APRIL及其受体在宫颈癌细胞中的表达以及APRIL突变体的制备
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摘要
APRIL(a proliferation-inducing ligand,增殖诱导配体)是肿瘤坏死因子(TNF)超家族的新成员之一。有膜结合型和可溶性两种活性形式。APRIL的105-250氨基酸区域为天然可溶性APRIL(soluble APRIL,sAPRIL),其与全长(即膜结合型)APRIL具有相同的生物学活性,二者在体外均可以促进多种肿瘤细胞系的增殖。APRIL在正常组织中表达量很低,但在多种肿瘤细胞株和肿瘤组织如结直肠癌、乳腺癌、肺癌、血液系统肿瘤、黑色素瘤、膀胱癌中有高水平表达。
作为一种配体蛋白,APRIL通过与其受体结合而发挥促瘤效应。B淋巴细胞成熟抗原(B cell maturation antigen,BCMA)和跨膜激动子和钙信号修饰环亲素配体作用子(transmembrane activator and calcium signal-modulating cyclophilin ligandinteractor,TACI)是目前公认的APRIL受体。最近有报道表明,粘蛋白多糖(syndecans,S)可能也是APRIL的受体。
目前研究尚无APRIL与宫颈癌或其细胞株增殖之间有否关联的报道。本研究拟观察sAPRIL是否具有促进宫颈癌细胞株HeLa增殖的作用,并对HeLa细胞及宫颈癌组织、癌前病变组织中的APRIL及其受体mRNA的表达情况以及APRIL蛋白在宫颈癌组织的表达情况进行研究,在此研究的基础上设计制备sAPRIL的两个突变体,观察突变体在体外对HeLa细胞增殖的影响以及对野生型sAPRIL的竞争抑制作用,从而为进一步了解APRIL在宫颈癌的发生、发展中的作用以及针对抑制APRIL的抗宫颈癌制剂的制备奠定基础。
为了了解APRIL在宫颈癌发病中的作用,本研究用RT-PCR及免疫组化检测了宫颈癌、癌前病变中APRIL mRNA及蛋白的表达水平,发现宫颈癌组织中APRIL的mRNA和蛋白的表达均显著高于癌前病变和正常组织。同时我们用RT-PCR检测了组织中APRIL受体mRNA的表达情况,发现与正常组织及癌前病变比较,癌组织中BCMA、TACI及粘蛋白多糖-4(S4)的表达水平无显著差异,而随着细胞异型性的加重,粘蛋白多糖-1(S1)表达逐渐下降,而粘蛋白多糖-2(S2)的水平逐渐增高。
之后我们用RT-PCR法检测了HeLa细胞中APRIL及其受体mRNA的表达情况,发现HeLa细胞表达APRIL、S1和S2,而不表达BCMA、TACI及S4。
为了进一步了解APRIL在宫颈癌发病中的作用,我们用BrdU-ELISA法检测了sAPRIL蛋白对人宫颈癌细胞株HeLa细胞增殖的作用,发现sAPRIL蛋白能以剂量依赖的方式促进HeLa细胞的增殖。
鉴于APRIL有促进宫颈癌细胞株HeLa细胞增殖的作用,抑制APRIL的功能活性,将可能为宫颈癌的治疗提供新途径。研究表明APRIL抗体和APRIL的可溶性受体能够在一定程度上抑制APRIL的功能,但是人源性抗体获得困难,而APRIL的受体多,一种可溶性受体并不能起到抑制APRIL与其他受体结合而起作用的功能。因此本课题拟从改建APRIL分子本身入手,构建能够与受体结合但不能引发受体后促瘤效应的APRIL突变体,以期获得APRIL的抑制剂,达到治疗肿瘤的目的。
本课题借鉴改建BLyS(B-lymphocyte stimulator,B淋巴细胞刺激因子)分子的方法,在与BlyS进行同源序列比对以及对APRIL分子进行结构分析后,选择APRIL第186、187位氨基酸作为突变位点,以pUC19/sAPRIL为模板,用一步反向PCR致突变法构建了人msAPRIL-1(186G187Q置换为186K187G)及msAPRIL-2(186G被K置换,187Q缺失)两个突变体DNA序列;将上述测序正确的突变型目的片段连接于原核表达载体pQE-80L,成功构建了重组原核表达质粒pQE-80L/msAPRIL-1和pQE-80L/msAPRIL-2;将重组原核表达质粒分别转化于大肠杆菌DH5α,经IPTG诱导,获得了较高水平的表达,SDS-PAGE分析可见,两重组蛋白的大小约为19kDa,主要是以包涵体的形式存在,Western blotting分析显示,两蛋白均在分子量约19kDa处出现单一条带;经Ni~(2+)-NTA纯化系统及尿素透析,两重组蛋白得到了有效纯化和复性。纯化蛋白在SDS-PAGE上呈现单一条带。经Sephadex G-75凝胶过滤层析得到两重组突变体蛋白三聚体分子。生物学功能分析显示,所制备的msAPRIL-1突变体蛋白能很好地与HeLa细胞结合,而msAPRIL-2与HeLa细胞只有微弱的结合;同时两突变体均不能促细胞增殖。进一步分析显示msAPRIL-1可以抑制野生型sAPRIL对HeLa细胞的促增殖作用。
本研究主要结果总结如下:
一、APRIL及其受体在宫颈鳞癌组织和细胞株中的表达
1.APRIL在宫颈鳞癌组织无论在mRNA还是在蛋白水平的表达均显著高于正常鳞状上皮和鳞状上皮内病变,随着细胞的增殖与异型性的加重表达水平逐渐增高;S1mRNA随着宫颈鳞状上皮细胞的增殖和异型性的加重表达逐渐下调,而S2 mRNA表达逐渐增高;BCMA、TACI及S4 mRNA在正常组织、炎症、癌前病变、原位癌及浸润癌中的表达无显著差异;
2.宫颈癌HeLa细胞有APRIL、S1及S2 mRNA的表达,而不表达BCMA、TACI及S4的mRNA;
二、sAPRIL在体外以剂量依赖方式促进人宫颈癌细胞株HeLa细胞的增殖。
通过以上两方面的结果,可初步得出如下结论:APRIL及其受体在宫颈癌的发展中可能起一定的作用,其中APRIL在宫颈癌中的作用可能是通过与S1和/或S2结合而发挥的;而S1 mRNA的降低和/或S2 mRNA及APRIL的表达升高可能可以作为病情进展的预警指标。
三、成功制备了sAPRIL的两个突变体
1.以APRIL第186、187位氨基酸作为突变位点,用一步反向PCR致突变法成功构建了人msAPRIL-1 DNA(186G187Q置换为186K187G)及msAPRIL-2 DNA(186G被K置换,187Q缺失)两个突变体序列。
2.将突变目的DNA片段连接于原核表达载体pQE-80L,成功构建了重组原核表达质粒pQE-80L/msAPRIL-1和pQE-80L/msAPRIL-2。
3.将重组原核表达质粒分别转化大肠杆菌DH5α,经IPTG诱导,使重组突变体蛋白获得了成功表达。
4.经Ni~(2+)-NTA纯化系统及尿素透析,两重组蛋白得到了有效纯化和复性;经Sephadex G-75凝胶过滤层析得到了两重组突变体蛋白三聚体分子。
四、突变体的功能分析
1.所制备的msAPRIL-1突变体可特异地与HeLa细胞结合,而msAPRIL-2与HeLa细胞的结合能力很弱。
2.msAPRIL-1和msAPRIL-2均丧失了促HeLa细胞增殖的功能。
3.msAPRIL-1突变体能在一定程度上竞争抑制野生型sAPRIL促HeLa细胞增殖的功能,而msAPRIL-2的作用则不明显。
以上三、四两部分的结果提示,msAPRIL-1及其衍生分子可能在宫颈癌等APRIL相关肿瘤的治疗中具有潜在应用前景。
APRIL(a proliferation-inducing ligand) is a new member of the tumor necrosis factor (TNF) family,which exists in two forms,cytomembrane APRIL and soluble APRIL(sAPRIL).It is expressed in small amounts in normal tissues but produced abundantly in many kinds of malignant tumors,such as colorectal carcinoma,breast cancer, lung cancer,malignancy of hematological system,bladder cancer and melanoma.APRIL and sAPRIL can not only promote growth of many malignant tumors in vivo and in vitro, but also prolong the life-span of the tumors.As a ligand,APRIL plays its roles by binding to its receptors,BCMA(B cell maturation antigen) and TACI(transmembrane activator and calcium signal-modulating cyclophilin ligand interactor).Besides the above two receptors, recent studies indicate that proteoglycan syndecans(S) may also be the receptors of APRIL.
Although it is affirmed that APRIL is highly expessed in a lot of malignant tumors and can promote growth of the tumors,there is few reprorts about its roles on cervix carcinoma. So in this study we want to primarily figure out the relationship between APRIL and cervix carcinoma.Firstly,mRNA expression profiles of APRIL and its receptors were analyzed by semi-quantitive RT-PCR in HeLa cells and cervix carcinoma tissues,taking the tissues from nomal cervix,chronic cervicitis and cervix introepithelium neoplasia as controls.APRIL protein expression profiles were detected by immunohistochemistry in cervix carcinoma tissues and the controls.Secondly,The proliferation-stimulating effect of sAPRIL to HeLa cells was detected by BrdU-ELISA assay.Thirdly,taking 186G and 187Q of human sAPRIL as mutation sites,one-step opposite orientation PCR was used to construct the two mutant sAPRIL(msAPRIL) DNAs,namely msAPRIL-1 DNA(in which 186G187Q replaced by 186K187G) and msAPRIL-2 DNA(in which 186G replaced by K and 187Q deleted). After inserting the two msAPRIL DNAs into pQE-80L vector respectively,the recombinant msAPRIL proteins were expressed in E.coli DH5αand purified by Ni~(2+)-NTA chromatography and the homotrimers of msAPRILs were isolated by Sephadex G-75. Finally,the binding profiles of the two homotrimers of msAPRILs to HeLa cells were analyzed by indirect immunofluorescence assay.The stimulating function of the two msAPRIL homotrimers(alone or with wild type sAPRIL) to HeLa cells were detected by BrdU-ELISA assay.The major results and conclusions are summarized as follows:
1.With the development of the proliferation and heteromorphism of cervix squamous cells,the mRNA expression of APRIL and S2 were increased gradually,whereas the expression of S1 mRNA was decreased,and the mRNA level of S4,BCMA and TACI had no difference among the tissues from cervix carcinoma,nomal cervix,chronic cervicitis and cervix introepithelium neoplasia.
2.The mRNAs of APRIL and S1 and S2,but not S4,BCMA and TACI,were expressed in HeLa cells.
3.With the development of the proliferation and heteromorphism of squamous cells, the expression of APRIL protein was up-regulated in cervix.
4.sAPRIL could dose-dependent promote the growth of HeLa cells in vitro.
Based on the above results,it might be concluded that there was a positive correlation between APRIL and cervix carcinoma.
5.The two recombinant msAPRIL proteins(msAPRIL-1 and msAPRIL-2) were successfully expressed in E.coli DH5αand purified effectively by Ni~(2+)-NTA chromatography,and the functional homotrimers of msAPRILs were isolated by Sephadex G-75.
6.The prepared msAPRIL-1 homotrimer,not msAPRIL-2 homotrimer,could strongly bind to HeLa cells.Both of the two msAPRIL proteins lost the function of stimulating growth of HeLa cells,and msAPRIL-1 could inhibit the stimulating activity of wild type sAPRIL to HeLa cells,which indicated that msAPRIL-1 and its derivates might have a therapeutic potential in treatment of APRIL-associated cervix carcinoma and other tumors.
作为一种配体蛋白,APRIL通过与其受体结合而发挥促瘤效应。B淋巴细胞成熟抗原(B cell maturation antigen,BCMA)和跨膜激动子和钙信号修饰环亲素配体作用子(transmembrane activator and calcium signal-modulating cyclophilin ligandinteractor,TACI)是目前公认的APRIL受体。最近有报道表明,粘蛋白多糖(syndecans,S)可能也是APRIL的受体。
目前研究尚无APRIL与宫颈癌或其细胞株增殖之间有否关联的报道。本研究拟观察sAPRIL是否具有促进宫颈癌细胞株HeLa增殖的作用,并对HeLa细胞及宫颈癌组织、癌前病变组织中的APRIL及其受体mRNA的表达情况以及APRIL蛋白在宫颈癌组织的表达情况进行研究,在此研究的基础上设计制备sAPRIL的两个突变体,观察突变体在体外对HeLa细胞增殖的影响以及对野生型sAPRIL的竞争抑制作用,从而为进一步了解APRIL在宫颈癌的发生、发展中的作用以及针对抑制APRIL的抗宫颈癌制剂的制备奠定基础。
为了了解APRIL在宫颈癌发病中的作用,本研究用RT-PCR及免疫组化检测了宫颈癌、癌前病变中APRIL mRNA及蛋白的表达水平,发现宫颈癌组织中APRIL的mRNA和蛋白的表达均显著高于癌前病变和正常组织。同时我们用RT-PCR检测了组织中APRIL受体mRNA的表达情况,发现与正常组织及癌前病变比较,癌组织中BCMA、TACI及粘蛋白多糖-4(S4)的表达水平无显著差异,而随着细胞异型性的加重,粘蛋白多糖-1(S1)表达逐渐下降,而粘蛋白多糖-2(S2)的水平逐渐增高。
之后我们用RT-PCR法检测了HeLa细胞中APRIL及其受体mRNA的表达情况,发现HeLa细胞表达APRIL、S1和S2,而不表达BCMA、TACI及S4。
为了进一步了解APRIL在宫颈癌发病中的作用,我们用BrdU-ELISA法检测了sAPRIL蛋白对人宫颈癌细胞株HeLa细胞增殖的作用,发现sAPRIL蛋白能以剂量依赖的方式促进HeLa细胞的增殖。
鉴于APRIL有促进宫颈癌细胞株HeLa细胞增殖的作用,抑制APRIL的功能活性,将可能为宫颈癌的治疗提供新途径。研究表明APRIL抗体和APRIL的可溶性受体能够在一定程度上抑制APRIL的功能,但是人源性抗体获得困难,而APRIL的受体多,一种可溶性受体并不能起到抑制APRIL与其他受体结合而起作用的功能。因此本课题拟从改建APRIL分子本身入手,构建能够与受体结合但不能引发受体后促瘤效应的APRIL突变体,以期获得APRIL的抑制剂,达到治疗肿瘤的目的。
本课题借鉴改建BLyS(B-lymphocyte stimulator,B淋巴细胞刺激因子)分子的方法,在与BlyS进行同源序列比对以及对APRIL分子进行结构分析后,选择APRIL第186、187位氨基酸作为突变位点,以pUC19/sAPRIL为模板,用一步反向PCR致突变法构建了人msAPRIL-1(186G187Q置换为186K187G)及msAPRIL-2(186G被K置换,187Q缺失)两个突变体DNA序列;将上述测序正确的突变型目的片段连接于原核表达载体pQE-80L,成功构建了重组原核表达质粒pQE-80L/msAPRIL-1和pQE-80L/msAPRIL-2;将重组原核表达质粒分别转化于大肠杆菌DH5α,经IPTG诱导,获得了较高水平的表达,SDS-PAGE分析可见,两重组蛋白的大小约为19kDa,主要是以包涵体的形式存在,Western blotting分析显示,两蛋白均在分子量约19kDa处出现单一条带;经Ni~(2+)-NTA纯化系统及尿素透析,两重组蛋白得到了有效纯化和复性。纯化蛋白在SDS-PAGE上呈现单一条带。经Sephadex G-75凝胶过滤层析得到两重组突变体蛋白三聚体分子。生物学功能分析显示,所制备的msAPRIL-1突变体蛋白能很好地与HeLa细胞结合,而msAPRIL-2与HeLa细胞只有微弱的结合;同时两突变体均不能促细胞增殖。进一步分析显示msAPRIL-1可以抑制野生型sAPRIL对HeLa细胞的促增殖作用。
本研究主要结果总结如下:
一、APRIL及其受体在宫颈鳞癌组织和细胞株中的表达
1.APRIL在宫颈鳞癌组织无论在mRNA还是在蛋白水平的表达均显著高于正常鳞状上皮和鳞状上皮内病变,随着细胞的增殖与异型性的加重表达水平逐渐增高;S1mRNA随着宫颈鳞状上皮细胞的增殖和异型性的加重表达逐渐下调,而S2 mRNA表达逐渐增高;BCMA、TACI及S4 mRNA在正常组织、炎症、癌前病变、原位癌及浸润癌中的表达无显著差异;
2.宫颈癌HeLa细胞有APRIL、S1及S2 mRNA的表达,而不表达BCMA、TACI及S4的mRNA;
二、sAPRIL在体外以剂量依赖方式促进人宫颈癌细胞株HeLa细胞的增殖。
通过以上两方面的结果,可初步得出如下结论:APRIL及其受体在宫颈癌的发展中可能起一定的作用,其中APRIL在宫颈癌中的作用可能是通过与S1和/或S2结合而发挥的;而S1 mRNA的降低和/或S2 mRNA及APRIL的表达升高可能可以作为病情进展的预警指标。
三、成功制备了sAPRIL的两个突变体
1.以APRIL第186、187位氨基酸作为突变位点,用一步反向PCR致突变法成功构建了人msAPRIL-1 DNA(186G187Q置换为186K187G)及msAPRIL-2 DNA(186G被K置换,187Q缺失)两个突变体序列。
2.将突变目的DNA片段连接于原核表达载体pQE-80L,成功构建了重组原核表达质粒pQE-80L/msAPRIL-1和pQE-80L/msAPRIL-2。
3.将重组原核表达质粒分别转化大肠杆菌DH5α,经IPTG诱导,使重组突变体蛋白获得了成功表达。
4.经Ni~(2+)-NTA纯化系统及尿素透析,两重组蛋白得到了有效纯化和复性;经Sephadex G-75凝胶过滤层析得到了两重组突变体蛋白三聚体分子。
四、突变体的功能分析
1.所制备的msAPRIL-1突变体可特异地与HeLa细胞结合,而msAPRIL-2与HeLa细胞的结合能力很弱。
2.msAPRIL-1和msAPRIL-2均丧失了促HeLa细胞增殖的功能。
3.msAPRIL-1突变体能在一定程度上竞争抑制野生型sAPRIL促HeLa细胞增殖的功能,而msAPRIL-2的作用则不明显。
以上三、四两部分的结果提示,msAPRIL-1及其衍生分子可能在宫颈癌等APRIL相关肿瘤的治疗中具有潜在应用前景。
APRIL(a proliferation-inducing ligand) is a new member of the tumor necrosis factor (TNF) family,which exists in two forms,cytomembrane APRIL and soluble APRIL(sAPRIL).It is expressed in small amounts in normal tissues but produced abundantly in many kinds of malignant tumors,such as colorectal carcinoma,breast cancer, lung cancer,malignancy of hematological system,bladder cancer and melanoma.APRIL and sAPRIL can not only promote growth of many malignant tumors in vivo and in vitro, but also prolong the life-span of the tumors.As a ligand,APRIL plays its roles by binding to its receptors,BCMA(B cell maturation antigen) and TACI(transmembrane activator and calcium signal-modulating cyclophilin ligand interactor).Besides the above two receptors, recent studies indicate that proteoglycan syndecans(S) may also be the receptors of APRIL.
Although it is affirmed that APRIL is highly expessed in a lot of malignant tumors and can promote growth of the tumors,there is few reprorts about its roles on cervix carcinoma. So in this study we want to primarily figure out the relationship between APRIL and cervix carcinoma.Firstly,mRNA expression profiles of APRIL and its receptors were analyzed by semi-quantitive RT-PCR in HeLa cells and cervix carcinoma tissues,taking the tissues from nomal cervix,chronic cervicitis and cervix introepithelium neoplasia as controls.APRIL protein expression profiles were detected by immunohistochemistry in cervix carcinoma tissues and the controls.Secondly,The proliferation-stimulating effect of sAPRIL to HeLa cells was detected by BrdU-ELISA assay.Thirdly,taking 186G and 187Q of human sAPRIL as mutation sites,one-step opposite orientation PCR was used to construct the two mutant sAPRIL(msAPRIL) DNAs,namely msAPRIL-1 DNA(in which 186G187Q replaced by 186K187G) and msAPRIL-2 DNA(in which 186G replaced by K and 187Q deleted). After inserting the two msAPRIL DNAs into pQE-80L vector respectively,the recombinant msAPRIL proteins were expressed in E.coli DH5αand purified by Ni~(2+)-NTA chromatography and the homotrimers of msAPRILs were isolated by Sephadex G-75. Finally,the binding profiles of the two homotrimers of msAPRILs to HeLa cells were analyzed by indirect immunofluorescence assay.The stimulating function of the two msAPRIL homotrimers(alone or with wild type sAPRIL) to HeLa cells were detected by BrdU-ELISA assay.The major results and conclusions are summarized as follows:
1.With the development of the proliferation and heteromorphism of cervix squamous cells,the mRNA expression of APRIL and S2 were increased gradually,whereas the expression of S1 mRNA was decreased,and the mRNA level of S4,BCMA and TACI had no difference among the tissues from cervix carcinoma,nomal cervix,chronic cervicitis and cervix introepithelium neoplasia.
2.The mRNAs of APRIL and S1 and S2,but not S4,BCMA and TACI,were expressed in HeLa cells.
3.With the development of the proliferation and heteromorphism of squamous cells, the expression of APRIL protein was up-regulated in cervix.
4.sAPRIL could dose-dependent promote the growth of HeLa cells in vitro.
Based on the above results,it might be concluded that there was a positive correlation between APRIL and cervix carcinoma.
5.The two recombinant msAPRIL proteins(msAPRIL-1 and msAPRIL-2) were successfully expressed in E.coli DH5αand purified effectively by Ni~(2+)-NTA chromatography,and the functional homotrimers of msAPRILs were isolated by Sephadex G-75.
6.The prepared msAPRIL-1 homotrimer,not msAPRIL-2 homotrimer,could strongly bind to HeLa cells.Both of the two msAPRIL proteins lost the function of stimulating growth of HeLa cells,and msAPRIL-1 could inhibit the stimulating activity of wild type sAPRIL to HeLa cells,which indicated that msAPRIL-1 and its derivates might have a therapeutic potential in treatment of APRIL-associated cervix carcinoma and other tumors.
引文
1. Hahne M, Kataoka T, Schroter M, et al. APRIL,a new ligand of the tumor necrosis factor family,stimulates tumor cell growth. J Exp Med. 1998, 188(6): 1185-1190.
2. Kelly k, mManos E, Jensen G, et al. APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell growth. Cancer Res. 2000,60(4): 1021-1027
3. Roth W, Wagenknecht B, Klumpp A, et aL. APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis. Cell Death Differ. 2001, 8(4): 403-410.
4. Phillips TA, Ni J, Hunt JS. Cell-specific expression of B lymphocyte (APRIL, BLyS)-and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas. J Leukoc Biol. 2003, 74(1): 81-87.
5. Lopez-Fraga M, Fernandez R, Albar JP, et al. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase. EMBO Rep. 2001, 2(10):945-951.
6. Deshayes F, Lapree G, Portier A, et al. Abnormal production of the TNF-homologue APRIL increases the proliferation of human malignant glioblastoma cell lines via a specific receptor. Oncogene. 2004 , 23(17): 3005-3012.
7. Medema JP, Planelles-Carazo L, Hardenberg G, et al. The uncertain glory of APRIL. Cell Death Differ. 2003, 10(10): 1121-1125.
8. Hzecka J, Ilzecki M. APRIL is increased in serum of patients with brain glioblastoma multiforme. Eur Cytokine Netw. 2006, 17(4):276-280.
9. Castillo-Gutierrez S, Medema JP, Morales-Luque A, et a.l. APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival Haematologica. 2007,92(9): 1284-1285.
10. Mhawech-Fauceglia P, Kaya G, Sauter G, et al. The source of APRIL up-regulation in human solid tumor lesions. J Leukoc Biol. 2006, 80(4):697-704.
11. Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007,109(2):703-710.
12. Xia XZ, Treanor J, Senaldi G, et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med. 2000, 192(1):137-143.
13. Shu HB, Johnson H. TALL-1 is a novel member of the TNF family that is down regulated by mitogens. Proc Natl Acad Sci USA. 2000, 97(16):9156-9161.
14. Wu Y, Bressette D, Carrell JA, et al. Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS. J Biol hem. 2000, 275(45): 35478-35485.
15. Bossen C, Cachero TG, Tardivel A, et al. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood. 2007 Oct 17; [Epub ahead of print]
16. Chiu A, Xu W, He B, et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL.Blood. 2007, 109(2):729-739.
17. Bossen C, Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. Semin Immunol. 2006, 18(5):263-275.
18. Schwaller J, Schneider P, Mhawech-Fauceglia P, et al. Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness. Blood. 2007, 109(1):331-338.
19. Hendriks J, Planelles L, de Jong-Odding J, et al. Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation. Cell Death Differ. 2005,12(6):637-648.
20. Ingold K, Zumsteg A, Tardivel A,et al. Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med. 2005 ,201(9): 1375-1383.
21. Oguri K, Okayama M. Can syndecan-1 become a prognostic factor in solid tumors ?J Gastroenterol. 2004 , 39(1): 197-199.
22. Mikami S , Ohashi K, Usui Y, et al . Loss of syndecan-1 andincreased expression of heparanase in invasive esophagealcarcinomas. Jpn J Cancer Res. 2001 , 92(10) : 1062-1073.
23. Liu y, Zhu X, Zhu,Y, et al. Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.Oncol Rep.2007,18(4):943-951.
24.Ling YL,Lei YT,Hong CG,et al.Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway.J Cell Biol.2007,177(5):829-841.
25.Rennert P,Schneider P,Cachero TG,et al.A soluble form of B cell maturation antigen,a receptor for the tumor necrosis factor family member APRIL,inhibits tumor cell growth.J Exp Med.2000,192(11):1677-1684
26.Nishio M,Endo T,Tsukada N,et al.Nurselike cells express BAFF and APRIL,which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-lalpha.Blood.2005,106(3):1012-1020
27.戴双双,何凤田,杨朝辉,等.人可溶性APRIL基因的克隆、表达及生物学活性检测.中国生物学与分子生物学学报.2005,21(1):61-64.
28.Dillon SR,Gross JA,Ansell SM,et al.An APRIL to remember:novel TNF ligands as therapeutic targets.Nat Rev Drug Discov.2006,5(3):235-246.
29.Schneider P,Takatsuka H,Wilson A,et al.Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen.J Exp Med.2001,194(11):1691-1697.
30.Patel DR,Wallweber HJ,Yin J,et al.Engineering an APRIL-specific B cell maturation antigen.J Biol Chem.2004,279(16):16727-16735.
31.Hymowitz SG,Patel DR,Wallweber HJ,et al.Structures of APRIL-receptor complexes:like BCMA,TACI employs only a single cysteine-rich domain for high affinity ligand binding.J Biol Chem.2005,280(8):7218-7227.
32.Liu Y,Xu L,Opalka N,et al.Crystal structure of sBAFF reveals a virus-like assembly of TNF family ligands.Cell.2002,108(3):383-394.
33.Mackay F,Tangye SG..The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers.Cur Opin Pharm.2004,4(4):347-354.
34.Wallweber HJ,Compaan DM,Starovasnik MA,et al.The crystal structure of a proliferation-inducing ligand,APRIL.J Mol Biol.2004,343(2):283-290.
35.Torres LA,Rojo HG,Torrea RA,et al.Cervical cancer:Currentview of it s epidemiology and drisk factors.Gynecol Obstet Mex.2004,72(3):466-474
36.Moreaux J,Legouffe E,Jourdan E,et al.BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood, 2004, 103(8):3148-3157.
37. Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007 ,109(2):703-710.
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2. Kelly k, Manos E, Jensen G, et al. APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell growth.. Cancer Res. 2000,60(4): 1021-1027.
3. Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007,109(2):703-710.
4. Medema JP, Planelles-Carazo L, Hardenberg G, et al. The uncertain glory of APRIL. Cell Death Differ. 2003,10(10): 1121-1125.
5. Roth W, Wagenknecht B, Klumpp A, et al. APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis. Cell Death Differ. 2001, 8(4):403-410.
6. Castillo-Gutierrez S, Medema JP, Morales-Luque A, et al. APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival Haematologica. 2007,92(9): 1284-1285.
7. Phillips TA, Ni J, Hunt JS. Cell-specific expression of B lymphocyte (APRIL, BLyS)-and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas. J Leukoc Biol. 2003,74(1):81-87.
8. Ilzecka J, Ilzecki M. APRIL is increased in serum of patients with brain glioblastoma multiforme. Eur Cytokine Netw. 2006,17(4):276-280.
9. Mhawech-Fauceglia P, Kaya G, Sauter G, et al. The source of APRIL up-regulation in human solid tumor lesions. J Leukoc Biol. 2006,80(4):697-704.
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2. Kelly k, mManos E, Jensen G, et al. APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell growth. Cancer Res. 2000,60(4): 1021-1027
3. Roth W, Wagenknecht B, Klumpp A, et aL. APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis. Cell Death Differ. 2001, 8(4): 403-410.
4. Phillips TA, Ni J, Hunt JS. Cell-specific expression of B lymphocyte (APRIL, BLyS)-and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas. J Leukoc Biol. 2003, 74(1): 81-87.
5. Lopez-Fraga M, Fernandez R, Albar JP, et al. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase. EMBO Rep. 2001, 2(10):945-951.
6. Deshayes F, Lapree G, Portier A, et al. Abnormal production of the TNF-homologue APRIL increases the proliferation of human malignant glioblastoma cell lines via a specific receptor. Oncogene. 2004 , 23(17): 3005-3012.
7. Medema JP, Planelles-Carazo L, Hardenberg G, et al. The uncertain glory of APRIL. Cell Death Differ. 2003, 10(10): 1121-1125.
8. Hzecka J, Ilzecki M. APRIL is increased in serum of patients with brain glioblastoma multiforme. Eur Cytokine Netw. 2006, 17(4):276-280.
9. Castillo-Gutierrez S, Medema JP, Morales-Luque A, et a.l. APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival Haematologica. 2007,92(9): 1284-1285.
10. Mhawech-Fauceglia P, Kaya G, Sauter G, et al. The source of APRIL up-regulation in human solid tumor lesions. J Leukoc Biol. 2006, 80(4):697-704.
11. Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007,109(2):703-710.
12. Xia XZ, Treanor J, Senaldi G, et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med. 2000, 192(1):137-143.
13. Shu HB, Johnson H. TALL-1 is a novel member of the TNF family that is down regulated by mitogens. Proc Natl Acad Sci USA. 2000, 97(16):9156-9161.
14. Wu Y, Bressette D, Carrell JA, et al. Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS. J Biol hem. 2000, 275(45): 35478-35485.
15. Bossen C, Cachero TG, Tardivel A, et al. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood. 2007 Oct 17; [Epub ahead of print]
16. Chiu A, Xu W, He B, et al. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL.Blood. 2007, 109(2):729-739.
17. Bossen C, Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. Semin Immunol. 2006, 18(5):263-275.
18. Schwaller J, Schneider P, Mhawech-Fauceglia P, et al. Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness. Blood. 2007, 109(1):331-338.
19. Hendriks J, Planelles L, de Jong-Odding J, et al. Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation. Cell Death Differ. 2005,12(6):637-648.
20. Ingold K, Zumsteg A, Tardivel A,et al. Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med. 2005 ,201(9): 1375-1383.
21. Oguri K, Okayama M. Can syndecan-1 become a prognostic factor in solid tumors ?J Gastroenterol. 2004 , 39(1): 197-199.
22. Mikami S , Ohashi K, Usui Y, et al . Loss of syndecan-1 andincreased expression of heparanase in invasive esophagealcarcinomas. Jpn J Cancer Res. 2001 , 92(10) : 1062-1073.
23. Liu y, Zhu X, Zhu,Y, et al. Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.Oncol Rep.2007,18(4):943-951.
24.Ling YL,Lei YT,Hong CG,et al.Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway.J Cell Biol.2007,177(5):829-841.
25.Rennert P,Schneider P,Cachero TG,et al.A soluble form of B cell maturation antigen,a receptor for the tumor necrosis factor family member APRIL,inhibits tumor cell growth.J Exp Med.2000,192(11):1677-1684
26.Nishio M,Endo T,Tsukada N,et al.Nurselike cells express BAFF and APRIL,which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-lalpha.Blood.2005,106(3):1012-1020
27.戴双双,何凤田,杨朝辉,等.人可溶性APRIL基因的克隆、表达及生物学活性检测.中国生物学与分子生物学学报.2005,21(1):61-64.
28.Dillon SR,Gross JA,Ansell SM,et al.An APRIL to remember:novel TNF ligands as therapeutic targets.Nat Rev Drug Discov.2006,5(3):235-246.
29.Schneider P,Takatsuka H,Wilson A,et al.Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen.J Exp Med.2001,194(11):1691-1697.
30.Patel DR,Wallweber HJ,Yin J,et al.Engineering an APRIL-specific B cell maturation antigen.J Biol Chem.2004,279(16):16727-16735.
31.Hymowitz SG,Patel DR,Wallweber HJ,et al.Structures of APRIL-receptor complexes:like BCMA,TACI employs only a single cysteine-rich domain for high affinity ligand binding.J Biol Chem.2005,280(8):7218-7227.
32.Liu Y,Xu L,Opalka N,et al.Crystal structure of sBAFF reveals a virus-like assembly of TNF family ligands.Cell.2002,108(3):383-394.
33.Mackay F,Tangye SG..The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers.Cur Opin Pharm.2004,4(4):347-354.
34.Wallweber HJ,Compaan DM,Starovasnik MA,et al.The crystal structure of a proliferation-inducing ligand,APRIL.J Mol Biol.2004,343(2):283-290.
35.Torres LA,Rojo HG,Torrea RA,et al.Cervical cancer:Currentview of it s epidemiology and drisk factors.Gynecol Obstet Mex.2004,72(3):466-474
36.Moreaux J,Legouffe E,Jourdan E,et al.BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood, 2004, 103(8):3148-3157.
37. Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007 ,109(2):703-710.
1. Hahne M, Kataoka T, Schroter M, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth.. J Exp Med. 1998, 188(6): 1185-1190.
2. Kelly k, Manos E, Jensen G, et al. APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell growth.. Cancer Res. 2000,60(4): 1021-1027.
3. Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway. Blood. 2007,109(2):703-710.
4. Medema JP, Planelles-Carazo L, Hardenberg G, et al. The uncertain glory of APRIL. Cell Death Differ. 2003,10(10): 1121-1125.
5. Roth W, Wagenknecht B, Klumpp A, et al. APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis. Cell Death Differ. 2001, 8(4):403-410.
6. Castillo-Gutierrez S, Medema JP, Morales-Luque A, et al. APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival Haematologica. 2007,92(9): 1284-1285.
7. Phillips TA, Ni J, Hunt JS. Cell-specific expression of B lymphocyte (APRIL, BLyS)-and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas. J Leukoc Biol. 2003,74(1):81-87.
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