Annexin Ⅱ在多发性骨髓瘤及其他血液肿瘤中的表达及机制研究
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摘要
Annexins蛋白是一类受Ca2+调节、能够与带负电荷的膜磷脂结合的蛋白家族,在许多原核和真核细胞中广泛表达。AnnexinⅡ(AnxA2,A2)作为Annexin家族的重要成员,于1979年被Rade和Martin首先发现。AnxA2多表达于内皮细胞、单核巨噬细胞、神经细胞和某些肿瘤细胞,在细胞膜、细胞质、细胞核和胞外均有表达。AnxA2蛋白在细胞内以单体和异四聚体两种形式存在。AnxA2单体由保守的C端和可变的N端组成,可与蛋白质配体P11蛋白(又名S100A10)形成异四聚体,执行其与生物膜结构相关的一系列功能。
AnxA2蛋白参与了众多生物学活动,在细胞膜构架的形成,膜聚合、内吞和胞吐,纤溶系统的稳定等生理活动中均扮演重要角色。AnxA2还参与某些病理过程,与心血管疾病、血液病、感染、肿瘤等多种疾病相关。无论在胞内还是胞外, AnxA2都具有广泛的功能,对其的研究也受到越来越多的关注。
一、AnxA2单抗的制备及功能研究
研究表明AnxA2的胞外区是t-PA和plasminagen的共受体,在纤溶活性的诱导过程中起重要作用,并是多种病毒、炎症介质的受体,在病毒感染,炎症活动中起一定作用,因此,制备针对AnxA2的胞外区的单克隆抗体对研究AnxA2在各种生理病理状态下的功能具有重要意义。
利用本科室已经建立起来的杂交瘤技术,将重组AnxA2蛋白经次氮基三乙酸镍琼脂糖(Ni-NTAagarose)柱纯化浓缩后免疫Balb/c小鼠,尾静脉加强后取脾细胞融合,ELISA法筛选阳性克隆,制备腹水。运用Western blot对抗体进行鉴定观察抗体与原核重组蛋白反应情况。结果可以看出:小鼠脾细胞与杂交瘤细胞融合后筛选获得两株持续分泌单克隆抗体的细胞株,命名为SZ-135,SZ-136。该株杂交瘤细胞单克隆后接种小鼠腹腔产生腹水,腹水经蛋白G-Sephrose4B亲和层析柱纯化。SZ-135,SZ-136单抗能特异性识别相对分子量为36kD的重组蛋白。同时SZ-135可以有效抑制HMEC-1体外的血管形成。
二、AnxA2在多发性骨髓瘤及各类血液病中的异常表达及机制研究
1. AnxA2在多发性骨髓瘤及各类血液病中的异常表达
AnxA2表达异常与人类许多疾病的发生发展相关,在多种类型的肿瘤中都可观察到AnxA2的表达异常。国外近年的研究表明,AnxA2在APL细胞膜表面的高表达与其原发性纤溶亢进有关,但在MM及其它类型的血液病中的表达却少有报道。
在我们的实验中,通过应用流式细胞仪检测了6例骨髓瘤病人和6例正常人浆细胞表面AnxA2表达,明确了骨髓瘤病人浆细胞表面AnxA2表达明显高于正常人。通过real-time PCR、Western blot、流式细胞仪检测U266和NB4、RPMI8226、XG7、Jurkat、Raji、U937、K562共8类血液病细胞株AnxA2表达,明确了骨髓瘤细胞株U266在mRNA、总蛋白、膜表面蛋白不同水平均较其它血液病细胞株高表达AnxA2。骨髓瘤细胞株RPMI8226在总蛋白水平亦高表达AnxA2。
2. AnxA2基因对骨髓瘤U266、RPMI8226细胞增殖、凋亡、侵袭力及细胞因子的影响
为了了解AnxA2基因对骨髓瘤U266、RPMI8226细胞增殖、凋亡、侵袭力及细胞因子的影响,我们应用RNAi技术进行研究。首先,采用siRNA转染人骨髓瘤U266、RPMI8226细胞,应用real-time PCR、Western blot和流式细胞术鉴定干扰效果。继而应用MTT法检测siRNA对细胞增殖的作用,应用Annexin V-FITC/PI双染流式细胞术检测其对细胞凋亡的影响,应用Transwell板检测细胞侵袭力,应用real-time PCR检测对血管新生、凋亡、侵袭等相关基因的影响。结果表明,AnxA2siRNA转染U266和RPMI8226细胞均对细胞增殖起抑制作用(P<0.05),并可诱导细胞凋亡增加(P<0.05),明显降低细胞侵袭力(P<0.05),同时降低血管新生相关因子VEGF-C、VEGF-R2,侵袭相关因子MMP-2、MMP-9、MT1-MMP和TIMP-2的表达。由此我们认为:siRNA沉默AnxA2基因可抑制U266和RPMI8226细胞增殖、侵袭,诱导凋亡增加,降低血管新生、侵袭相关因子的表达。
三、各类药物对血液病细胞株AnxA2表达的影响
1.AnxA2与沙利度胺、地塞米松诱导骨髓瘤病人血栓形成的相关性为了了解沙利度胺(thalidomide)、地塞米松(Dexamethasone,DXM)在体外对人多发性骨髓瘤(Multiple myeloma MM)细胞株RPMI8226、人微血管内皮细胞株HMEC-1、人静脉内皮细胞株EAHY926中AnxA2基因表达的调节作用,探讨AnxA2基因与沙利度胺、地塞米松诱发骨髓瘤病人血栓形成的相关性。我们在体外培养上述细胞,real time PCR检测在不同浓度下沙利度胺及地塞米松对三种细胞株AnxA2基因表达的影响,流式细胞仪、激光共聚焦检测对三种细胞株膜表面AnxA2蛋白表达的影响,细胞促纤溶活性实验检测对三种细胞株膜表面纤溶酶活性的影响。结果表明,12.5μg/ml、25μg/ml、50μg/ml沙利度胺,2.5μg/ml地塞米松,25μg/ml沙利度胺加2.5μg/ml地塞米松均能诱导RPMI8226、HMEC-1、Eahy926细胞株AnxA2mRNA和蛋白表达下降(P<0.05)。AnxA2抗体、12.5μg/ml、25μg/ml、50μg/ml沙利度胺,2.5μg/ml地塞米松,25μg/ml沙利度胺加2.5μg/ml地塞米松均能诱导RPMI8226、HMEC-1、Eahy926细胞株纤溶活性下降(P<0.05),差异有统计学意义。故我们认为,沙利度胺和地塞米松能抑制RPMI8226、HMEC-1、Eahy926细胞株AnxA2mRNA和蛋白表达。由于AnxA2为t-PA和PLA的共受体,具促纤溶作用,沙利度胺和地塞米松通过下调AnxA2,抗纤溶,可能为其诱发MM血栓形成的原因之一。
2.AS2O3通过下调AnxA2抑制NB4细胞侵袭力
为了研究三氧化二砷(Arsenic trioxide ,AS2O3)是否可通过下调AnxA2抑制人急性早幼粒白血病细胞(NB4)侵袭力的作用。我们在体外培养NB4细胞,并通过流式细胞仪检测不同浓度AS2O3对NB4细胞膜表面AnxA2蛋白表达的影响,Transwell板检测AnxA2抗体和AS2O3对NB4细胞侵袭力的影响。结果表明AS2O3在0.31μg/ml,0.63μg/ml,1.25μg/ml浓度均能诱导NB4细胞膜表面AnxA2蛋白水平表达下降(P<0.05),存在剂量依赖性;AnxA2抗体在0.01μg/ml,0.02μg/ml,0.04μg/ml浓度和AS2O3在0.31μg/ml,0.63μg/ml,1.25μg/ml浓度均抑制NB4细胞侵袭力下降(P<0.05),并有量效关系。因此我们认为AnxA2抗体可抑制NB4细胞侵袭力,AS2O3可通过下调AnxA2蛋白膜表面表达,抑制NB4细胞侵袭力。
Studies on the expression and function of annexinⅡin multiple myeloma and other neoplastic hematologic disorders
Annexins are Ca2+ and phospholipid binding proteins forming an evolutionary conserved multigene family with members of the family being expressed throughout animal and plant kingdoms. AnnexinⅡ(AnxA2) belongs to the family of annexins, which was discovered by Rade and Martin in 1979. It distributes in endothelial cells, mononuclear macrophages, nerve cells and some tumor cells. It exists as either a membrane-associated, cytosolic or soluble form in serum. AnxA2 presences inside cells in the two forms of monomer and tetramer. The monomer molecular structures include the conserved core and a second principal domain, which NH2-terminally precedes the core, is unique for a given member of the family and most likely specifies individual annexin properties in vivo. The monomer can form the tetramer with the protein of P11(S100A10), and carry out a series of function.
AnxA2 can act as a membrane scaffold protein, and is involved in membrane organization, membrane fusion, endocytosis and exocytosis. It also partakes in some pathological processes and is associated with cardiovascular diseases, leukemia, infection and cancer, etc. Wherever inside or outside cells, AnxA2 has extensive function.The research about it has got more and more attention.
Preparation and function study of monoclonal antibody against AnxA2 By using our established method, the recombined protein was purified by Ni-NTA agarose column and Balb/c mice were immunized. After the spleen cells of the mice and SP2/0 hybridoma cells were hybridized, positive clones was screened by ELISA assay and the selected hybridoma cells were used to prepare ascites. Western blot was used to detect whether the prepared anti-AnxA2 antibody can bind AnxA2 protein. The results show that: After the spleen cells and hybridoma cells SP2/0 were hybridized, we got two strain of cell that can last secreting anti-AnxA2 antibody named SZ-135, SZ136. The selected hybridoma cells was used to prepare ascites, the titers of anti-AnxA2 antibody in ascites was detected by indirect ELISA. The concentrations of purified anti-AnxA2 antibody were purified by proteinG-Sephrose4B affinity chromatography column. The antibodies could identify 36kD recombinated protein of AnxA2 and the antibody of SZ-135 can inhibite HMEC-1 angiogenesis in vitro effectively.
The expression and significient of AnxA2 in multiple myeloma
The abnormal expression of AnxA2(A2) has been associated with the development of many tumors, however, it’s expression and function in multiple myeloma(MM) patients and cell lines is less known. We compared the expression of AnxA2 in myeloma cells from MM patients with that in plasma cells from normal person and found that myeloma cells from patients had high expression of AnxA2.At the same time,we compared the expression of AnxA2 in MM cell lines U266 and RPMI8226 with other hematologic tumor cell lines and found that the myeloma cell lines U266 and RPMI8226 had also high expression of AnxA2. By transfecting U266 and RPMI8226 cells with the small interfering RNA(siRNA) that targets human AnxA2, AnxA2 expression was significantly downregulated. This resulted in the decreased proliferation, invasive potential, and increased apoptosis of U266 and RPMI8226 cell lines. Silencing AnxA2 gene by siRNA can also inhibit the expression of pro-angiogenic molecules including VEGF-C, VEGF-R2, MMP-2, MMP-9, MT1-MMP and TIMP-2 in the two cell lines. Our data suggested that the AnxA2 has high expression in MM patients and myeloma cell lines U266 and RPMI8226. The AnxA2 played a critical role in the proliferation, apoptosis and invasive potential of MM cell lines U266 and RPMI8226.
The Relationship of AnxA2 and The Thrombosis Induced by Thalidomide and Dexamethasone in Multiple Myeloma
My major is to investigate the effect of thalidomide and Dexamethasone(DXM) on gene of AnxA2(A2) of RPMI8226,HMEC-1 and EAhy926 cell lines in vitro, and compare the change of AnxA2 with thrombosis induced by thalidomide and DXM in multiple myeloma. We cultivated RPMI8226, HMEC-1 and EAhy926 cell lines in vitro. Real time quantitative PCR (RQ-PCR) was used to detect the influence of thalidomide and DXM on the expression of mRNA of AnxA2, Flow Cytometry(FCM) and Confocal microscope were used to detect the protein expression on the cells surface after the samples were stimulated with thalidomide and DXM. Substrate chromatography was used to measure the plasminogen activation. The results showed that the mRNA and protein level of AnxA2 in RPMI8226, HMEC-1 and EAhy926 cells line treated by thalidomide in the different concentration of 12.5μg/ml, 25μg/ml, 50μg/ml and DXM was decreased compared with the unblocked (P<0.05). The plasminogen activation can also be decreased by AnxA2 antibody,thalidomide and DXM. Our conclusions was that thalidomide and DXM can inhibite the expression of AnxA2 in RPMI8226, HMEC-1 and EAhy926 cell line,then inhibite the plasminogen activation.It’s possibly one of the reason of thrombosis production induced by thalidomide and DXM in multiple myeloma.
Arsenic trioxide inhibits invasive potential of NB4 cells through down regulation of AnxA2
My objective is to investigate the effect of arsenic trioxide (As2O3) on inhibiting invasive potential of NB4 through down regulation of AnxA2(A2). We cultured NB4 cells in vitro. Flow Cytometry (FCM) was used to detect the protein level on the cells surface after the samples were incubated with As2O3 in different concentrations.The influence of anti-AnxA2 antibody and As2O3 on the invasive potential of NB4 cells was investigated by using transwell plates. The results showed that the protein level of AnxA2 in NB4 cells treated by As2O3 in the different concentrations of 0.31, 0.63, and 1.25μg/ml was decreased compared with the unblocked (P<0.05). the invasive potential of NB4 cells treated with anti-AnxA2 antibody in the different concentrations of 0.01, 0.02, and 0.04μg/ml as well as As2O3 in the different concentrations of 0.31, 0.63, and 1.25μg/ml was decreased compared with the blank (P<0.05). Our data suggested that the down regulation of AnxA2 can inhibit invasive potential of NB4, As2O3 can inhibit invasive potential of NB4 cells through down regulation of AnxA2.
AnxA2蛋白参与了众多生物学活动,在细胞膜构架的形成,膜聚合、内吞和胞吐,纤溶系统的稳定等生理活动中均扮演重要角色。AnxA2还参与某些病理过程,与心血管疾病、血液病、感染、肿瘤等多种疾病相关。无论在胞内还是胞外, AnxA2都具有广泛的功能,对其的研究也受到越来越多的关注。
一、AnxA2单抗的制备及功能研究
研究表明AnxA2的胞外区是t-PA和plasminagen的共受体,在纤溶活性的诱导过程中起重要作用,并是多种病毒、炎症介质的受体,在病毒感染,炎症活动中起一定作用,因此,制备针对AnxA2的胞外区的单克隆抗体对研究AnxA2在各种生理病理状态下的功能具有重要意义。
利用本科室已经建立起来的杂交瘤技术,将重组AnxA2蛋白经次氮基三乙酸镍琼脂糖(Ni-NTAagarose)柱纯化浓缩后免疫Balb/c小鼠,尾静脉加强后取脾细胞融合,ELISA法筛选阳性克隆,制备腹水。运用Western blot对抗体进行鉴定观察抗体与原核重组蛋白反应情况。结果可以看出:小鼠脾细胞与杂交瘤细胞融合后筛选获得两株持续分泌单克隆抗体的细胞株,命名为SZ-135,SZ-136。该株杂交瘤细胞单克隆后接种小鼠腹腔产生腹水,腹水经蛋白G-Sephrose4B亲和层析柱纯化。SZ-135,SZ-136单抗能特异性识别相对分子量为36kD的重组蛋白。同时SZ-135可以有效抑制HMEC-1体外的血管形成。
二、AnxA2在多发性骨髓瘤及各类血液病中的异常表达及机制研究
1. AnxA2在多发性骨髓瘤及各类血液病中的异常表达
AnxA2表达异常与人类许多疾病的发生发展相关,在多种类型的肿瘤中都可观察到AnxA2的表达异常。国外近年的研究表明,AnxA2在APL细胞膜表面的高表达与其原发性纤溶亢进有关,但在MM及其它类型的血液病中的表达却少有报道。
在我们的实验中,通过应用流式细胞仪检测了6例骨髓瘤病人和6例正常人浆细胞表面AnxA2表达,明确了骨髓瘤病人浆细胞表面AnxA2表达明显高于正常人。通过real-time PCR、Western blot、流式细胞仪检测U266和NB4、RPMI8226、XG7、Jurkat、Raji、U937、K562共8类血液病细胞株AnxA2表达,明确了骨髓瘤细胞株U266在mRNA、总蛋白、膜表面蛋白不同水平均较其它血液病细胞株高表达AnxA2。骨髓瘤细胞株RPMI8226在总蛋白水平亦高表达AnxA2。
2. AnxA2基因对骨髓瘤U266、RPMI8226细胞增殖、凋亡、侵袭力及细胞因子的影响
为了了解AnxA2基因对骨髓瘤U266、RPMI8226细胞增殖、凋亡、侵袭力及细胞因子的影响,我们应用RNAi技术进行研究。首先,采用siRNA转染人骨髓瘤U266、RPMI8226细胞,应用real-time PCR、Western blot和流式细胞术鉴定干扰效果。继而应用MTT法检测siRNA对细胞增殖的作用,应用Annexin V-FITC/PI双染流式细胞术检测其对细胞凋亡的影响,应用Transwell板检测细胞侵袭力,应用real-time PCR检测对血管新生、凋亡、侵袭等相关基因的影响。结果表明,AnxA2siRNA转染U266和RPMI8226细胞均对细胞增殖起抑制作用(P<0.05),并可诱导细胞凋亡增加(P<0.05),明显降低细胞侵袭力(P<0.05),同时降低血管新生相关因子VEGF-C、VEGF-R2,侵袭相关因子MMP-2、MMP-9、MT1-MMP和TIMP-2的表达。由此我们认为:siRNA沉默AnxA2基因可抑制U266和RPMI8226细胞增殖、侵袭,诱导凋亡增加,降低血管新生、侵袭相关因子的表达。
三、各类药物对血液病细胞株AnxA2表达的影响
1.AnxA2与沙利度胺、地塞米松诱导骨髓瘤病人血栓形成的相关性为了了解沙利度胺(thalidomide)、地塞米松(Dexamethasone,DXM)在体外对人多发性骨髓瘤(Multiple myeloma MM)细胞株RPMI8226、人微血管内皮细胞株HMEC-1、人静脉内皮细胞株EAHY926中AnxA2基因表达的调节作用,探讨AnxA2基因与沙利度胺、地塞米松诱发骨髓瘤病人血栓形成的相关性。我们在体外培养上述细胞,real time PCR检测在不同浓度下沙利度胺及地塞米松对三种细胞株AnxA2基因表达的影响,流式细胞仪、激光共聚焦检测对三种细胞株膜表面AnxA2蛋白表达的影响,细胞促纤溶活性实验检测对三种细胞株膜表面纤溶酶活性的影响。结果表明,12.5μg/ml、25μg/ml、50μg/ml沙利度胺,2.5μg/ml地塞米松,25μg/ml沙利度胺加2.5μg/ml地塞米松均能诱导RPMI8226、HMEC-1、Eahy926细胞株AnxA2mRNA和蛋白表达下降(P<0.05)。AnxA2抗体、12.5μg/ml、25μg/ml、50μg/ml沙利度胺,2.5μg/ml地塞米松,25μg/ml沙利度胺加2.5μg/ml地塞米松均能诱导RPMI8226、HMEC-1、Eahy926细胞株纤溶活性下降(P<0.05),差异有统计学意义。故我们认为,沙利度胺和地塞米松能抑制RPMI8226、HMEC-1、Eahy926细胞株AnxA2mRNA和蛋白表达。由于AnxA2为t-PA和PLA的共受体,具促纤溶作用,沙利度胺和地塞米松通过下调AnxA2,抗纤溶,可能为其诱发MM血栓形成的原因之一。
2.AS2O3通过下调AnxA2抑制NB4细胞侵袭力
为了研究三氧化二砷(Arsenic trioxide ,AS2O3)是否可通过下调AnxA2抑制人急性早幼粒白血病细胞(NB4)侵袭力的作用。我们在体外培养NB4细胞,并通过流式细胞仪检测不同浓度AS2O3对NB4细胞膜表面AnxA2蛋白表达的影响,Transwell板检测AnxA2抗体和AS2O3对NB4细胞侵袭力的影响。结果表明AS2O3在0.31μg/ml,0.63μg/ml,1.25μg/ml浓度均能诱导NB4细胞膜表面AnxA2蛋白水平表达下降(P<0.05),存在剂量依赖性;AnxA2抗体在0.01μg/ml,0.02μg/ml,0.04μg/ml浓度和AS2O3在0.31μg/ml,0.63μg/ml,1.25μg/ml浓度均抑制NB4细胞侵袭力下降(P<0.05),并有量效关系。因此我们认为AnxA2抗体可抑制NB4细胞侵袭力,AS2O3可通过下调AnxA2蛋白膜表面表达,抑制NB4细胞侵袭力。
Studies on the expression and function of annexinⅡin multiple myeloma and other neoplastic hematologic disorders
Annexins are Ca2+ and phospholipid binding proteins forming an evolutionary conserved multigene family with members of the family being expressed throughout animal and plant kingdoms. AnnexinⅡ(AnxA2) belongs to the family of annexins, which was discovered by Rade and Martin in 1979. It distributes in endothelial cells, mononuclear macrophages, nerve cells and some tumor cells. It exists as either a membrane-associated, cytosolic or soluble form in serum. AnxA2 presences inside cells in the two forms of monomer and tetramer. The monomer molecular structures include the conserved core and a second principal domain, which NH2-terminally precedes the core, is unique for a given member of the family and most likely specifies individual annexin properties in vivo. The monomer can form the tetramer with the protein of P11(S100A10), and carry out a series of function.
AnxA2 can act as a membrane scaffold protein, and is involved in membrane organization, membrane fusion, endocytosis and exocytosis. It also partakes in some pathological processes and is associated with cardiovascular diseases, leukemia, infection and cancer, etc. Wherever inside or outside cells, AnxA2 has extensive function.The research about it has got more and more attention.
Preparation and function study of monoclonal antibody against AnxA2 By using our established method, the recombined protein was purified by Ni-NTA agarose column and Balb/c mice were immunized. After the spleen cells of the mice and SP2/0 hybridoma cells were hybridized, positive clones was screened by ELISA assay and the selected hybridoma cells were used to prepare ascites. Western blot was used to detect whether the prepared anti-AnxA2 antibody can bind AnxA2 protein. The results show that: After the spleen cells and hybridoma cells SP2/0 were hybridized, we got two strain of cell that can last secreting anti-AnxA2 antibody named SZ-135, SZ136. The selected hybridoma cells was used to prepare ascites, the titers of anti-AnxA2 antibody in ascites was detected by indirect ELISA. The concentrations of purified anti-AnxA2 antibody were purified by proteinG-Sephrose4B affinity chromatography column. The antibodies could identify 36kD recombinated protein of AnxA2 and the antibody of SZ-135 can inhibite HMEC-1 angiogenesis in vitro effectively.
The expression and significient of AnxA2 in multiple myeloma
The abnormal expression of AnxA2(A2) has been associated with the development of many tumors, however, it’s expression and function in multiple myeloma(MM) patients and cell lines is less known. We compared the expression of AnxA2 in myeloma cells from MM patients with that in plasma cells from normal person and found that myeloma cells from patients had high expression of AnxA2.At the same time,we compared the expression of AnxA2 in MM cell lines U266 and RPMI8226 with other hematologic tumor cell lines and found that the myeloma cell lines U266 and RPMI8226 had also high expression of AnxA2. By transfecting U266 and RPMI8226 cells with the small interfering RNA(siRNA) that targets human AnxA2, AnxA2 expression was significantly downregulated. This resulted in the decreased proliferation, invasive potential, and increased apoptosis of U266 and RPMI8226 cell lines. Silencing AnxA2 gene by siRNA can also inhibit the expression of pro-angiogenic molecules including VEGF-C, VEGF-R2, MMP-2, MMP-9, MT1-MMP and TIMP-2 in the two cell lines. Our data suggested that the AnxA2 has high expression in MM patients and myeloma cell lines U266 and RPMI8226. The AnxA2 played a critical role in the proliferation, apoptosis and invasive potential of MM cell lines U266 and RPMI8226.
The Relationship of AnxA2 and The Thrombosis Induced by Thalidomide and Dexamethasone in Multiple Myeloma
My major is to investigate the effect of thalidomide and Dexamethasone(DXM) on gene of AnxA2(A2) of RPMI8226,HMEC-1 and EAhy926 cell lines in vitro, and compare the change of AnxA2 with thrombosis induced by thalidomide and DXM in multiple myeloma. We cultivated RPMI8226, HMEC-1 and EAhy926 cell lines in vitro. Real time quantitative PCR (RQ-PCR) was used to detect the influence of thalidomide and DXM on the expression of mRNA of AnxA2, Flow Cytometry(FCM) and Confocal microscope were used to detect the protein expression on the cells surface after the samples were stimulated with thalidomide and DXM. Substrate chromatography was used to measure the plasminogen activation. The results showed that the mRNA and protein level of AnxA2 in RPMI8226, HMEC-1 and EAhy926 cells line treated by thalidomide in the different concentration of 12.5μg/ml, 25μg/ml, 50μg/ml and DXM was decreased compared with the unblocked (P<0.05). The plasminogen activation can also be decreased by AnxA2 antibody,thalidomide and DXM. Our conclusions was that thalidomide and DXM can inhibite the expression of AnxA2 in RPMI8226, HMEC-1 and EAhy926 cell line,then inhibite the plasminogen activation.It’s possibly one of the reason of thrombosis production induced by thalidomide and DXM in multiple myeloma.
Arsenic trioxide inhibits invasive potential of NB4 cells through down regulation of AnxA2
My objective is to investigate the effect of arsenic trioxide (As2O3) on inhibiting invasive potential of NB4 through down regulation of AnxA2(A2). We cultured NB4 cells in vitro. Flow Cytometry (FCM) was used to detect the protein level on the cells surface after the samples were incubated with As2O3 in different concentrations.The influence of anti-AnxA2 antibody and As2O3 on the invasive potential of NB4 cells was investigated by using transwell plates. The results showed that the protein level of AnxA2 in NB4 cells treated by As2O3 in the different concentrations of 0.31, 0.63, and 1.25μg/ml was decreased compared with the unblocked (P<0.05). the invasive potential of NB4 cells treated with anti-AnxA2 antibody in the different concentrations of 0.01, 0.02, and 0.04μg/ml as well as As2O3 in the different concentrations of 0.31, 0.63, and 1.25μg/ml was decreased compared with the blank (P<0.05). Our data suggested that the down regulation of AnxA2 can inhibit invasive potential of NB4, As2O3 can inhibit invasive potential of NB4 cells through down regulation of AnxA2.
引文
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[2] Gerke V and Moss SE. Annexins:From Structure to Function. Physiol Rev, 2002;82:331-371.
[3] Rescher U and Gerke V. Annexins–unique membrane binding proteins with diverse functions. Cell Sci, 2004;117:2631-2639.
[4] Lu J, Vishwanatha JK. Regulation of nucleo-cytoplasmic shuttling of human AnxA2: a proposed mechanism. Mol Cell Biochem, 2007;303:211 -220.
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[6] Rescher U, Ludwig C, Konietzko V, et al. Tyrosine phosphorylation of AnxA2 regulates Rho-mediated actin rearrangement and cell adhesion. J Cell Sci, 2008;121:2177-2185.
[7] Mayran N, Parton RG, Gruenberg J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. EMBO J, 2003;22:3242- 3253.
[8] Morel E, Gruenberg J. AnxA2 binding to endosomes and functions in endosomal transport are regulated by tyrosine 23 phosphorylation. J Biol Chem, 2009;284: 1604-1611.
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[12] Lu G, Maeda H, Reddy SV, et al. Cloning and characterization of the AnxA2receptor on human marrow stromal cells. J Bio Chem, 2006;281:30542-30550.
[13] Jung Y, Wang J, Song J, et al. AnxA2 expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood, 2007;110:82-90.
[14] Camors E, Monceau V and Daniéle Charlemagne. Annexins and Ca2+ handling in the heart. Cardiovasc Res, 2005; 65:793-802.
[15] Hayashi T, Morishita E, Ohtake H, et al. AnxA2 in human atherosclerotic abdominal aortic aneurysms. Thromb Res, 2008;123: 274-80.
[16] Mayer G, Poirier S, Seidah NG. AnxA2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem, 2008;283:31791-801.
[17] Sharma MR, Koltowski L, Ownbey RT, et al. Angiogenesis- associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol, 2006;81:146-156.
[18] Hou Y, Yang L, Mou M, et al. AnxA2 regulates the levels of plasmin, S100A10 and Fascin in L5178Y cells. Cancer Invest, 2008;26:809-15.
[19] Zhong LP, Wei KJ, Yang X, et al. Increased expression of AnxA2 in oral squamous cell carcinoma. Arch Oral Biol, 2009;54:17-25.
[20] Takano S, Togawa A, Yoshitomi H, et al. Annexin II Overexpression Predicts Rapid Recurrence after Surgery in Pancreatic Cancer Patients Undergoing Gemcitabine- Adjuvant Chemotherapy. Ann Surg Oncol, 2008;15:3157-3168.
[21] Arseni Markoff and Volker Gerke. Expression and functions of annexins in the kidney. Am J Physiol Renal Physiol, 2005;289:F949 -F956.
[22] Shiozawa Y, Havens AM, Jung Y, et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem, 2008;105:370-80.
[23] Liu JW, Shen JJ, Tanzillo-Swarts A, et al. Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration. Oncogene, 2003;22: 1475-85.
[24] Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J Med, 1999;340: 994-1004.
[25] LeBouder F, Morello E, Rimmelzwaan GF, et al. Annexin II incorporated into influenza virus particles supports virus replication by converting plasminogen into plasmin. J Virol, 2008;82:6820-6828.
[26] Ryzhova EV, Vos RM, Albrighta V, et al.AnxA2:a novel human immunodeficiency virus type 1 Gag binding protein involved in replication in monocyte-derived macrophages. J Virol, 2006;80:2694-2704.
[27] Kirschnek S, Adams C, Gulb NE, et al. Annexin II is a novel receptor for Pseudomonas aeruginosa. Biochem Biophys Res Commun, 2005;327: 900-906.
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[10]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. JBC, 2005;280: 20833-20841.
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[12]Tanaka T, Akatsuka S, Ozeki M, et al. Redox regulation of AnxA2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. Oncogene, 2004;23:3980-3989.
1. Kyle RA. and Rajkumar SV. Multiple Myeloma. Blood, 2008;111: 2962-2972.
2. Huff CA and Matsui W. Multiple Myeloma Cancer Stem Cells. J Clin Oncol, 2008;26: 2895-2900.
3. Mehta P. Clinical Malignant Hematology. JAMA, 2008; 299: 460-475.
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5. Morel E and Gruenberg J. The p11/S100A10 Light Chain of AnxA2 is Dispensable for AnxA2 Association to Endosomes and Functions in Endosomal Transport. PLoS ONE, 2007; 210: 1110-1118.
6. Brownstein C, Deora AB, Jacovina AT, et al. Annexin II Mediates Plasminogen- Dependent Matrix Invasion by Human Monocytes:Enhanced Expression by Macrophages. Blood, 2004; 103: 317-324.
7. Falcone DJ, Borth W, Khan KMF, et al. Plasminogen-Mediated Matrix Invasion and Degradation by Macrophages is Dependent on Surface Expression of Annexin II. Blood, 2001; 97: 777-784.
8. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J. Med, 1999; 340: 994-1004.
9. Hastie C, Masters JR, Moss SE, et al. IFN-γReduces Cell Surface Expression of AnxA2 and Suppresses the Invasive Capacity of Prostate Cancer Cells. J Biol Chem, 2008;283:12595-12603.
10. Bastian BC. Annexins in Cancer and Autoimmune Diseases. Cell mol life sci, 1997;53:554-556.
11. Frohlich M, Motte P, Galvin K, et al . Enhanced Expression of the Protein Kinase Substrate p36 in Human Hepatocellular Carcinoma. Mol Cell Biol, 1990;10:3216-3223.
12. Emoto K, Sawada H, Yamada Y, et al. Annexin II Overexpression is Correlated with Poor Prognosis in Human Gastric Carcinoma. Anticancer Res, 2001;21:1339-1345.
13. Huang Y, Jin Y, Yan CH, et al. Involvement of AnxA2 in p53 Induced Apoptosis in Lung Cancer. Mol Cell Biochem, 2008;309:117-123.
14. Ortiz-Zapater E, Peiro S, Roda O, et al. Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and AnxA2. Am J Pathol, 2007;170:1573-1584.
15. Tanaka T, Akatsuka S, Ozeki M, et al. Redox Regulation of AnxA2 and its Implications for Oxidative Stress-induced Renal Carcinogenesis and Metastasis. Oncogene, 2004;23:3980–3989.
16. Gillette JM, Chan DC, and Nielsen-Preiss SM. AnxA2 Expression is Reduced in Human Osteosarcoma Metastases. J Cell Biochem, 2004;92:820-832.
17. Wang JH, Hodis HN, Hsiai TK, et al. Role of Annexin II in Estrogen-induced Macrophage Matrix Metalloproteinase-9 Activity:the Modulating Effect of Statins. Atherosclerosis, 2006; 189:76-82.
18. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. Mary Ann McLaughlin, N Engl J Med, 1999;340:994- 1004.
19. Chiang Y, Davis RG, and Vishwanatha JK. Altered expression of annexin II in human B-cell lymphoma cell lines. Biochim Biophys Acta, 1996;1313:295-301.
20. Hajjar KA, Ruan J, Sui GZ, et al. AnxA2 Mediates Plasminogen-Related Recruitment of Neovascular Mural Cells in Lymphoma Angiogenesis. Blood, 2007; 110: 3708-3721.
21. Claudio JO, Masih-Khan E, Tang HC, et al. A Molecular Compendium of Genes Expressed in Multiple Myeloma. Blood, 2002;100:2175-2186.
22. Munshi NC, Hideshima T, Carrasco D, et al. Identification of Genes Modulated in Multiple Myeloma Using Genetically Identical Twin Samples. Blood, 2004;103:1799-1806.
23. Zhan FH, Tian E, Bumm K, et al. Gene Expression Profiling of Human Plasma Cell Differentiation and Classification of Multiple Myeloma Based on Similarities to Distinct Stages of Late-Stage B-cell Development. Blood, 2003;101:1128-1140.
24. Verdelli D, Mattioli M, Fabris S, et al. Molecular and Biological Characterization of Three Novel Interleukin-6-Dependent Human Myeloma Cell Lines. Haematologica, 2005; 90:1541-1548.
25. Gerke V and Moss SE. Annexins:From Structure to Function. Physiol Rev, 2002; 82:331-371.
26. Rescher U and Gerke V. Annexins-Unique Membrane Binding Proteins with Diverse Functions. J Cell Sci, 2004;117:2631-2639.
27. Mickleburgh I, Burtle B, Hollas H, et al. AnxA2 Binds to the Localization Signal in the 3’untranslated Region of C-myc mRNA. FEBS J, 2005;272:413-421.
28. Chasserot-Golaz S, Vitale N, Umbrecht-Jenck E, et al. AnxA2 Promotes the Formation of Lipid Microdomains Required for Calcium- regulated Exocytosis of Dense-CoreVesicles. Mol Biol Cell, 2005;16: 1108-1119.
29. Zibouche M, Vincent M, Illien F, et al. The N-terminal Domain of AnxA2 Serves as a Secondary Binding Site uring Membrane Bridging. J Biol Chem, 2008; 283:22121-22127.
30. Graauw M, Tijdens I, Smeets MB, et al. AnxA2 Phosphorylation Mediates Cell Scattering and Branching Morphogenesis via Cofilin Activation. Mol Cell Biol, 2008;28:1029-1040.
31. Filipenko NR, MacLeod TJ, Chang-Soon Y, et al. AnxA2 Is a Novel RNA-Binding Protein. J Biol Chem, 2004;279:8723-8731.
32. Laumonnier Y, Syrovets T, Burysek L, et al. Identification of the AnxA2 Heterotetramer as a Receptor for the Plasmin-Induced Signaling in Human Peripheral Monocytes. Blood, 2006;107:3342-3349.
33. MacLeod TJ, Kwon M, Filipenko NR, et al. Phospholipid-associated AnxA2- S100A10 Heterotetramer and Its Subunits: Characterization of the Interaction with Tissue Plasminogen Activator,Plasminogen,and Plasmin. J Biol Chem,2003;278:25577-25584.
34. Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. J Biol Chem, 2005;280:20833-20841.
35. Rescher U, Ludwig C, Vera Konietzko V, et al. Tyrosine Phosphorylation of AnxA2 Regulates Rho-mediated Actin Rearrangement and Cell Adhesion. J Cell Sci 2008;121:2177-2185.
36. Ma G, Greenwell-Wild T, Lei K, et al. Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection. J Exp Med, 2004;200:1337-1346.
37 Sharma MR, Koltowski L, Ownbey RT, et al. Angiogenesis- associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol, 2006;81:146-156.
38 Hou Y, Yang L, Mou M, et al. AnxA2 regulates the levels of plasmin, S100A10 and Fascin in L5178Y cells. Cancer Invest, 2008;26:809-815.
39 Zhong LP, Wei KJ, Yang X, et al. Increased expression of AnxA2 in oral squamous cell carcinoma. Arch Oral Biol, 2009;54:17-25.
40 Takano S, Togawa A, Yoshitomi H, et al. Annexin II Overexpression Predicts Rapid Recurrence after Surgery in Pancreatic Cancer Patients Undergoing Gemcitabine- Adjuvant Chemotherapy. Ann Surg Oncol, 2008;15:3157-3168.
41 Arseni Markoff and Volker Gerke. Expression and functions of annexins in thekidney. Am J Physiol Renal Physiol, 2005;289:949-956.
42 Shiozawa Y, Havens AM, Jung Y, et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem, 2008;105:370-80.
43 Liu JW, Shen JJ, Tanzillo-Swarts A, et al. Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration. Oncogene, 2003;22:1475-85.
[1] Claudio JO, Masih-Khan E, Tang HC, et al. A molecular compendium of genes expressed in multiple myeloma. Blood, 2002;100:2175-2186.
[2] Munshi NC, Hideshima T, Carrasco D, et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood, 2004;103: 1799-1806.
[3] Zhan FH, Tian E, Bumm K, et al. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood, 2003;101:1128-1140.
[4] Verdelli D, Mattioli M, Fabris S, et al. Molecular and biological characterization ofthree novel interleukin-6-dependent human myeloma cell lines. Haematologica, 2005; 90:1541-1548.
[5] Fonseca R and Stewart AK. Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach. Mol Cancer Ther, 2007;6:802-810.
[6] Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood, 2004;103:20-32.
[7] Katzel JA, Hari P, Vesole DH. Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin, 2007;57:301-318.
[8] Bensinger W. Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Drugs. J Clin Oncol, 2008;26:480-492.
[9] Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatme nt of multiple myeloma: 10 years later. Blood, 2008;111:3968-3977.
[10] Chanan-Khan AA and Cheson BD. Lenalidomide for the Treatment of B-Cell Malignancies. J Clin Oncol, 2008;26:1544-1552.
[11] Iconomou A, and Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood, 2008;112: 1593-1599.
[12] Utecht KN and Kolesar J. Bortezomib: A novel chemo therapeutic agent for hematologic malignancies. Am J Health Syst Pharm, 2008; 65: 1221-1231.
[13] Gerke V, Moss SE. Annexins: From Structure to Function. Physiol Rev, 2002; 82:331-371.
[14] Mickleburgh I, Burtle B, Hollas H, et al. AnxA2 binds to the localization signal in the 3’untranslated region of c-myc mRNA. FEBS, 2005;23:413-421.
[15] Sylvette Chasserot-Golaz S, Vitale N, Umbrecht-Jenck E, et al. AnxA2 Promotes the Formation of Lipid Microdomains Required for Calcium- regulated Exocytosis of Dense-CoreVesicles. Molecular Biology of the Cell, 2005;71:1108-1119.
[16] Zibouche M, Vincent M, Illien F, et al. The N-terminal Domain of AnxA2 Serves as a Secondary Binding Site during Membrane Bridging. J Biol Chem, 2008;283:22121-22127.
[17] Rescher U and Gerke V. Annexins–unique membrane binding proteins with diverse functions J. Cell Sci, 2004;117:2631-2639.
[18] Graauw M, Tijdens I, Smeets MB, et al. AnxA2 Phosphorylation Mediates Cell Scattering and Branching Morphogenesis via Cofilin Activation. Mol Cell Biol, 2008;28:1029-1040.
[19] Filipenko NR, MacLeod TJ, Chang-Soon Y, et al. AnxA2 Is a Novel RNA-binding Protein.J. Biol Chem, 2004;279:8723-8731.
[20] Laumonnier Y, Syrovets T, Burysek L, et al. Identification of the AnxA2 heterotetramer as a receptor for the plasmin-induced signaling in human peripheral monocytes. Blood, 2006;107:3342-3349.
[21] MacLeod TJ, Kwon M, Filipenko NR, et al. Phospholipid-associated AnxA2-S100A10 Heterotetramer and Its Subunits: Characterization of the interaction with tissue plasminogen activator,plasminogen,and plasmin. J Biol Chem, 2003;278:25577-25584.
[22] Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. J Biol Chem, 2005;280:20833-20841.
[23] Rescher U, Ludwig C, Konietzko V, et al. Tyrosine phosphorylation of AnxA2 regulates Rho-mediated actin rearrangement and cell adhesion. J Cell Sci, 2008;121:2177-2185.
[24] Ma G, Greenwell-Wild T, Lei KJ, et al. Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection. The Journal of Experimental Medicine, 2004;26:1337-1346.
[25] Hastie C, Masters JR, Moss SE, et al. IFNγreduces cell surface expression of AnxA2 and suppresses the invasive capacity of prostate cancer cells. The Journal of Biological Chemistry, 2008;162:1811-1823
[26] Bastian BC. Annexins in cancer and autoimmune diseases. CMLS, Cell mol life sci, 1997;53:554-556.
[27] Frohlich M, Motte P, Galvin K, et al. Enhanced expression of the protein kinasesubstrate p36 in human hepatocellular carcinoma. Mol Cell Biol, 1990;10:3216 -3223.
[28] Emoto K, Sawada H, Yamada Y, et al. Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. Anticancer Res, 2001;21:1339-1345.
[29] Huang Y, Jin Y, Yan CH, et al. Involvement of AnxA2 in p53 induced apoptosis in lung cancer. Mol Cell Biochem, 2008;309:117-123.
[30] Ortiz-Zapater E, Peiro S, Roda O, et al. Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and AnxA2. The American Journal of Pathology, 2007;170: 1573-1584.
[31] Tanaka T, Akatsuka S, Ozeki M, et al. Redox regulation of AnxA2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. Oncogene, 2004;23:3980-3989.
[32] Gillette JM, Chan DC, and Nielsen- Preiss SM. AnxA2 Express- ion is Reduced in Human Osteosarcoma Metastases. Journal of Cellular Biochemistry, 2004;92:820 -832.
[33] Wang JH, Hodis HN, Hsiai TK, et al. Role of annexin II in estrogen-induced macrophage matrix metalloproteinase-9 activity: the modulating effect of statins. Atherosclerosis, 2006;189:76-82.
[34] Bhattacharjee G, Ahamed J, Pawlinski R, et al. Factor Xa Binding to AnxA2 Mediates Signal Transduction via Protease-Activated Receptor 1. Circ Res, 2008;102:457-464.
[1] Gerke V, Moss SE. Annexins: From Structure to Function. Physiol Rev, 2002; 82:331-371.
[2] Farber SA, De Rose RA, Olson ES, et al. The Zebrafish Annexin Gene Family.Genome Res, 2003;13:1082-1096.
[3] Zhan FH, Tian E, Bumm K, et al. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood, 2003;101:1128-1140.
[4] Verdelli D, Mattioli M, Fabris S, et al. Molecular and biological characterization of three novel interleukin-6-dependent human myeloma cell lines. Haematologica, 2005;90:1541-1548.
[5] Munshi NC, Hideshima T, Carrasco D, et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood, 2004;103: 1799-1806.
[6] Hastie C, Masters JR, Moss SE, et al. IFNγreduces cell surface expression of AnxA2 and suppresses the invasive capacity of prostate cancer cells. The Journal of Biological Chemistry, 2008;283:12595-12603.
[7] Laumonnier Y, Syrovets T, Burysek L, et al. Identification of the annexinA2 heterotetramer as a receptor for the plasmin- induced signaling in human peripheral monocytes. Blood, 2006;107:3342-3349.
[8] Brownstein C, Deora AB, Jacovina AT, et al. Annexin II mediates plasminogen- dependent matrix invasion by human monocytes: enhanced expression by macrophages. Blood, 2004;103:317-324.
[9] Semov A, Moreno MJ, Onichtchenko A, et al. etastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. The Journalof Biological Chemistry, 2005;20833-20841.
[10] Falcone DJ, Borth W, Faisal Khan KM, et al. lasminogen- mediated matrix invasion and degradation by macrophages is dependent on surface expression of annexin II. Blood, 2001;97:777-784.
[11] Eleutherakis-Papaiakovou V, Dimopoulos ABMA, et al. Thalidomi de in cancer medicine. Annals of Oncology, 2004;15:1151-1160.
[12] Katzel JA, Hari P and Vesole DH. Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin, 2007;57:301-318.
[13] Palumbo A, Facon T, Sonneveld P, et al. halidomide for treatme nt of multiple myeloma: 10 years later. Blood, 2008;111:3968-3977.
[14] Dimopoulos BMA, Anagnostopoulos A and Weber D. Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives. Journal of Clinical Oncology, 2003;21:4444-4454.
[15] Munshi NC, Hideshima T, Carrasco D, et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood, 2004;103: 1799-1806.
[16] Mickleburgh I, Burtle B, Hollas H, et al. AnxA2 binds to the localization signal in the 3’untranslated region of c-myc mRNA. FEBS Journal, 2005; 272:413-421.
[17] Chasserot-Golaz S, Vitale N, Umbrecht-Jenck E, et al. AnxA2 Promotes the Formation of Lipid Microdomains Required for Calcium-regulated Exocytosis of Dense-CoreVesicles. Molecular Biology of the Cell, 2005;16:1108-1119.
[18] Ma G, Greenwell-Wild T, Lei K, et al. Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection. The Journal of Experimental Medicine, 2004;200:1337-1346.
[19] Jung YH, Wang JC, Song JH, et al. Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood, 2007;110:82-90.
[20] Bhattacharjee G, Ahamed J, Pawlinski R, et al. Factor Xa Binding to AnxA2 Mediates Signal Transduction via Protease-Activated Receptor 1. Circulation Research, 2008;102:457-464.
[21] Katzel JA, Hari P, Vesole DH. Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin, 2007;57:301-318.
[22] Fonseca R and Stewart AK. Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach. Mol Cancer Ther, 2007;6:802-810.
[23] Jiménez-Zepeda Víctor Hugo and Domínguez-Martínez Virginia Jeanet. Acquired activated protein C resistance and thrombosis in multiple myeloma patients. Thrombosis Journal, 2006;4:11.
[24] Falanga and Ann LZ. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. A. Onc, 2005;16:696-701.
[25] Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood, 2001; 98: 1614-1615.
[26]朱琦,胡钧培,叶为德.沙利度胺对多发性骨髓瘤患者止凝血功能的影响.血栓与止血学. 2006;12:111-113.
[1] Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J Med, 1999;340:994-1004.
[2] Zhang X, Zhou H, Wang J, et al. Arsenic Trioxide, Retinoic Acid and Ara-c Regulated The Expression of Annexin II on The Surface of APL Cells, a Novel Co-receptor for Plasminogen/Tissue Plasminogen Activator. Thromb Res, 2002; 106:63-70.
[3] Wang Z and Chen Z. Acute Promyelocytic Leukemia: from Highly Fatal to Highly Curable.Blood, 2008;111:2505-2515.
[4] Miller WH, Schipper JHM, Lee JS, et al. Mechanisms of Action of Arsenic Trioxide.Cancer Res, 2002;62:3893-3903.
[5] Douer D and Tallman MS. Arsenic Trioxide: New Clinical Experience With an Old Medication in Hematologic Malignancies. J Clin Oncol, 2005; 23:2396-2410.
[6] Yu J, Qian H, Li Y, et al. Arsenic Trioxide (As2O3) Reduces The Invasive and Metastatic Properties of Cervical Cancer Cells in Vitro and in Vivo. Gynecol Oncol, 2007;106:400-406.
[7]魏亚明,欧英贤,白海等. As2O3诱导白血病细胞凋亡过程中活性氧自由基的变化.肿瘤杂志,2002;22:362-365.
[8] Mickleburgh I, Burtle B, Hollas H, et al. AnxA2 Binds to The Localization Signal in The 3’untranslated Region of C-myc mRNA. FEBS J, 2005;272:413-421.
[9] Ma G, Greenwell-Wild T, Lei K, et al. Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection. J Exp Med, 2004;200: 1337-1346.
[10] Brownstein C, Deora AB, Jacovina AT, et al. Annexin II Mediates Plasminogen- dependent Matrix Invasion by Human Monocytes: Enhanced Expression by Macrophages. Blood, 2004;103: 317-324.
[2] Gerke V and Moss SE. Annexins:From Structure to Function. Physiol Rev, 2002;82:331-371.
[3] Rescher U and Gerke V. Annexins–unique membrane binding proteins with diverse functions. Cell Sci, 2004;117:2631-2639.
[4] Lu J, Vishwanatha JK. Regulation of nucleo-cytoplasmic shuttling of human AnxA2: a proposed mechanism. Mol Cell Biochem, 2007;303:211 -220.
[5] Aukrust I, Hollas H, Strand E, et al. The mRNA-binding site of AnxA2 resides in helices C-D of its domain IV. J Mol Biol, 2007;18:1367-1378.
[6] Rescher U, Ludwig C, Konietzko V, et al. Tyrosine phosphorylation of AnxA2 regulates Rho-mediated actin rearrangement and cell adhesion. J Cell Sci, 2008;121:2177-2185.
[7] Mayran N, Parton RG, Gruenberg J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. EMBO J, 2003;22:3242- 3253.
[8] Morel E, Gruenberg J. AnxA2 binding to endosomes and functions in endosomal transport are regulated by tyrosine 23 phosphorylation. J Biol Chem, 2009;284: 1604-1611.
[9] Knop M, Aareskjold E, Bode G, et al. Rab3D and AnxA2 play a role in regulated secretion of vWF, but not tPA, from endothelial cells. EMBO J, 2004;23:2982-2992.
[10] Ling Q, Jacovina AT, Deora A, et al. AnxA2 regulates fibrin homeostasis and neoangenesis in vivo. J Clin Invest, 2004;113: 38-48
[11] Filipenko NR, Macleod TJ, Yoon CS, et al. AnxA2 is a novel RNA-binding protein. J Biol Chem, 2004;279:8723-8731
[12] Lu G, Maeda H, Reddy SV, et al. Cloning and characterization of the AnxA2receptor on human marrow stromal cells. J Bio Chem, 2006;281:30542-30550.
[13] Jung Y, Wang J, Song J, et al. AnxA2 expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood, 2007;110:82-90.
[14] Camors E, Monceau V and Daniéle Charlemagne. Annexins and Ca2+ handling in the heart. Cardiovasc Res, 2005; 65:793-802.
[15] Hayashi T, Morishita E, Ohtake H, et al. AnxA2 in human atherosclerotic abdominal aortic aneurysms. Thromb Res, 2008;123: 274-80.
[16] Mayer G, Poirier S, Seidah NG. AnxA2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem, 2008;283:31791-801.
[17] Sharma MR, Koltowski L, Ownbey RT, et al. Angiogenesis- associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol, 2006;81:146-156.
[18] Hou Y, Yang L, Mou M, et al. AnxA2 regulates the levels of plasmin, S100A10 and Fascin in L5178Y cells. Cancer Invest, 2008;26:809-15.
[19] Zhong LP, Wei KJ, Yang X, et al. Increased expression of AnxA2 in oral squamous cell carcinoma. Arch Oral Biol, 2009;54:17-25.
[20] Takano S, Togawa A, Yoshitomi H, et al. Annexin II Overexpression Predicts Rapid Recurrence after Surgery in Pancreatic Cancer Patients Undergoing Gemcitabine- Adjuvant Chemotherapy. Ann Surg Oncol, 2008;15:3157-3168.
[21] Arseni Markoff and Volker Gerke. Expression and functions of annexins in the kidney. Am J Physiol Renal Physiol, 2005;289:F949 -F956.
[22] Shiozawa Y, Havens AM, Jung Y, et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem, 2008;105:370-80.
[23] Liu JW, Shen JJ, Tanzillo-Swarts A, et al. Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration. Oncogene, 2003;22: 1475-85.
[24] Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J Med, 1999;340: 994-1004.
[25] LeBouder F, Morello E, Rimmelzwaan GF, et al. Annexin II incorporated into influenza virus particles supports virus replication by converting plasminogen into plasmin. J Virol, 2008;82:6820-6828.
[26] Ryzhova EV, Vos RM, Albrighta V, et al.AnxA2:a novel human immunodeficiency virus type 1 Gag binding protein involved in replication in monocyte-derived macrophages. J Virol, 2006;80:2694-2704.
[27] Kirschnek S, Adams C, Gulb NE, et al. Annexin II is a novel receptor for Pseudomonas aeruginosa. Biochem Biophys Res Commun, 2005;327: 900-906.
[1] Kaetzel MA, Dedman JR. Annexins: novel Ca12-dependent regulators of membrane function. News in Physiol Sci, 1995;10: 171-176.
[2] Hajjar KA, Jacovina AT, Chacko J. An endothelial cell receptor for plasminogen/ tissue activator,identity with AnxA2. J Biol Chem, 1994;269: 21191-21197.
[3] Kassam G, Choi K-S, Ghuman J, et al. The role of AnxA2 tetramer in the activation of plasminogen. J Biol Chem, 1998;273: 4790-4799.
[4] Menell JS, Cesarman GM, Jacovina AT, et al. AnxA2 and bleeding in acute promyelocytic leukemia. N Engl J Med, 1999;340: 994-1004.
[5] Yeatman TJ, Updyke TV, Kaetzel MA, et al. Expression of annexins on the surfaces of non-metastatic and metastatic human and rodent tumor cells. Clin Exp Metastasis, 1993;11:37-44.
[6] Falcone DJ, Borth W, Faisal-Khan KM, et al. Plasminogen- mediated matrix invasion and degradation by macrophages is dependent on surface expression of AnxA2. blood, 2001;97: 777-784.
[7] Volker G and Stephen EM. Annexins: From Structure to Function. Physiol Rev, 2001; 82:331-371.
[8] Ursula Rescher and Volker Gerke. Annexins–unique membrane binding proteins with diverse functions. Journal of Cell Science, 2004;117:2631-2639
[9] Klinik und Poliklinik fu¨r Hautkrankheiten, Julius- Maximilians Uni6ersita¨t Wu¨rzburg, osef-Schneider-Str. Annexins in cancer and autoimmune diseases. CMLS, 1997;53: 554-556.
[10]Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. JBC, 2005;280: 20833-20841.
[11] Takayuki Matsunaga, Toshiya Inaba, Hirotaka Matsui, et al. Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. Blood, 2004;103:3185-3191.
[12]Tanaka T, Akatsuka S, Ozeki M, et al. Redox regulation of AnxA2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. Oncogene, 2004;23:3980-3989.
1. Kyle RA. and Rajkumar SV. Multiple Myeloma. Blood, 2008;111: 2962-2972.
2. Huff CA and Matsui W. Multiple Myeloma Cancer Stem Cells. J Clin Oncol, 2008;26: 2895-2900.
3. Mehta P. Clinical Malignant Hematology. JAMA, 2008; 299: 460-475.
4. Heyraud S, Jaquinod M, Durmort C, et al. Contribution of AnxA2 to The Architecture of Mature Endothelial Adherens Junctions. Mol Cell Biol, 2008; 28: 1657-1668.
5. Morel E and Gruenberg J. The p11/S100A10 Light Chain of AnxA2 is Dispensable for AnxA2 Association to Endosomes and Functions in Endosomal Transport. PLoS ONE, 2007; 210: 1110-1118.
6. Brownstein C, Deora AB, Jacovina AT, et al. Annexin II Mediates Plasminogen- Dependent Matrix Invasion by Human Monocytes:Enhanced Expression by Macrophages. Blood, 2004; 103: 317-324.
7. Falcone DJ, Borth W, Khan KMF, et al. Plasminogen-Mediated Matrix Invasion and Degradation by Macrophages is Dependent on Surface Expression of Annexin II. Blood, 2001; 97: 777-784.
8. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. N Engl J. Med, 1999; 340: 994-1004.
9. Hastie C, Masters JR, Moss SE, et al. IFN-γReduces Cell Surface Expression of AnxA2 and Suppresses the Invasive Capacity of Prostate Cancer Cells. J Biol Chem, 2008;283:12595-12603.
10. Bastian BC. Annexins in Cancer and Autoimmune Diseases. Cell mol life sci, 1997;53:554-556.
11. Frohlich M, Motte P, Galvin K, et al . Enhanced Expression of the Protein Kinase Substrate p36 in Human Hepatocellular Carcinoma. Mol Cell Biol, 1990;10:3216-3223.
12. Emoto K, Sawada H, Yamada Y, et al. Annexin II Overexpression is Correlated with Poor Prognosis in Human Gastric Carcinoma. Anticancer Res, 2001;21:1339-1345.
13. Huang Y, Jin Y, Yan CH, et al. Involvement of AnxA2 in p53 Induced Apoptosis in Lung Cancer. Mol Cell Biochem, 2008;309:117-123.
14. Ortiz-Zapater E, Peiro S, Roda O, et al. Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and AnxA2. Am J Pathol, 2007;170:1573-1584.
15. Tanaka T, Akatsuka S, Ozeki M, et al. Redox Regulation of AnxA2 and its Implications for Oxidative Stress-induced Renal Carcinogenesis and Metastasis. Oncogene, 2004;23:3980–3989.
16. Gillette JM, Chan DC, and Nielsen-Preiss SM. AnxA2 Expression is Reduced in Human Osteosarcoma Metastases. J Cell Biochem, 2004;92:820-832.
17. Wang JH, Hodis HN, Hsiai TK, et al. Role of Annexin II in Estrogen-induced Macrophage Matrix Metalloproteinase-9 Activity:the Modulating Effect of Statins. Atherosclerosis, 2006; 189:76-82.
18. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and Bleeding in Acute Promyelocytic Leukemia. Mary Ann McLaughlin, N Engl J Med, 1999;340:994- 1004.
19. Chiang Y, Davis RG, and Vishwanatha JK. Altered expression of annexin II in human B-cell lymphoma cell lines. Biochim Biophys Acta, 1996;1313:295-301.
20. Hajjar KA, Ruan J, Sui GZ, et al. AnxA2 Mediates Plasminogen-Related Recruitment of Neovascular Mural Cells in Lymphoma Angiogenesis. Blood, 2007; 110: 3708-3721.
21. Claudio JO, Masih-Khan E, Tang HC, et al. A Molecular Compendium of Genes Expressed in Multiple Myeloma. Blood, 2002;100:2175-2186.
22. Munshi NC, Hideshima T, Carrasco D, et al. Identification of Genes Modulated in Multiple Myeloma Using Genetically Identical Twin Samples. Blood, 2004;103:1799-1806.
23. Zhan FH, Tian E, Bumm K, et al. Gene Expression Profiling of Human Plasma Cell Differentiation and Classification of Multiple Myeloma Based on Similarities to Distinct Stages of Late-Stage B-cell Development. Blood, 2003;101:1128-1140.
24. Verdelli D, Mattioli M, Fabris S, et al. Molecular and Biological Characterization of Three Novel Interleukin-6-Dependent Human Myeloma Cell Lines. Haematologica, 2005; 90:1541-1548.
25. Gerke V and Moss SE. Annexins:From Structure to Function. Physiol Rev, 2002; 82:331-371.
26. Rescher U and Gerke V. Annexins-Unique Membrane Binding Proteins with Diverse Functions. J Cell Sci, 2004;117:2631-2639.
27. Mickleburgh I, Burtle B, Hollas H, et al. AnxA2 Binds to the Localization Signal in the 3’untranslated Region of C-myc mRNA. FEBS J, 2005;272:413-421.
28. Chasserot-Golaz S, Vitale N, Umbrecht-Jenck E, et al. AnxA2 Promotes the Formation of Lipid Microdomains Required for Calcium- regulated Exocytosis of Dense-CoreVesicles. Mol Biol Cell, 2005;16: 1108-1119.
29. Zibouche M, Vincent M, Illien F, et al. The N-terminal Domain of AnxA2 Serves as a Secondary Binding Site uring Membrane Bridging. J Biol Chem, 2008; 283:22121-22127.
30. Graauw M, Tijdens I, Smeets MB, et al. AnxA2 Phosphorylation Mediates Cell Scattering and Branching Morphogenesis via Cofilin Activation. Mol Cell Biol, 2008;28:1029-1040.
31. Filipenko NR, MacLeod TJ, Chang-Soon Y, et al. AnxA2 Is a Novel RNA-Binding Protein. J Biol Chem, 2004;279:8723-8731.
32. Laumonnier Y, Syrovets T, Burysek L, et al. Identification of the AnxA2 Heterotetramer as a Receptor for the Plasmin-Induced Signaling in Human Peripheral Monocytes. Blood, 2006;107:3342-3349.
33. MacLeod TJ, Kwon M, Filipenko NR, et al. Phospholipid-associated AnxA2- S100A10 Heterotetramer and Its Subunits: Characterization of the Interaction with Tissue Plasminogen Activator,Plasminogen,and Plasmin. J Biol Chem,2003;278:25577-25584.
34. Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. J Biol Chem, 2005;280:20833-20841.
35. Rescher U, Ludwig C, Vera Konietzko V, et al. Tyrosine Phosphorylation of AnxA2 Regulates Rho-mediated Actin Rearrangement and Cell Adhesion. J Cell Sci 2008;121:2177-2185.
36. Ma G, Greenwell-Wild T, Lei K, et al. Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection. J Exp Med, 2004;200:1337-1346.
37 Sharma MR, Koltowski L, Ownbey RT, et al. Angiogenesis- associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol, 2006;81:146-156.
38 Hou Y, Yang L, Mou M, et al. AnxA2 regulates the levels of plasmin, S100A10 and Fascin in L5178Y cells. Cancer Invest, 2008;26:809-815.
39 Zhong LP, Wei KJ, Yang X, et al. Increased expression of AnxA2 in oral squamous cell carcinoma. Arch Oral Biol, 2009;54:17-25.
40 Takano S, Togawa A, Yoshitomi H, et al. Annexin II Overexpression Predicts Rapid Recurrence after Surgery in Pancreatic Cancer Patients Undergoing Gemcitabine- Adjuvant Chemotherapy. Ann Surg Oncol, 2008;15:3157-3168.
41 Arseni Markoff and Volker Gerke. Expression and functions of annexins in thekidney. Am J Physiol Renal Physiol, 2005;289:949-956.
42 Shiozawa Y, Havens AM, Jung Y, et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem, 2008;105:370-80.
43 Liu JW, Shen JJ, Tanzillo-Swarts A, et al. Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration. Oncogene, 2003;22:1475-85.
[1] Claudio JO, Masih-Khan E, Tang HC, et al. A molecular compendium of genes expressed in multiple myeloma. Blood, 2002;100:2175-2186.
[2] Munshi NC, Hideshima T, Carrasco D, et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood, 2004;103: 1799-1806.
[3] Zhan FH, Tian E, Bumm K, et al. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood, 2003;101:1128-1140.
[4] Verdelli D, Mattioli M, Fabris S, et al. Molecular and biological characterization ofthree novel interleukin-6-dependent human myeloma cell lines. Haematologica, 2005; 90:1541-1548.
[5] Fonseca R and Stewart AK. Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach. Mol Cancer Ther, 2007;6:802-810.
[6] Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood, 2004;103:20-32.
[7] Katzel JA, Hari P, Vesole DH. Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin, 2007;57:301-318.
[8] Bensinger W. Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Drugs. J Clin Oncol, 2008;26:480-492.
[9] Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatme nt of multiple myeloma: 10 years later. Blood, 2008;111:3968-3977.
[10] Chanan-Khan AA and Cheson BD. Lenalidomide for the Treatment of B-Cell Malignancies. J Clin Oncol, 2008;26:1544-1552.
[11] Iconomou A, and Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood, 2008;112: 1593-1599.
[12] Utecht KN and Kolesar J. Bortezomib: A novel chemo therapeutic agent for hematologic malignancies. Am J Health Syst Pharm, 2008; 65: 1221-1231.
[13] Gerke V, Moss SE. Annexins: From Structure to Function. Physiol Rev, 2002; 82:331-371.
[14] Mickleburgh I, Burtle B, Hollas H, et al. AnxA2 binds to the localization signal in the 3’untranslated region of c-myc mRNA. FEBS, 2005;23:413-421.
[15] Sylvette Chasserot-Golaz S, Vitale N, Umbrecht-Jenck E, et al. AnxA2 Promotes the Formation of Lipid Microdomains Required for Calcium- regulated Exocytosis of Dense-CoreVesicles. Molecular Biology of the Cell, 2005;71:1108-1119.
[16] Zibouche M, Vincent M, Illien F, et al. The N-terminal Domain of AnxA2 Serves as a Secondary Binding Site during Membrane Bridging. J Biol Chem, 2008;283:22121-22127.
[17] Rescher U and Gerke V. Annexins–unique membrane binding proteins with diverse functions J. Cell Sci, 2004;117:2631-2639.
[18] Graauw M, Tijdens I, Smeets MB, et al. AnxA2 Phosphorylation Mediates Cell Scattering and Branching Morphogenesis via Cofilin Activation. Mol Cell Biol, 2008;28:1029-1040.
[19] Filipenko NR, MacLeod TJ, Chang-Soon Y, et al. AnxA2 Is a Novel RNA-binding Protein.J. Biol Chem, 2004;279:8723-8731.
[20] Laumonnier Y, Syrovets T, Burysek L, et al. Identification of the AnxA2 heterotetramer as a receptor for the plasmin-induced signaling in human peripheral monocytes. Blood, 2006;107:3342-3349.
[21] MacLeod TJ, Kwon M, Filipenko NR, et al. Phospholipid-associated AnxA2-S100A10 Heterotetramer and Its Subunits: Characterization of the interaction with tissue plasminogen activator,plasminogen,and plasmin. J Biol Chem, 2003;278:25577-25584.
[22] Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation. J Biol Chem, 2005;280:20833-20841.
[23] Rescher U, Ludwig C, Konietzko V, et al. Tyrosine phosphorylation of AnxA2 regulates Rho-mediated actin rearrangement and cell adhesion. J Cell Sci, 2008;121:2177-2185.
[24] Ma G, Greenwell-Wild T, Lei KJ, et al. Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection. The Journal of Experimental Medicine, 2004;26:1337-1346.
[25] Hastie C, Masters JR, Moss SE, et al. IFNγreduces cell surface expression of AnxA2 and suppresses the invasive capacity of prostate cancer cells. The Journal of Biological Chemistry, 2008;162:1811-1823
[26] Bastian BC. Annexins in cancer and autoimmune diseases. CMLS, Cell mol life sci, 1997;53:554-556.
[27] Frohlich M, Motte P, Galvin K, et al. Enhanced expression of the protein kinasesubstrate p36 in human hepatocellular carcinoma. Mol Cell Biol, 1990;10:3216 -3223.
[28] Emoto K, Sawada H, Yamada Y, et al. Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. Anticancer Res, 2001;21:1339-1345.
[29] Huang Y, Jin Y, Yan CH, et al. Involvement of AnxA2 in p53 induced apoptosis in lung cancer. Mol Cell Biochem, 2008;309:117-123.
[30] Ortiz-Zapater E, Peiro S, Roda O, et al. Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and AnxA2. The American Journal of Pathology, 2007;170: 1573-1584.
[31] Tanaka T, Akatsuka S, Ozeki M, et al. Redox regulation of AnxA2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. Oncogene, 2004;23:3980-3989.
[32] Gillette JM, Chan DC, and Nielsen- Preiss SM. AnxA2 Express- ion is Reduced in Human Osteosarcoma Metastases. Journal of Cellular Biochemistry, 2004;92:820 -832.
[33] Wang JH, Hodis HN, Hsiai TK, et al. Role of annexin II in estrogen-induced macrophage matrix metalloproteinase-9 activity: the modulating effect of statins. Atherosclerosis, 2006;189:76-82.
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