3):1385-95.
6 Neddermann P，Clementi A，De F，et al．Hyperphosphorylation of the hepatitis C virus NS5A proteinrequires an active NS3protease，NS4A，NS4B，and NS5A encoded on the same polyprotein．J Virol,1999,73(12):9984-9991.
7 Sato C．Effects of hepatitis C virus proteins on the interferon-stimulated signal transduction．NihonRinsho,2001,59(7):1271-6.
8 Lin LY，Li SC，L SL．Hepatitis C virus nonstructural 5A protein inhibits tumor necrosis factor alphamediated apoptosis of HepG2 cells．Zhonghua Nei Ke Za Zhi,2003,42(6):392-5.
9 Sato C．Effects of hepatitis C virus proteins on the interferon-stimulated signal transduction．NihonRinsho,2001,59(7):1271-6.
10 Kanda T, Steele R, Ray R, et al．Inhibition of intrahepatic gamma interferon production by hepatitis Cvirus nonstructural protein 5A in transgenic mice．J Virol,2009,83(17):8463-9.
11 Fukuzawa K，Takahashi K，Furuta K，et al．Expression of fas/fas ligand (Fasl) and its involvement ininfiltrating lymphocytes in hepatocellular carcinoma (HCC)．J Gastroenterol,2001,36(10):681-8.
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18 Cho SH，Ahn AK，Bhargava P，et al．Glycolytic rate and lymphomagenesis depend on PARP14, an ADPribosyltransferase of the B aggressive lymphoma (BAL) family．Proc Natl Acad Sci USA，2011,108(38):15972-7.
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24 Tourneur L，Mistou S，Michiels FM，et al．Loss of FADD protein expression results in a biasedFas-signaling pathway and correlates with the development of tumoral status in thyroid follicularcells．Oncogene,2003,22(18):2795-804.
1 Williams R. Global challenges in liver disease. Hepatology,2006 ,44(3):521-6.
2 Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellularsignaling pathways．J Gastroenterol Hepatol,2007,22 (Suppl 1):S108-11.
3 Tamura R, Kanda T, Imazeki F, et al.Hepatitis C Virus nonstructural 5A protein inhibitslipopolysaccharide-mediated apoptosis of hepatocytes by decreasing expression of Toll-like receptor 4.Infect Dis,2011,204(5):793-801.
4 Shi L, Zhang SL, Li K, et al. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett2008,259(2):192-7.
5 Yuan RH, Jeng YM, Pan HW, et al.Overexpression of KIAA0101 predicts high stage, early tumorrecurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res,2007,13(18 Pt 1):5368-76.
6 Kais Z, Barsky SH, Mathsyaraja H, et al.KIAA0101 interacts with BRCA1 and regulates centrosomenumber . Mol Cancer Res,2011,9(8):1091-9.
7 Kato T, Daigo Y, Aragaki M, et al. Overexpression of KIAA0101 predicts poor prognosis in primary lungcancer patients . Lung Cancer,2012,75(1):110-8.
8 Jain M, Zhang L, Patterson EE, et al. KIAA0101 Is Overexpressed, and Promotes Growth and Invasion inAdrenal Cancer .PLoS One,2011,6(11):e26866.
9 Yu P, Huang B, Shen M, et al.p15(PAF), a novel PCNA associated factor with increased expression intumor tissues. Oncogene,2001,20(4):484-9.
10 Mizutani K, Onda M, Asaka S, et al.Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as anovel gene responsible for anaplastic thyroid carcinoma . Cancer,2005,103(9):1785-90.
11 Hosokawa M, Takehara A, Matsuda K, et al.Oncogenic role of KIAA0101 interacting with proliferatingcell nuclear antigen in pancreatic cancer. Cancer Res,2007,67(6):2568-76.
12 Guo M, Li J, Wan D, et al.KIAA0101 (OEACT-1), an expressionally down-regulated andgrowth-inhibitory gene in human hepatocellular carcinoma. BMC Cancer,2006,6:109.
13 Simpson F, Lammerts van Bueren K, Butterfield N, et al.The PCNA-associated factorKIAA0101/p15(PAF) binds the potential tumor suppressor product p33ING1b . Exp CellRes,2006,312(1):73-85.
1 Grakoui A, Wychowski C, Lin C, et al.Expression and identification of hepatitis C virus polyproteincleavageproducts. Virol,1993,67(3):1385-95.
2 Failla C, Tomei L, De Francesco R. Both NS3 and NS4A are required for proteolytic processing ofhepatitis C virus nonstructural proteins.Virol,1994,68(6):3753-60.
3 Lin C, Rice CM. The hepatitis C virus NS3 serine proteinase and NS4A cofactor: establishment of acell-free trans-processing assay.Proc Natl Acad Sci U S A, 1995,92(17):7622-6.
4 Neddermann P, Clementi A, De F.Hyperphosphorylation of the hepatitis C virus NS5A protein requires anactive NS3protease，NS4A，NS4B，and NS5A encoded on the same polyprotein.J Virol,1999,73(12):9984-9991.
5 Tanji Y，Kaneko T，Satoh S，et al.Phosphorylation of hepatitis C virus-encoded nonstructural proteinNS5A.Virol,1995,69(7):3980-3986.
6 Shimakami T，Hijikata M，Luo H，et al.Effect of interaction between hepatitis C virus NS5A and NS5B onhepatitis C virus RNA replication with the hepatitis C virus replicon.Virol,2004, 78(6):2738-2748.
7 Enomoto N, Sakuma I, Asahina Y. Comparison of full-length sequences of interferon-sensitive andresistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5Aregion.Clin Invest,1995,96(1):224-30.
8 Hung CH, Lee CM, Lu SN, et al. Mutations in the NS5A and E2-PePHD region of hepatitis C virus type1b and correlation with the response to combination therapy with interferon and ribavirin.ViralHepat,2003,10(2):87-94.
9 Pascu M, Martus P, H hne M, et al. Sustained virological response in hepatitis C virus type 1b infectedpatients is predicted by the number of mutations within the NS5A-ISDR: a meta-analysis focused ongeographical differences. Gut,2004,53(9):1345-51.
10 Ghosh AK, Steele R, Meyer K, et al. Meyer KHepatitis C virus NS5A protein modulates cell cycleregulatory genes and promotes cell growth. J Gen Virol, 1999 ,80 ( Pt 5):1179-83.
11 Ghosh AK, Majumder M, Steele R, et al．Hepatitis C virus NS5A protein protects against TNF-alphamediated apoptotic cell death.Virus Res, 2000,67(2):173-8.
12 Arima N, Kao CY, Licht T, et al．Modulation of cell growth by the hepatitis C virus nonstructural proteinNS5A. J Biol Chem, 2001，276(16):12675-84.
13 Majumder M, Ghosh A K, Steele R, et al.Hepatitis C virus NS5 A physically associates with p53 andregulates p21/waf1 gene expression in a p53-dependent manner. Virol, 2001,75:1401-1407.
14 Shi ST, Polyak SJ, Tu H, et al.Hepatitis C virus NS5A colocalizes with the core protein on lipid dropletsand interacts with apolipoproteins.Virology, 2002,292(2):198-210.
15 Wang AG, Lee DS, Moon HB, et al. Non-structural 5A protein of hepatitis C virus induces a range of liverpathology in transgenic mice.Pathol,2009,219(2):253-62.
16 Xiang Z, Qiao L, Zhou Y, et al. Hepatitis C virus nonstructural protein-5A activates sterol regulatoryelement-binding protein-1c through transcription factor Sp1.Biochem Biophys ResCommun,2010,402(3):549-53.
17 Majumder M，Ghosh AK，Steele R，et al．Hepatitis C virus NS5A protein impairs TNF-mediated hepaticapoptosis, but not by an anti-FAS antibody, in transgenic mice．Virology,2002,294(1):94-105.
18 Lin LY，Li SC，L SL．Hepatitis C virus nonstructural 5A protein inhibits tumor necrosis factor alphamediated apoptosis of HepG2 cells．Zhonghua Nei Ke Za Zhi,2003,42(6):392-5.
19 Sato C．Effects of hepatitis C virus proteins on the interferon-stimulated signal transduction．NihonRinsho,2001,59(7):1271-6.
20 Kanda T, Steele R, Ray R, et al．Inhibition of intrahepatic gamma interferon production by hepatitis Cvirus nonstructural protein 5A in transgenic mice．J Virol,2009,83(17):8463-9.
21 Lan KH, Sheu ML, Hwang SJ, et al．HCV NS5A interacts with p53 and inhibits p53-mediatedapoptosis.Oncogene,2002, 21(31):4801-11.
22 Chung YL，Sheu ML，Yen SH．Hepatitis C virus NS5A as a potential viral Bcl-2 homologue interacts withBax and inhibits apoptosis in hepatocellular carcinoma．Int J Cancer, 2003,107(1):65-73.
23 Nanda SK, Herion D, Liang TJ. The SH3 binding motif of HCV [corrected] NS5A protein interacts withBin1 and is important for apoptosis and infectivity.Gastroenterology,2006,130(3):794-809.
24 Pedersen IM, Cheng G, Wieland S, et al. Interferon modulation of cellular microRNAs as an antiviralmechanism. Nature, 2007, 449(7164):919-22.
25 Esau C, Davis S, Murray SF.miR-122 regulation of lipid metabolism revealed by in vivo antisensetargeting.Cell Metab,2006,3(2): 87-98.
26 Kojima S, Gatfield D, Esau CC, et al.MicroRNA-122 modulates the rhythmic expression profile of thecircadian deadenylase Nocturnin in mouse liver.PLoS One, 2010,5(6):e11264.
27 Jopling CL, Norman KL, Sarnow P. Positive and negative modulation of viral and cellular mRNAs byliver-specific microRNA miR-122.Cold Spring Harb Symp Quant Biol,2006,71:369-76.
1 Yu P, Huang B, Shen M, et al. p15(PAF), a novel PCNA associated factor with increased expression intumor tissues. Oncogene, 2001,20(4):484-9.
2李强,梁耀东,成军,等.丙型肝炎病毒非结构蛋白NS5A反式激活基因NS5ATP9的克隆化研究.胃肠病学和肝病学杂志, 2003,12(3):254-256.
3 Mizutani K, Onda M, Asaka S, et al. Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as anovel gene responsible for anaplastic thyroid carcinoma. Cancer, 2005,103(9):1785-90.
4 Li H, Ma WL, Zuo CQ, et al. [Functional prediction of KIAA0101 gene in human non-small cell lungcancer]. Nan Fang Yi Ke Da Xue Xue Bao, 2010,30(1):157-9.
5 Simpson F, Lammerts vBK, Butterfield N, et al. The PCNA-associated factor KIAA0101/p15(PAF) bindsthe potential tumor suppressor product p33ING1b. Exp Cell Res, 2006,312(1):73-85.
6 Guo M, Li J, Wan D, et al. KIAA0101 (OEACT-1), an expressionally down-regulated andgrowth-inhibitory gene in human hepatocellular carcinoma. BMC Cancer, 2006,6:109.
7 Novakovic B, Rakyan V, Ng HK, et al. Specific tumour-associated methylation in normal human termplacenta and first-trimester cytotrophoblasts. Mol Hum Reprod, 2008,14(9):547-54.
8 Li K, Ma Q, Shi L, et al. NS5ATP9 gene regulated by NF-kappaB signal pathway. Arch Biochem Biophys,2008,479(1):15-9.
9 Hosokawa M, Takehara A, Matsuda K, et al. Oncogenic role of KIAA0101 interacting with proliferatingcell nuclear antigen in pancreatic cancer. Cancer Res, 2007,67(6):2568-76.
10 Turchi L, Fareh M, Aberdam E, et al. ATF3 and p15PAF are novel gatekeepers of genomic integrity uponUV stress. Cell Death Differ, 2009,16(5):728-37.
11 Emanuele MJ, Ciccia A, Elia AE, et al. Proliferating cell nuclear antigen (PCNA)-associatedKIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate.Proc Natl Acad Sci U S A, 2011,108(24):9845-50.
12 Kais Z, Barsky SH, Mathsyaraja H, et al. KIAA0101 interacts with BRCA1 and regulates centrosomenumber. Mol Cancer Res, 2011,9(8):1091-9.
13 Jain M, Zhang L, Patterson EE, et al. KIAA0101 is overexpressed, and promotes growth and invasion inadrenal cancer. PLOS ONE, 2011,6(11):e26866.
14 van BKL, Bennetts JS, Fowles LF, et al. Murine embryonic expression of the gene for the UV-responsiveprotein p15(PAF). Gene Expr Patterns, 2007,7(1-2):47-50.
15 Kato T, Daigo Y, Aragaki M, et al. Overexpression of KIAA0101 predicts poor prognosis in primary lungcancer patients. Lung Cancer, 2012,75(1):110-8.
16 Bjorck E, Ek S, Landgren O, et al. High expression of cyclin B1 predicts a favorable outcome in patientswith follicular lymphoma. Blood, 2005,105(7):2908-15.
17 Nakamura T, Yana I, Kobayashi T, et al. p53 gene mutations associated with anaplastic transformation ofhuman thyroid carcinomas. Jpn J Cancer Res,1992,83(12): 1293-8.
18 Garcia-Rostan G, Tallini G, Herrero A, et al.Frequent mutation and nuclear localization of beta-catenin inanaplastic thyroid carcinoma. Cancer Res,1999,59(8): 1811-5.
19 Onda M, Nagai H, Yoshida A, et al. Up-regulation of transcriptional factor E2F1 in papillary andanaplastic thyroid cancers. J Hum Genet. 2004,49(6):312-8.
20 Yuan RH, Jeng YM, Pan HW, et al. Overexpression of KIAA0101 predicts high stage, early tumorrecurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res, 2007,13(18 Pt 1):5368-76.
21 Collado M, Garcia V, Garcia JM, et al. Genomic profiling of circulating plasma RNA for the analysis ofcancer. Clin Chem, 2007,53(10):1860-3.
22 Miller WR, Larionov A. Changes in expression of oestrogen regulated and proliferation genes withneoadjuvant treatment highlight heterogeneity of clinical resistance to the aromatase inhibitor, letrozole.Breast Cancer Res, 2010,12(4):R52.
23 Shi L, Zhang SL, Li K, et al. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett,2008,259(2):192-7.
24 Lan KH, Sheu ML, Hwang SJ, et al. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis.Oncogene,2002,21(31): 4801-11.
25 Ghosh AK, Steele R, Meyer K, Ray R, Ray RB. Hepatitis C virus NS5A protein modulates cell cycleregulatory genes and promotes cell growth. J Gen Virol. 1999,80 ( Pt 5):1179-83.