TIEG1基因在TGF-β1介导肝癌细胞生长抑制中的作用及抗肿瘤研究
|
摘要
第一部分TIEG1基因在TGF-β1介导肝癌细胞生长抑制中的作用
研究背景:肝癌是世界上第五大恶性肿瘤,晚期患者治疗难度大、疗效差,目前尚无有效的治疗策略。因此研究肝癌的发病机制,寻找新的治疗靶点和疗法是目前研究热点。TGF-β在体外能抑制肝细胞增殖和诱导细胞凋亡,在体内控制肝细胞的生长,维持肝脏大小。然而,在肝癌细胞中,往往对TGF-β失去敏感性,被认为是肝癌发病的机制之一,但其机理尚未完全阐明。
研究目的:通过筛选对TGF-β1不同敏感程度的细胞株(包括正常肝细胞和肝癌细胞),以此为模型,研究肝癌细胞对TGF-β敏感性缺失的主要原因以及TIEG1抑制肝癌细胞生长的作用机制。
研究方法:选取了对TGF-β敏感的肝癌细胞株Hep3B和正常永生化的肝细胞株MIHA,以及对TGF-β不敏感的两株肝癌细胞株(HepG2、Bel7404)做为细胞模型。TGF-β1处理0、0.5、1、2、4 h后,RT-PCR方法检测TGF-β不同敏感程度的细胞株之间TGF-β信号通路主要相关基因表达的差异;利用siRNA抑制TGF-β敏感肝癌细胞Hep3B的TIEG1表达,观察细胞对TGF-β1敏感性的改变;利用慢病毒载体在TGF-β不敏感肝癌细胞(HepG2、Bel7404)中过表达TIEG1,研究TIEG1在TGF-β1对肝癌细胞生长抑制中的作用。Western blot检测TGF-β1和TIEG1对stathmin表达的影响;萤光素酶报告基因检测TIEG1对stathmin启动子的调控;采用染色质免疫共沉淀方法,观察TIEG1对stathmin启动子区域的直接结合作用;并进一步在TIEG1过表达的肝癌细胞中同时过表达stathmin,研究对逆转TIEG1抑制细胞生长的作用。
研究结果:(1)在检测TGF-β1处理细胞后的早期基因反应中,发现在TGF-β敏感的细胞(Hep3B、MIHA)中,TGF-β1能强烈诱导TIEG1基因表达上调(7～11倍),并在1h时达到高峰;而在对TGF-β不敏感的细胞(HepG2、Bel7404)中,TIEG1基因表达只有微弱的上调(2～3倍),TGF-β敏感的细胞中TIEG1基因表达变化显著高于TGF-β不敏感的细胞。(2)应用siRNA抑制TGF-β敏感肝癌细胞Hep3B中TIEG1基因表达,可以使Hep3B细胞对TGF-β1的敏感性降低。(3)在TGF-β不敏感的肝癌细胞(HepG2、Bel7404)中过表达TIEG1,可以抑制肝癌细胞的增殖和诱导凋亡。(4) TIEG1可以通过直接结合stathmin启动子区域,调控启动子活性,下调stathmin的表达;TGF-β1处理敏感肝癌细胞Hep3B也可使stathmin表达下调。(5)在TIEG1过表达的肝癌细胞中同时过表达stathmin,可以明显逆转TIEG1对肝癌细胞的生长抑制作用。
结论:(1) TGF-β1处理后,TIEG1基因早期表达反应能力的减弱,是导致肝癌细胞对TGF-β1丧失敏感性的主要原因。(2)阐明了TGF-β1对TIEG1基因及下游stathmin的调控作用,提出假设的“TGF-β1—＞TIEG1—＞stathmin—＞细胞增殖抑制”新的信号通路,揭示TIEG1基因在TGF-β1介导肝癌细胞生长抑制中的重要作用。本研究为探讨肝癌发病机制,寻找新的治疗靶点提供了实验依据。
第二部分慢病毒载体过表达TIEG1对胰腺癌细胞生长抑制和化疗药物的增敏作用
研究背景:胰腺癌是目前已知的恶性程度最高的肿瘤之一。近年来,人胰腺癌的发病率和死亡率呈上升趋势,严重影响着人们的生活质量。大部分胰腺癌细胞对化疗药物耐药,导致胰腺癌预后极差。寻找更加有效的治疗方法,成为目前胰腺癌治疗的关键。TIEG1可以诱导TGF-β敏感胰腺癌细胞凋亡,抑制细胞生长,但对TGF-β不敏感胰腺癌细胞生长和化疗药物敏感性的影响尚未阐明。
研究目的:研究在胰腺癌细胞中过表达TIEG1对胰腺癌细胞生长和化疗药物敏感性的影响,并探讨其作用机制。
研究方法:利用慢病毒转基因系统,在胰腺癌细胞株(SW1990和Canpan-2)以及永生化正常胰腺导管细胞株(HPDE6-E6E7-c7)中过表达TIEG1,MTT法测定其对胰腺癌细胞和正常细胞生长抑制作用的差异;DAPI染色法检测TIEG1对胰腺癌细胞凋亡的影响;MTT法测定过表达TIEG1后,胰腺癌细胞对化疗药物吉西他滨敏感性的改变;实时定量PCR和Western blot方法检测TIEG1对胰腺癌细胞stathmin表达的影响;用慢病毒过表达stathmin,研究对逆转TIEG1抑制胰腺癌细胞生长的作用;利用特异性siRNA抑制stathmin的表达,观察对胰腺癌细胞生长的影响。
研究结果:(1)慢病毒载体过表达TIEG1基因能抑制胰腺细胞生长,并且在肿瘤细胞中抑制效果明显高于正常胰腺癌细胞株,具有统计学意义。(2)过表达TIEG1基因可以诱导胰腺癌细胞凋亡,促进肿瘤细胞对化疗药物吉西他滨的敏感性。(3) TIEG1可以下调胰腺癌细胞stathmin的表达;同时用慢病毒转染方法过表达stathmin可以一定程度逆转TIEG1基因对肿瘤细胞的生长抑制作用。(4)用siRNA转染胰腺癌细胞,下调stathmin的表达,也可以抑制胰腺癌细胞的生长。
结论:TIEG1基因主要通过下调stathmin表达抑制胰腺癌细胞株的生长,促进对化疗药物吉西他滨的敏感性,有可能成为胰腺癌基因治疗及联合化疗药物治疗的新靶点。
PartⅠThe role of TIEG1 gene in TGF-β1 mediated hepatoma cells growth inhibition
Background:Hepatocellular carcinoma(HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide,with few effective therapeutic options for advanced disease.The new therapeutic strategy and pathogenesis of HCC become more and more important.In hepatocytes,TGF-βacts as a tumor suppressor through growth inhibition and induces apoptosis in vitro and in vivo to control the excessive growth of hepatocytes and maintenance of liver size.However,HCC cells are frequently thought to have lost their sensitivity to TGF-β.In the liver,derangement of TGF-βsignaling is associated with an increased incidence of HCC,but the mechanism remains obscure.
Objective:Various TGF-βsensitive cell lines(including hepatocyte and hepatoma cell lines) and TGF-βresistant hepatoma cell lines were employed for investigation. The present study investigated the role of transforming growth factor-beta(TGF-β) inducible early gene 1(TIEG1) in TGF-βmediated hepatoma cells growth inhibition and the mechanism of TIEG1 induced HCC cells growth inhibition.
Methods:In this study,one TGF-βsensitive hepatocyte cell line(i.e.MIHA),one TGF-βsensitive hepatoma cell line(i.e.Hep3B) and two TGF-βinsensitive hepatoma cell lines(HepG2,Bel7404) were employed for investigation.RT-PCR detected the TGF-βsignal relative gene expression level changes in response to TGF-β1 with time(0, 0.5,1,2,4 h).SiRNA targeting TIEG1 in TGF-βsensitive hepatoma cell line Hep3B, observe the change of cells TGF-βsensitive extent.Overexpression of TIEG1 in TGF-βresistant hepatoma cells by lentivirus,study the role of TIEG1 in TGF-β1 mediated hepatoma cells growth inhibition.Western blot analysis was performed to detect stathmin expression by TGF-β1 treatment or TIEG1 overexpression.Luciferase reporter assay detected the stathmin promoter activity with TIEG1 gene.And chromatin immunoprecipitation was performed to detect TIEG1 protein associated with stathmin promoter.Ectopic overexpression of stathmin in HCC cells by lentivirus,observe the effect of rescue the growth inhibition caused by TIEG1.
Results:(1) Studies revealed that TIEG1 mRNA sharply increased of TGF-β1 treatment of TGF-βsensitive cells(Hep3B,MIHA) and reached a maximum of approximately 7～11 fold above control levels at 1 h post treatment,however TIEG1 mRNA weakly increased(2～3 fold) of TGF-β1 treatment of TGF-βinsensitive cells (HepG2,Be17404),the TIEG1 expression level in TGF-βinsensitive cells was significantly lower than that of TGF-βsensitive cells.(2) The siRNA targeting TIEG1 decreased the mRNA expression level of TIEG1 and consequently increased the survival rate of the cells by～25%with TGF-β1 treatment.(3) Overexpression of TIEG1 mediated cell growth inhibition and induced apoptosis in TGF-β1 resistant hepatoma cells(HepG2,Bel7404).(4) Overexpression of TIEG1 was found to decrease stathmin expression at both the transcription and translational levels thought regulation of stathmin promoter activity,stathmin expression was also inhibited by TGF-β1 in Hep3B cells with time.(5)Overexpression of stathmin could rescue TIEG1 mediated cell growth inhibition in HCC cells.
Conclusion:(1) The gain or lose in TIEG1 expression in response to TGF-β1 treatment is well correlated with the TGF-βcell proliferation inhibitory pathway.(2) A signaling pathway including the TGF-β,TIEG1 and stathmin is deduced,also suggested a novel strategy which is to overexpress TIEG1 and to suppress stathmin expression at the same time for treating HCC cells,despite the existence of TGF-βresistance.Overall, a detailed understanding of the underlying molecular mechanisms involved in the progression of HCC could hold promise for new therapeutic approaches in human HCCs.
PartⅡLentiviral Vector mediated overexpression of TIEG1 inhibit pancreatic cancer cell growth and render cells more sensitive to gemicitabine in vitro
Background:Pancreatic cancer is one of the most malignant tumors in the world. The incidence and mortality rates of pancreatic cancer have been rising over the years. For this disease is basically a drug-resistant tumor,new therapeutic strategyis pressingly needed to overcome the drug-resistance and to improve the long-term survival rate. Transforming growth factor-beta(TGF-β) inducible early gene 1(TIEG1) is known to induce apoptosis in TGF-βsensitive pancreatic cancer cells,yet its effect on TGF-βresistant pancreatic cancer cells growth and chemosensitivity remains unclear.
Objective:The purpose of this study was to determine whether overexpression of TIEG1 inhibit pancreatic cancer cell growth and render cells more sensitive to gemicitabine in vitro.
Methods:Overexpression of TIEG1 gene in pancreatic cancer cell lines SW1990, Canpan-2 and immortalized human pancreatic ductal cell line HPDE6-E6E7-c7 by lentivirus,measurement of cell proliferation and gemcitabine chemosensitivity by methylthiazoletetrazolium(MTT) assay.Real time PCR and Western blot analysis were performed to detect stathmin expression after lenti-TIEG1 infected.Ectopic overexpression of stathmin by lentivirus,observe the effect of rescue the growth inhibition caused by TIEG1.SiRNAs targeting stathmin(siSTMN) was transfected into Capan-2 and SW1990 cells,observe the the inhibitory effect on stathmin expression and cell proliferation in pancreatic cancer cells.
Results:(1) Overexpression of TIEG1 could inhibite pancreatic cancer cell growth, and the growth inhibitory efficiency of immortalized human pancreatic ductal cell line HPDE6-E6E7-c7 caused by TIEG1 was significantly lower than that of pancreatic cancer Capan-2 and SW1990 cells.(2) Overexpression of TIEG1 could induce apoptosis and enhance gemcitabine chemosensitivity of pancreatic cells.(3) Stathmin was a downstream target of TIEG1 leading to cell growth inhibition,owerexpression of stathmin significantly prevented TIEG1 mediated pancreatic cells growth inhibition.(4) SiRNA targeting stathmin has also found to inhibited pancreatic cancer cell growth.
Conclusion:TIEG1 was found to induce growth inhibition of pancreatic cancer cells and concurrently enhanced gemcitabine chemosensitivity through downregulation of stathmin.This study suggests a synergistic antitumor ability by combining TIEG1 gene therapy with conventional chemotherapy.
研究背景:肝癌是世界上第五大恶性肿瘤,晚期患者治疗难度大、疗效差,目前尚无有效的治疗策略。因此研究肝癌的发病机制,寻找新的治疗靶点和疗法是目前研究热点。TGF-β在体外能抑制肝细胞增殖和诱导细胞凋亡,在体内控制肝细胞的生长,维持肝脏大小。然而,在肝癌细胞中,往往对TGF-β失去敏感性,被认为是肝癌发病的机制之一,但其机理尚未完全阐明。
研究目的:通过筛选对TGF-β1不同敏感程度的细胞株(包括正常肝细胞和肝癌细胞),以此为模型,研究肝癌细胞对TGF-β敏感性缺失的主要原因以及TIEG1抑制肝癌细胞生长的作用机制。
研究方法:选取了对TGF-β敏感的肝癌细胞株Hep3B和正常永生化的肝细胞株MIHA,以及对TGF-β不敏感的两株肝癌细胞株(HepG2、Bel7404)做为细胞模型。TGF-β1处理0、0.5、1、2、4 h后,RT-PCR方法检测TGF-β不同敏感程度的细胞株之间TGF-β信号通路主要相关基因表达的差异;利用siRNA抑制TGF-β敏感肝癌细胞Hep3B的TIEG1表达,观察细胞对TGF-β1敏感性的改变;利用慢病毒载体在TGF-β不敏感肝癌细胞(HepG2、Bel7404)中过表达TIEG1,研究TIEG1在TGF-β1对肝癌细胞生长抑制中的作用。Western blot检测TGF-β1和TIEG1对stathmin表达的影响;萤光素酶报告基因检测TIEG1对stathmin启动子的调控;采用染色质免疫共沉淀方法,观察TIEG1对stathmin启动子区域的直接结合作用;并进一步在TIEG1过表达的肝癌细胞中同时过表达stathmin,研究对逆转TIEG1抑制细胞生长的作用。
研究结果:(1)在检测TGF-β1处理细胞后的早期基因反应中,发现在TGF-β敏感的细胞(Hep3B、MIHA)中,TGF-β1能强烈诱导TIEG1基因表达上调(7～11倍),并在1h时达到高峰;而在对TGF-β不敏感的细胞(HepG2、Bel7404)中,TIEG1基因表达只有微弱的上调(2～3倍),TGF-β敏感的细胞中TIEG1基因表达变化显著高于TGF-β不敏感的细胞。(2)应用siRNA抑制TGF-β敏感肝癌细胞Hep3B中TIEG1基因表达,可以使Hep3B细胞对TGF-β1的敏感性降低。(3)在TGF-β不敏感的肝癌细胞(HepG2、Bel7404)中过表达TIEG1,可以抑制肝癌细胞的增殖和诱导凋亡。(4) TIEG1可以通过直接结合stathmin启动子区域,调控启动子活性,下调stathmin的表达;TGF-β1处理敏感肝癌细胞Hep3B也可使stathmin表达下调。(5)在TIEG1过表达的肝癌细胞中同时过表达stathmin,可以明显逆转TIEG1对肝癌细胞的生长抑制作用。
结论:(1) TGF-β1处理后,TIEG1基因早期表达反应能力的减弱,是导致肝癌细胞对TGF-β1丧失敏感性的主要原因。(2)阐明了TGF-β1对TIEG1基因及下游stathmin的调控作用,提出假设的“TGF-β1—＞TIEG1—＞stathmin—＞细胞增殖抑制”新的信号通路,揭示TIEG1基因在TGF-β1介导肝癌细胞生长抑制中的重要作用。本研究为探讨肝癌发病机制,寻找新的治疗靶点提供了实验依据。
第二部分慢病毒载体过表达TIEG1对胰腺癌细胞生长抑制和化疗药物的增敏作用
研究背景:胰腺癌是目前已知的恶性程度最高的肿瘤之一。近年来,人胰腺癌的发病率和死亡率呈上升趋势,严重影响着人们的生活质量。大部分胰腺癌细胞对化疗药物耐药,导致胰腺癌预后极差。寻找更加有效的治疗方法,成为目前胰腺癌治疗的关键。TIEG1可以诱导TGF-β敏感胰腺癌细胞凋亡,抑制细胞生长,但对TGF-β不敏感胰腺癌细胞生长和化疗药物敏感性的影响尚未阐明。
研究目的:研究在胰腺癌细胞中过表达TIEG1对胰腺癌细胞生长和化疗药物敏感性的影响,并探讨其作用机制。
研究方法:利用慢病毒转基因系统,在胰腺癌细胞株(SW1990和Canpan-2)以及永生化正常胰腺导管细胞株(HPDE6-E6E7-c7)中过表达TIEG1,MTT法测定其对胰腺癌细胞和正常细胞生长抑制作用的差异;DAPI染色法检测TIEG1对胰腺癌细胞凋亡的影响;MTT法测定过表达TIEG1后,胰腺癌细胞对化疗药物吉西他滨敏感性的改变;实时定量PCR和Western blot方法检测TIEG1对胰腺癌细胞stathmin表达的影响;用慢病毒过表达stathmin,研究对逆转TIEG1抑制胰腺癌细胞生长的作用;利用特异性siRNA抑制stathmin的表达,观察对胰腺癌细胞生长的影响。
研究结果:(1)慢病毒载体过表达TIEG1基因能抑制胰腺细胞生长,并且在肿瘤细胞中抑制效果明显高于正常胰腺癌细胞株,具有统计学意义。(2)过表达TIEG1基因可以诱导胰腺癌细胞凋亡,促进肿瘤细胞对化疗药物吉西他滨的敏感性。(3) TIEG1可以下调胰腺癌细胞stathmin的表达;同时用慢病毒转染方法过表达stathmin可以一定程度逆转TIEG1基因对肿瘤细胞的生长抑制作用。(4)用siRNA转染胰腺癌细胞,下调stathmin的表达,也可以抑制胰腺癌细胞的生长。
结论:TIEG1基因主要通过下调stathmin表达抑制胰腺癌细胞株的生长,促进对化疗药物吉西他滨的敏感性,有可能成为胰腺癌基因治疗及联合化疗药物治疗的新靶点。
PartⅠThe role of TIEG1 gene in TGF-β1 mediated hepatoma cells growth inhibition
Background:Hepatocellular carcinoma(HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide,with few effective therapeutic options for advanced disease.The new therapeutic strategy and pathogenesis of HCC become more and more important.In hepatocytes,TGF-βacts as a tumor suppressor through growth inhibition and induces apoptosis in vitro and in vivo to control the excessive growth of hepatocytes and maintenance of liver size.However,HCC cells are frequently thought to have lost their sensitivity to TGF-β.In the liver,derangement of TGF-βsignaling is associated with an increased incidence of HCC,but the mechanism remains obscure.
Objective:Various TGF-βsensitive cell lines(including hepatocyte and hepatoma cell lines) and TGF-βresistant hepatoma cell lines were employed for investigation. The present study investigated the role of transforming growth factor-beta(TGF-β) inducible early gene 1(TIEG1) in TGF-βmediated hepatoma cells growth inhibition and the mechanism of TIEG1 induced HCC cells growth inhibition.
Methods:In this study,one TGF-βsensitive hepatocyte cell line(i.e.MIHA),one TGF-βsensitive hepatoma cell line(i.e.Hep3B) and two TGF-βinsensitive hepatoma cell lines(HepG2,Bel7404) were employed for investigation.RT-PCR detected the TGF-βsignal relative gene expression level changes in response to TGF-β1 with time(0, 0.5,1,2,4 h).SiRNA targeting TIEG1 in TGF-βsensitive hepatoma cell line Hep3B, observe the change of cells TGF-βsensitive extent.Overexpression of TIEG1 in TGF-βresistant hepatoma cells by lentivirus,study the role of TIEG1 in TGF-β1 mediated hepatoma cells growth inhibition.Western blot analysis was performed to detect stathmin expression by TGF-β1 treatment or TIEG1 overexpression.Luciferase reporter assay detected the stathmin promoter activity with TIEG1 gene.And chromatin immunoprecipitation was performed to detect TIEG1 protein associated with stathmin promoter.Ectopic overexpression of stathmin in HCC cells by lentivirus,observe the effect of rescue the growth inhibition caused by TIEG1.
Results:(1) Studies revealed that TIEG1 mRNA sharply increased of TGF-β1 treatment of TGF-βsensitive cells(Hep3B,MIHA) and reached a maximum of approximately 7～11 fold above control levels at 1 h post treatment,however TIEG1 mRNA weakly increased(2～3 fold) of TGF-β1 treatment of TGF-βinsensitive cells (HepG2,Be17404),the TIEG1 expression level in TGF-βinsensitive cells was significantly lower than that of TGF-βsensitive cells.(2) The siRNA targeting TIEG1 decreased the mRNA expression level of TIEG1 and consequently increased the survival rate of the cells by～25%with TGF-β1 treatment.(3) Overexpression of TIEG1 mediated cell growth inhibition and induced apoptosis in TGF-β1 resistant hepatoma cells(HepG2,Bel7404).(4) Overexpression of TIEG1 was found to decrease stathmin expression at both the transcription and translational levels thought regulation of stathmin promoter activity,stathmin expression was also inhibited by TGF-β1 in Hep3B cells with time.(5)Overexpression of stathmin could rescue TIEG1 mediated cell growth inhibition in HCC cells.
Conclusion:(1) The gain or lose in TIEG1 expression in response to TGF-β1 treatment is well correlated with the TGF-βcell proliferation inhibitory pathway.(2) A signaling pathway including the TGF-β,TIEG1 and stathmin is deduced,also suggested a novel strategy which is to overexpress TIEG1 and to suppress stathmin expression at the same time for treating HCC cells,despite the existence of TGF-βresistance.Overall, a detailed understanding of the underlying molecular mechanisms involved in the progression of HCC could hold promise for new therapeutic approaches in human HCCs.
PartⅡLentiviral Vector mediated overexpression of TIEG1 inhibit pancreatic cancer cell growth and render cells more sensitive to gemicitabine in vitro
Background:Pancreatic cancer is one of the most malignant tumors in the world. The incidence and mortality rates of pancreatic cancer have been rising over the years. For this disease is basically a drug-resistant tumor,new therapeutic strategyis pressingly needed to overcome the drug-resistance and to improve the long-term survival rate. Transforming growth factor-beta(TGF-β) inducible early gene 1(TIEG1) is known to induce apoptosis in TGF-βsensitive pancreatic cancer cells,yet its effect on TGF-βresistant pancreatic cancer cells growth and chemosensitivity remains unclear.
Objective:The purpose of this study was to determine whether overexpression of TIEG1 inhibit pancreatic cancer cell growth and render cells more sensitive to gemicitabine in vitro.
Methods:Overexpression of TIEG1 gene in pancreatic cancer cell lines SW1990, Canpan-2 and immortalized human pancreatic ductal cell line HPDE6-E6E7-c7 by lentivirus,measurement of cell proliferation and gemcitabine chemosensitivity by methylthiazoletetrazolium(MTT) assay.Real time PCR and Western blot analysis were performed to detect stathmin expression after lenti-TIEG1 infected.Ectopic overexpression of stathmin by lentivirus,observe the effect of rescue the growth inhibition caused by TIEG1.SiRNAs targeting stathmin(siSTMN) was transfected into Capan-2 and SW1990 cells,observe the the inhibitory effect on stathmin expression and cell proliferation in pancreatic cancer cells.
Results:(1) Overexpression of TIEG1 could inhibite pancreatic cancer cell growth, and the growth inhibitory efficiency of immortalized human pancreatic ductal cell line HPDE6-E6E7-c7 caused by TIEG1 was significantly lower than that of pancreatic cancer Capan-2 and SW1990 cells.(2) Overexpression of TIEG1 could induce apoptosis and enhance gemcitabine chemosensitivity of pancreatic cells.(3) Stathmin was a downstream target of TIEG1 leading to cell growth inhibition,owerexpression of stathmin significantly prevented TIEG1 mediated pancreatic cells growth inhibition.(4) SiRNA targeting stathmin has also found to inhibited pancreatic cancer cell growth.
Conclusion:TIEG1 was found to induce growth inhibition of pancreatic cancer cells and concurrently enhanced gemcitabine chemosensitivity through downregulation of stathmin.This study suggests a synergistic antitumor ability by combining TIEG1 gene therapy with conventional chemotherapy.
引文
[1] Zender L,Kubicka S.Molecular pathogenesis and targeted therapy of hepatocellular carcinoma.Onkologie 2008;31(10):550-5.
[2] Kudo M.Hepatocellular carcinoma 2009 and beyond:from the surveillance to molecular targeted therapy.Oncology 2008;75 Suppl 1:1-12.
[3] Thomas M.Molecular targeted therapy for hepatocellular carcinoma.J Gastroenterol 2009;44 Suppl 19:136-41.
[4] Watabe T,Miyazono K.Roles of TGF-beta family signaling in stem cell renewal and differentiation.Cell Res 2009;19(1):103-15.
[5] Kitisin K,Saha T,Blake T,Golestaneh N,Deng M,Kim C,Tang Y,Shetty K,Mishra B,Mishra L.Tgf-Beta signaling in development.Sci STKE 2007;2007(399):cm1.
[6] Kitisin K,Ganesan N,Tang Y,Jogunoori W,Volpe EA,Kim SS,Katuri V,Kallakury B,Pishvaian M,Albanese C,Mendelson J,Zasloff M,Rashid A,Fishbein T,Evans SR,Sidawy A,Reddy EP,Mishra B,Johnson LB,Shetty K,Mishra L.Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin Dl activation.Oncogene 2007;26(50):7103-10.
[7] Damdinsuren B,Nagano H,Kondo M,Natsag J,Hanada H,Nakamura M,Wada H,Kato H,Marubashi S,Miyamoto A,Takeda Y,Umeshita K,Dono K,Monden M.TGF-beta 1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.Oncol Rep 2006;15(2):401-8.
[8] Padua D,Massague J.Roles of TGFbeta in metastasis.Cell Res 2009;19(1):89-102.
[9] Truty MJ,Urrutia R.Basics of TGF-beta and pancreatic cancer.Pancreatology 2007;7(5-6):423-35.
[10] Nakamura T,Tomita Y,Hirai R,Yamaoka K,Kaji K,Ichihara A.Inhibitory effect of transforming growth factor-beta on DNA synthesis of adult rat hepatocytes in primary culture.Biochem Biophys Res Commun 1985;133(3):1042-50.
[11]Oberhammer F,Bursch W,Parzefall W,Breit P,Erber E,Stadler M,Schulte-Hermann R.Effect of transforming growth factor beta on cell death of cultured rat hepatocytes.Cancer Res 1991;51(9):2478-85.
[12]Tang Y,Kitisin K,Jogunoori W,Li C,Deng CX,Mueller SC,Ressom HW,Rashid A,He AR,Mendelson JS,Jessup JM,Shetty K,Zasloff M,Mishra B,Reddy EP,Johnson L,Mishra L.Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling.Proc Natl Acad Sci U S A 2008;105(7):2445-50.
[13]Pearson R,Fleetwood J,Eaton S,Crossley M,Bao S.Kriippel-like transcription factors:a functional family.Int J Biochem Cell Biol 2008;40(10):1996-2001.
[14]Subramaniam M,Hawse JR,Johnsen SA,Spelsberg TC.Role of TIEG1 in biological processes and disease states.J Cell Biochem 2007;102(3):539-48.
[15]Zhang YE.Non-Smad pathways in TGF-beta signaling.Cell Res 2009;19(1):128-39.
[16]Inoue Y,Imamura T.Regulation of TGF-beta family signaling by E3 ubiquitin ligases.Cancer Sci 2008;99(11):2107-12.
[17]Ribeiro A,Bronk SF,Roberts PJ,Urrutia R,Gores GJ.The transforming growth factor beta(1)-inducible transcription factor TIEGl,mediates apoptosis through oxidative stress.Hepatology 1999;30(6):1490-7.
[18]Chalaux E,Lopez-Rovira T,Rosa JL,Pons G,Boxer LM,Bartrons R,Ventura F.A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell death in epithelial Mvl Lu cells.FEBS Lett 1999;457(3):478-82.
[19]Tachibana I,Imoto M,Adjei PN,Gores GJ,Subramaniam M,Spelsberg TC,Urrutia R.Overexpression of the TGFbeta-regulated zinc finger encoding gene,TIEG,induces apoptosis in pancreatic epithelial cells.J Clin Invest 1997;99(10):2365-74.
[20]Johnsen SA,Subramaniam M,Monroe DG,Janknecht R,Spelsberg TC.Modulation of transforming growth factor beta(TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta inducible early gene-1 by human seven in absentia homologue.J Biol Chem 2002;277(34):30754-9.
[21]Johnsen SA,Subramaniam M,Janknecht R,Spelsberg TC.TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses.Oncogene 2002;21(37):5783-90.
[22]Lin X,Liu S,Luo X,Ma X,Guo L,Li L,Li Z,Tao Y,Cao Y.EBV-encoded LMP1 regulates Op 18/stathmin signaling pathway by cdc2 mediation in nasopharyngeal carcinoma cells.Int J Cancer 2009;124(5):1020-7.
[23]Chen Y,Lin MC,Yao H,Wang H,Zhang AQ,Yu J,Hui CK,Lau GK,He ML,Sung J,Kung HF.Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin.Hepatology 2007;46(1):200-8.
[24]El-Bassiouny AE,Zoheiry MM,Nosseir MM,El-Ahwany EG,Ibrahim RA,El-Bassiouni NE.Expression of cyclooxygenase-2 and transforming growth factor-beta 1 in HCV-induced chronic liver disease and hepatocellular carcinoma.MedGenMed 2007;9(3):45.
[25]Matsuzaki K,Murata M,Yoshida K,Sekimoto G,Uemura Y,Sakaida N,Kaibori M,Kamiyama Y,Nishizawa M,Fujisawa J,Okazaki K,Seki T.Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling,promoting cirrhosis and hepatocellular carcinoma.Hepatology 2007;46(1):48-57.
[26]Hjelmeland AB,Hjelmeland MD,Shi Q,Hart JL,Bigner DD,Wang XF,Kontos CD,Rich JN.Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.Cancer Res 2005;65(24):11276-81.
[27]Mouri H,Sakaguchi K,Sawayama T,Senoh T,Ohta T,Nishimura M,Fujiwara A,Terao M,Shiratori Y,Tsuji T.Suppressive effects of transforming growth factor-beta 1 produced by hepatocellular carcinoma cell lines on interferon-gamma production by peripheral blood mononuclear cells.Acta Med Okayama 2002;56(6):309-15.
[28]Gong Y,Zhang M,Minuk GY.Regulation of transforming growth factor-betal gene expression and cell proliferation in human hepatocellular carcinoma cells(PLC/PRF/5)by tamoxifen.J Lab Clin Med 1999;134(1):90-5.
[29]Hung WC,Chuang LY,Tsai JH,Chang CC.Effects of insulin on TGF-beta 1-induced cell growth inhibition in the human hepatoma cell lines.Biochem Mol Biol Int 1993;30(4):655-63.
[30]Hashimoto O,Ueno T,Kimura R,Ohtsubo M,Nakamura T,Koga H,Torimura T,Uchida S,Yamashita K,Sata M.Inhibition of proteasome-dependent degradation of Weel in G2-arrested Hep3B cells by TGF beta 1.Mol Carcinog 2003;36(4):171-82.
[31]Nishikawa Y,Kar S,Wiest L,Pegg AE,Carr BI.Inhibition of spermidine synthase gene expression by transforming growth factor-beta 1 in hepatoma cells.Biochem J 1997;321(Pt 2):537-43.
[32]Inagaki M,Wang Z,Carr BI.Transforming growth factor beta 1 selectively increases gene expression of the serine/threonine kinase receptor 1(SKR1)in human hepatoma cell lines.Cell Struct Funct 1994;19(5):305-13.
[33]Katabami K,Mizuno H,Sano R,Saito Y,Ogura M,Itoh S,Tsuji T.Transforming growth factor-beta 1 upregulates transcription of alpha3 integrin gene in hepatocellular carcinoma cells via Ets-transcription factor-binding motif in the promoter region.Clin Exp Metastasis 2005;22(7):539-48.
[34]Subramaniam M,Harris SA,Oursler MJ,Rasmussen K,Riggs BL,Spelsberg TC.Identification of a novel TGF-beta-regulated gene encoding a putative zinc finger protein in human osteoblasts.Nucleic Acids Res 1995;23(23):4907-12.
[35]Chrisman HR,Tindall DJ.Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha.DNA Cell Biol 2003;22(3):187-99.
[36]Cook T,Urrutia R.TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth.Am J Physiol Gastrointest Liver Physiol 2000;278(4):G513-21.
[37]Noti JD,Johnson AK,Dillon JD.The zinc finger transcription factor transforming growth factor beta-inducible early gene-1 confers myeloid-specific activation of the leukocyte integrin CDlld promoter.J Biol Chem 2004;279(26):26948-58.
[38] Frecha C,Szecsi J,Cosset FL,Verhoeyen E.Strategies for targeting lentiviral vectors.Curr Gene Ther 2008;8(6):449-60.
[39] Yang YA,Zhang GM,Feigenbaum L,Zhang YE.Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2.Cancer Cell 2006;9(6):445-57.
[40] Singer S,Ehemann V,Brauckhoff A,Keith M,Vreden S,Schirmacher P,Breuhahn K. Protumorigenic overexpression of stathmin/Op 18 by gain-of-function mutation in p53 in human hepatocarcinogenesis.Hepatology 2007;46(3):759-68.
[41] Sellin ME,Holmfeldt P,Stenmark S,Gullberg M.Op18/Stathmin counteracts the activity of overexpressed tubulin-disrupting proteins in a human leukemia cell line.Exp Cell Res 2008;314(6):1367-77.
[42] Rana S,Maples PB,Senzer N,Nemunaitis J.Stathmin 1:a novel therapeutic target for anticancer activity.Expert Rev Anticancer Ther 2008;8(9):1461-70.
[43] Sadow PM,Rumilla KM,Erickson LA,Lloyd RV.Stathmin expression in pheochromocytomas,paragangliomas,and in other endocrine tumors.Endocr Pathol 2008;19(2):97-103.
[44] Jeha S,Luo XN,Beran M,Kantarjian H,Atweh GF.Antisense RNA inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells.Cancer Res 1996;56(6):1445-50.
[45] Wang X,Chen Y,Han QB,Chan CY,Wang H,Liu Z,Cheng CH,Yew DT,Lin MC,He ML,Xu HX,Sung JJ,Kung HF.Proteomic identification of molecular targets of gambogic acid:role of stathmin in hepatocellular carcinoma.Proteomics 2009;9(2):242-53.
[46] Alli E,Yang JM,Hait WN.Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53.Oncogene 2007;26(7):1003-12.
[47] Jemal A,Siegel R,Ward E,Murray T,Xu J,Smigal C,Thun MJ.Cancer statistics,2006.CA Cancer J Clin 2006;56(2):106-30.
[48] Borja-Cacho D,Jensen EH,Saluja AK,Buchsbaum DJ,Vickers SM.Molecular targeted therapies for pancreatic cancer.Am J Surg 2008;196(3):430-41.
[49]Subramaniam M,Hefferan TE,Tau K,Peus D,Pittelkow M,Jalal S,Riggs BL,Roche P,Spelsberg TC.Tissue,cell type,and breast cancer stage-specific expression of a TGF-beta inducible early transcription factor gene.J Cell Biochem 1998;68(2):226-36.
[50]Fautsch MP,Vrabel A,Subramaniam M,Hefferen TE,Spelsberg TC,Wieben ED.TGFbeta-inducible early gene(TIEG)also codes for early growth response alpha(EGRalpha):evidence of multiple transcripts from alternate promoters.Genomics 1998;51(3):408-16.
[51]Blok LJ,Grossmann ME,Perry JE,Tindall DJ.Characterization of an early growth response gene,which encodes a zinc finger transcription factor,potentially involved in cell cycle regulation.Mol Endocrinol 1995;9(11):1610-20.
[52]Yajima S,Lammers CH,Lee SH,Hara Y,Mizuno K,Mouradian MM.Cloning and characterization of murine glial cell-derived neurotrophic factor inducible transcription factor(MGIF).J Neurosci 1997;17(22):8657-66.
[53]Cook T,Gebelein B,Belal M,Mesa K,Urrutia R.Three conserved transcriptional repressor domains are a defining feature of the TIEG subfamily of Sp1-like zinc finger proteins.J Biol Chem 1999;274(41):29500-4.
[54]Eid MA,Kumar MV,Iczkowski KA,Bostwick DG,Tindall DJ.Expression of early growth response genes in human prostate cancer.Cancer Res 1998;58(11):2461-8.
[55]Chen GG,Xu H,Lee JF,Subramaniam M,Leung KL,Wang SH,Chan UP,Spelsberg TC.15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway.Int J Cancer 2003;107(5):837-43.
[56]Antonello D,Moore PS,Zamboni G,Falconi M,Scarpa A.Absence of mutations in the transforming growth factor-beta inducible early gene 1,TIEG1,in pancreatic cancer.Cancer Lett 2002;183(2):179-83.
[57]Reinholz MM,An MW,Johnsen SA,Subramaniam M,Suman VJ,Ingle IN,Roche PC,Spelsberg TC.Differential gene expression of TGF beta inducible early gene(TIEG),Smad7,Smad2 and Bardl in normal and malignant breast tissue.Breast Cancer Res Treat 2004;86(1):75-88.
[58] Shiraishi K,Okita K,Kusano N,Harada T,Kondoh S,Okita S,Ryozawa S,Ohmura R,Noguchi T,Iida Y,Akiyama T,Oga A,Fukumoto Y,Furuya T,Kawauchi S,Sasaki K.A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver,biliary tract and pancreas.Oncology 2001;60(2):151-61.
[59] Schleger C,Arens N,Zentgraf H,Bleyl U,Verbeke C.Identification of frequent chromosomal aberrations in ductal adenocarcinoma of the pancreas by comparative genomic hybridization(CGH).J Pathol 2000;191(1):27-32.
[60] Sato N,Mizumoto K,Nakamura M,Maehara N,Minamishima YA,Nishio S,Nagai E,Tanaka M.Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells.Cancer Genet Cytogenet 2001;126(1):13-9.
[61] lancu-Rubin C,Atweh GF.p27(Kipl)and stathmin share the stage for the first time.Trends Cell Biol 2005;15(7):346-8.
[62] lacobuzio-Donahue CA,Maitra A,Shen-Ong GL,van Heek T,Ashfaq R,Meyer R,Walter K,Berg K,Hollingsworth MA,Cameron JL,Yeo CJ,Kern SE,Goggins M,Hruban RH.Discovery of novel tumor markers of pancreatic cancer using global gene expression technology.Am J Pathol 2002;160(4):1239-49.
[63] Teraoka H,Sawada T,Nishihara T,Yashiro M,Ohira M,Ishikawa T,Nishino H,Hirakawa K.Enhanced VEGF production and decreased immunogenicity induced by TGF-beta 1 promote liver metastasis of pancreatic cancer.Br J Cancer 2001;85(4):612-7.
[64] Bender H,Wang Z,Schuster N,Krieglstein K.TIEG1 facilitates transforming growth factor-beta-mediated apoptosis in the oligodendroglial cell line OLI-neu.J Neurosci Res 2004;75(3):344-52.
[65] Kleeff J,Ishiwata T,Maruyama H,Friess H,Truong P,Buchler MW,Falb D,Korc M.The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer.Oncogene 1999;18(39):5363-72.
[66]Nakano Y,Tanno S,Koizumi K,Nishikawa T,Nakamura K,Minoguchi M,Izawa T,Mizukami Y,Okumura T,Kohgo Y.Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.Br J Cancer 2007;96(3):457-63.
[67]Kunnumakkara AB,Guha S,Krishnan S,Diagaradjane P,Gelovani J,Aggarwal BB.Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation,angiogenesis,and inhibition of nuclear factor-kappaB-regulated gene products.Cancer Res 2007;67(8):3853-61.
[68]Yu C,Zhang X,Sun G,Guo X,Li H,You Y,Jacobs JL,Gardner K,Yuan D,Xu Z,Du Q,Dai C,Qian Z,Jiang K,Zhu Y,Li QQ,Miao Y.RNA interference-mediated silencing of the polo-like kinase 1 gene enhances chemosensitivity to gemcitabine in pancreatic adenocarcinoma cells.J Cell Mol Med 2008;12(6A):2334-49.
[69]Chen Y,Lin MC,Wang H,Chan CY,Jiang L,Ngai SM,Yu J,He ML,Shaw PC,Yew DT,Sung JJ,Kung HF.Proteomic analysis of EZH2 downstream target proteins in hepatocellular carcinoma.Proteomics 2007;7(17):3097-104.
[70]Mistry SJ,Bank A,Atweh GF.Targeting stathmin in prostate cancer.Mol Cancer Ther 2005;4(12):1821-9.
[71]Johnsen JI,Aurelio ON,Kwaja Z,Jorgensen GE,Pellegata NS,Plattner R,Stanbridge EJ,Cajot JF.p53-mediated negative regulation of stathmin/Op18 expression is associated with G(2)/M cell-cycle arrest.Int J Cancer 2000;88(5):685-91.
[72]lancu C,Mistry SJ,Arkin S,Atweh GF.Taxol and anti-stathmin therapy:a synergistic combination that targets the mitotic spindle.Cancer Res 2000;60(13):3537-41.
[1] Subramaniam M,Harris SA,Oursler MJ,Rasmussen K,Riggs BL,Spelsberg TC.Identification of a novel TGF-beta regulated gene encoding a putative zinc finger protein in human osteoblasts.Nucleic Acids Res 1995;23(23):4907-12.
[2] Hefferan TE,Subramaniam M,Khosla S,Riggs BL,Spelsberg TC.Cytokine-specific induction of the TGF-beta inducible early gene(TIEG):regulation by specific members of the TGF-beta family.J Cell Biochem 2000;78(3):380-90.
[3] Fautsch MP,Vrabel A,Rickard D,Subramaniam M,Spelsberg TC,Wieben ED.Characterization of the mouse TGFbeta-inducible early gene(TIEG):conservation of exon and transcriptional regulatory sequences with evidence of additional transcripts.Mamm Genome 1998;9(10):838-42.
[4] Cook T,Gebelein B,Belal M,Mesa K,Urrutia R.Three conserved transcriptional repressor domains are a defining feature of the TIEG subfamily of Sp1-like zinc finger proteins.J Biol Chem 1999;274(41):29500-4.
[5] Chrisman HR,Tindall DJ.Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha.DNA Cell Biol 2003;22(3):187-99.
[6] Cook T,Urrutia R.TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth.Am J Physiol Gastrointest Liver Physiol 2000;278(4):G513-21.
[7] Subramaniam M,Hawse JR,Johnsen SA,Spelsberg TC.Role of TIEG1 in biological processes and disease states.J Cell Biochem 2007;102(3):539-48.
[8] Blok LJ,Grossmann ME,Perry JE,Tindall DJ.Characterization of an early growth response gene,which encodes a zinc finger transcription factor,potentially involved in cell cycle regulation.Mol Endocrinol 1995;9(11):1610-20.
[9] Wang Z,Peters B,Klussmann S,Bender H,Herb A,Krieglstein K.Gene structure and evolution of Tieg3,a new member of the Tieg family of proteins.Gene 2004;325:25-34.
[10] Johnsen SA,Subramaniam M,Monroe DG,Janknecht R,Spelsberg TC.Modulation of transforming growth factor beta(TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta-inducible early gene-1 by human seven in absentia homologue.J Biol Chem 2002;277(34):30754-9.
[11] Ou XM,Chen K,Shih JC.Dual functions of transcription factors,transforming growth factor-beta-inducible early gene(TIEG)2 and Sp3,are mediated by CACCC element and Spl sites of human monoamine oxidase(MAO)B gene.J Biol Chem 2004;279(20):21021-8.
[12] Pearson R,Fleetwood J,Eaton S,Crossley M,Bao S.Kriippel-like transcription factors:a functional family.Int J Biochem Cell Biol 2008;40(10):1996-2001.
[13] Hefferan TE,Reinholz GG,Rickard DJ,Johnsen SA,Waters KM,Subramaniam M,Spelsberg TC.Overexpression of a nuclear protein,TIEG,mimics transforming growth factor-beta action in human osteoblast cells.J Biol Chem 2000;275(27):20255-9.
[14] Chalaux E,Lopez-Rovira T,Rosa JL,Pons G,Boxer LM,Bartrons R,Ventura F.A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell death in epithelial Mv1Lu cells.FEBS Lett 1999;457(3):478-82.
[15] Tachibana I,Imoto M,Adjei PN,Gores GJ,Subramaniam M,Spelsberg TC,Urrutia R.Overexpression of the TGFbeta-regulated zinc finger encoding gene,TIEG,induces apoptosis in pancreatic epithelial cells.J Clin Invest 1997;99(10):2365-74.
[16] Ribeiro A,Bronk SF,Roberts PJ,Urrutia R,Gores GJ.The transforming growth factor beta(1)-inducible transcription factor TIEG1,mediates apoptosis through oxidative stress.Hepatology 1999;30(6):1490-7.
[17] Johnsen SA,Subramaniam M,Janknecht R,Spelsberg TC.TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses.Oncogene 2002;21(37):5783-90.
[18] Subramaniam M,Hefferan TE,Tau K,Peus D,Pittelkow M,Jalal S,Riggs BL,Roche P,Spelsberg TC.Tissue,cell type,and breast cancer stage-specific expression of a TGF-beta inducible early transcription factor gene.J Cell Biochem 1998;68(2):226-36.
[19]Eid MA,Kumar MV,Iczkowski KA,Bostwick DG,Tindall DJ.Expression of early growth response genes in human prostate cancer.Cancer Res 1998;58(11):2461-8.
[20]Chen GG,Xu H,Lee JF,Subramaniam M,Leung KL,Wang SH,Chan UP,Spelsberg TC.15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway.Int J Cancer 2003;107(5):837-43.
[21]Antonello D,Moore PS,Zamboni G,Falconi M,Scarpa A.Absence of mutations in the transforming growth factor-beta inducible early gene 1,TIEG1,in pancreatic cancer.Cancer Lett 2002;183(2):179-83.
[22]Reinholz MM,An MW,Johnsen SA,Subramaniam M,Suman VJ,Ingle JN,Roche PC,Spelsberg TC.Differential gene expression of TGF beta inducible early gene(TIEG),Smad7,Smad2 and Bard1 in normal and malignant breast tissue.Breast Cancer Res Treat 2004;86(1):75-88.
[23]Jiang L,Chen Y,Chan CY,Wang X,Lin L,He ML,Lin MC,Yew DT,Sung J J,Li JC,Kung HF.Down-regulation of stathmin is required for TGF-beta inducible early gene 1 induced growth inhibition of pancreatic cancer cells.Cancer Lett 2009;274(1):101-8.
[24]Mitsumoto M,Mitsumoto A,Demple B.Nitric oxide-mediated upregulation of the TGF-beta-inducible early response gene-1(TIEG1)in human fibroblasts by mRNA stabilization independent of TGF-beta.Free Radic Biol Med 2003;34(12):1607-13.
[25]Partin JV,Anglin IE,Kyprianou N.Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.Br J Cancer 2003;88(10):1615-21.
[26]Jin W,Qu LF,Min P,Chen S,Li H,Lu H,Hou YT.Identification of genes responsive to apoptosis in HL-60 cells.Acta Pharmacol Sin 2004;25(3):319-26.
[27]Chen Y,Lin MC,Wang H,Chan CY,Jiang L,Ngai SM,Yu J,He ML,Shaw PC,Yew DT,Sung JJ,Kung HF.Proteomic analysis of EZH2 downstream target proteins in hepatocellular carcinoma.Proteomics 2007;7(17):3097-104.
[28] Chen Y,Lin MC,Yao H,Wang H,Zhang AQ,Yu J,Hui CK,Lau GK,He ML,Sung J,Kung HF.Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin.Hepatology 2007;46(1):200-8.
[29] Wang X,Chen Y,Han QB,Chan CY,Wang H,Liu Z,Cheng CH,Yew DT,Lin MC,He ML,Xu HX,Sung JJ,Kung HF.Proteomic identification of molecular targets of gambogic acid:role of stathmin in hepatocellular carcinoma.Proteomics 2009;9(2):242-53.
[30] Alli E,Yang JM,Hait WN.Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53.Oncogene 2007;26(7):1003-12.
[31] Rana S,Maples PB,Senzer N,Nemunaitis J.Stathmin 1:a novel therapeutic target for anticancer activity.Expert Rev Anticancer Ther 2008;8(9):1461-70.
[32] Bensamoun SF,Hawse JR,Subramaniam M,Ilharreborde B,Bassillais A,Benhamou CL,Fraser DG,Oursler MJ,Amadio PC,An KN,Spelsberg TC.TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture.Bone 2006;39(6):1244-51.
[33] Subramaniam M,Gorny G,Johnsen SA,Monroe DG,Evans GL,Fraser DG,Rickard DJ,Rasmussen K,van Deursen JM,Turner RT,Oursler MJ,Spelsberg TC.TIEG1 null mouse-derived osteoblasts are defective in mineralization and in support of osteoclast differentiation in vitro.Mol Cell Biol 2005;25(3):1191-9.
[34] Rajamannan NM,Subramaniam M,Abraham TP,Vasile VC,Ackerman MJ,Monroe DG,Chew TL,Spelsberg TC.TGFbeta inducible early gene-1(TIEG1)and cardiac hypertrophy:Discovery and characterization of a novel signaling pathway.J Cell Biochem 2007;100(2):315-25.
[35] Wang J,Xu N,Feng X,Hou N,Zhang J,Cheng X,Chen Y,Zhang Y,Yang X.Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure.Circ Res 2005;97(8):821-8.
[36] Tsubone T,Moran SL,Subramaniam M,Amadio PC,Spelsberg TC,An KN.Effect of TGF-beta inducible early gene deficiency on flexor tendon healing.J Orthop Res 2006;24(3):569-75.
[37]Bensamoun SF,Tsubone T,Subramaniam M,Hawse JR,Boumediene E,Spelsberg TC,An KN,Amadio PC.Age-dependent changes in the mechanical properties of tail tendons in TGF-beta inducible early gene-1 knockout mice.J Appl Physiol 2006;101(5):1419-24.
[2] Kudo M.Hepatocellular carcinoma 2009 and beyond:from the surveillance to molecular targeted therapy.Oncology 2008;75 Suppl 1:1-12.
[3] Thomas M.Molecular targeted therapy for hepatocellular carcinoma.J Gastroenterol 2009;44 Suppl 19:136-41.
[4] Watabe T,Miyazono K.Roles of TGF-beta family signaling in stem cell renewal and differentiation.Cell Res 2009;19(1):103-15.
[5] Kitisin K,Saha T,Blake T,Golestaneh N,Deng M,Kim C,Tang Y,Shetty K,Mishra B,Mishra L.Tgf-Beta signaling in development.Sci STKE 2007;2007(399):cm1.
[6] Kitisin K,Ganesan N,Tang Y,Jogunoori W,Volpe EA,Kim SS,Katuri V,Kallakury B,Pishvaian M,Albanese C,Mendelson J,Zasloff M,Rashid A,Fishbein T,Evans SR,Sidawy A,Reddy EP,Mishra B,Johnson LB,Shetty K,Mishra L.Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin Dl activation.Oncogene 2007;26(50):7103-10.
[7] Damdinsuren B,Nagano H,Kondo M,Natsag J,Hanada H,Nakamura M,Wada H,Kato H,Marubashi S,Miyamoto A,Takeda Y,Umeshita K,Dono K,Monden M.TGF-beta 1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.Oncol Rep 2006;15(2):401-8.
[8] Padua D,Massague J.Roles of TGFbeta in metastasis.Cell Res 2009;19(1):89-102.
[9] Truty MJ,Urrutia R.Basics of TGF-beta and pancreatic cancer.Pancreatology 2007;7(5-6):423-35.
[10] Nakamura T,Tomita Y,Hirai R,Yamaoka K,Kaji K,Ichihara A.Inhibitory effect of transforming growth factor-beta on DNA synthesis of adult rat hepatocytes in primary culture.Biochem Biophys Res Commun 1985;133(3):1042-50.
[11]Oberhammer F,Bursch W,Parzefall W,Breit P,Erber E,Stadler M,Schulte-Hermann R.Effect of transforming growth factor beta on cell death of cultured rat hepatocytes.Cancer Res 1991;51(9):2478-85.
[12]Tang Y,Kitisin K,Jogunoori W,Li C,Deng CX,Mueller SC,Ressom HW,Rashid A,He AR,Mendelson JS,Jessup JM,Shetty K,Zasloff M,Mishra B,Reddy EP,Johnson L,Mishra L.Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling.Proc Natl Acad Sci U S A 2008;105(7):2445-50.
[13]Pearson R,Fleetwood J,Eaton S,Crossley M,Bao S.Kriippel-like transcription factors:a functional family.Int J Biochem Cell Biol 2008;40(10):1996-2001.
[14]Subramaniam M,Hawse JR,Johnsen SA,Spelsberg TC.Role of TIEG1 in biological processes and disease states.J Cell Biochem 2007;102(3):539-48.
[15]Zhang YE.Non-Smad pathways in TGF-beta signaling.Cell Res 2009;19(1):128-39.
[16]Inoue Y,Imamura T.Regulation of TGF-beta family signaling by E3 ubiquitin ligases.Cancer Sci 2008;99(11):2107-12.
[17]Ribeiro A,Bronk SF,Roberts PJ,Urrutia R,Gores GJ.The transforming growth factor beta(1)-inducible transcription factor TIEGl,mediates apoptosis through oxidative stress.Hepatology 1999;30(6):1490-7.
[18]Chalaux E,Lopez-Rovira T,Rosa JL,Pons G,Boxer LM,Bartrons R,Ventura F.A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell death in epithelial Mvl Lu cells.FEBS Lett 1999;457(3):478-82.
[19]Tachibana I,Imoto M,Adjei PN,Gores GJ,Subramaniam M,Spelsberg TC,Urrutia R.Overexpression of the TGFbeta-regulated zinc finger encoding gene,TIEG,induces apoptosis in pancreatic epithelial cells.J Clin Invest 1997;99(10):2365-74.
[20]Johnsen SA,Subramaniam M,Monroe DG,Janknecht R,Spelsberg TC.Modulation of transforming growth factor beta(TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta inducible early gene-1 by human seven in absentia homologue.J Biol Chem 2002;277(34):30754-9.
[21]Johnsen SA,Subramaniam M,Janknecht R,Spelsberg TC.TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses.Oncogene 2002;21(37):5783-90.
[22]Lin X,Liu S,Luo X,Ma X,Guo L,Li L,Li Z,Tao Y,Cao Y.EBV-encoded LMP1 regulates Op 18/stathmin signaling pathway by cdc2 mediation in nasopharyngeal carcinoma cells.Int J Cancer 2009;124(5):1020-7.
[23]Chen Y,Lin MC,Yao H,Wang H,Zhang AQ,Yu J,Hui CK,Lau GK,He ML,Sung J,Kung HF.Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin.Hepatology 2007;46(1):200-8.
[24]El-Bassiouny AE,Zoheiry MM,Nosseir MM,El-Ahwany EG,Ibrahim RA,El-Bassiouni NE.Expression of cyclooxygenase-2 and transforming growth factor-beta 1 in HCV-induced chronic liver disease and hepatocellular carcinoma.MedGenMed 2007;9(3):45.
[25]Matsuzaki K,Murata M,Yoshida K,Sekimoto G,Uemura Y,Sakaida N,Kaibori M,Kamiyama Y,Nishizawa M,Fujisawa J,Okazaki K,Seki T.Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling,promoting cirrhosis and hepatocellular carcinoma.Hepatology 2007;46(1):48-57.
[26]Hjelmeland AB,Hjelmeland MD,Shi Q,Hart JL,Bigner DD,Wang XF,Kontos CD,Rich JN.Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.Cancer Res 2005;65(24):11276-81.
[27]Mouri H,Sakaguchi K,Sawayama T,Senoh T,Ohta T,Nishimura M,Fujiwara A,Terao M,Shiratori Y,Tsuji T.Suppressive effects of transforming growth factor-beta 1 produced by hepatocellular carcinoma cell lines on interferon-gamma production by peripheral blood mononuclear cells.Acta Med Okayama 2002;56(6):309-15.
[28]Gong Y,Zhang M,Minuk GY.Regulation of transforming growth factor-betal gene expression and cell proliferation in human hepatocellular carcinoma cells(PLC/PRF/5)by tamoxifen.J Lab Clin Med 1999;134(1):90-5.
[29]Hung WC,Chuang LY,Tsai JH,Chang CC.Effects of insulin on TGF-beta 1-induced cell growth inhibition in the human hepatoma cell lines.Biochem Mol Biol Int 1993;30(4):655-63.
[30]Hashimoto O,Ueno T,Kimura R,Ohtsubo M,Nakamura T,Koga H,Torimura T,Uchida S,Yamashita K,Sata M.Inhibition of proteasome-dependent degradation of Weel in G2-arrested Hep3B cells by TGF beta 1.Mol Carcinog 2003;36(4):171-82.
[31]Nishikawa Y,Kar S,Wiest L,Pegg AE,Carr BI.Inhibition of spermidine synthase gene expression by transforming growth factor-beta 1 in hepatoma cells.Biochem J 1997;321(Pt 2):537-43.
[32]Inagaki M,Wang Z,Carr BI.Transforming growth factor beta 1 selectively increases gene expression of the serine/threonine kinase receptor 1(SKR1)in human hepatoma cell lines.Cell Struct Funct 1994;19(5):305-13.
[33]Katabami K,Mizuno H,Sano R,Saito Y,Ogura M,Itoh S,Tsuji T.Transforming growth factor-beta 1 upregulates transcription of alpha3 integrin gene in hepatocellular carcinoma cells via Ets-transcription factor-binding motif in the promoter region.Clin Exp Metastasis 2005;22(7):539-48.
[34]Subramaniam M,Harris SA,Oursler MJ,Rasmussen K,Riggs BL,Spelsberg TC.Identification of a novel TGF-beta-regulated gene encoding a putative zinc finger protein in human osteoblasts.Nucleic Acids Res 1995;23(23):4907-12.
[35]Chrisman HR,Tindall DJ.Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha.DNA Cell Biol 2003;22(3):187-99.
[36]Cook T,Urrutia R.TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth.Am J Physiol Gastrointest Liver Physiol 2000;278(4):G513-21.
[37]Noti JD,Johnson AK,Dillon JD.The zinc finger transcription factor transforming growth factor beta-inducible early gene-1 confers myeloid-specific activation of the leukocyte integrin CDlld promoter.J Biol Chem 2004;279(26):26948-58.
[38] Frecha C,Szecsi J,Cosset FL,Verhoeyen E.Strategies for targeting lentiviral vectors.Curr Gene Ther 2008;8(6):449-60.
[39] Yang YA,Zhang GM,Feigenbaum L,Zhang YE.Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2.Cancer Cell 2006;9(6):445-57.
[40] Singer S,Ehemann V,Brauckhoff A,Keith M,Vreden S,Schirmacher P,Breuhahn K. Protumorigenic overexpression of stathmin/Op 18 by gain-of-function mutation in p53 in human hepatocarcinogenesis.Hepatology 2007;46(3):759-68.
[41] Sellin ME,Holmfeldt P,Stenmark S,Gullberg M.Op18/Stathmin counteracts the activity of overexpressed tubulin-disrupting proteins in a human leukemia cell line.Exp Cell Res 2008;314(6):1367-77.
[42] Rana S,Maples PB,Senzer N,Nemunaitis J.Stathmin 1:a novel therapeutic target for anticancer activity.Expert Rev Anticancer Ther 2008;8(9):1461-70.
[43] Sadow PM,Rumilla KM,Erickson LA,Lloyd RV.Stathmin expression in pheochromocytomas,paragangliomas,and in other endocrine tumors.Endocr Pathol 2008;19(2):97-103.
[44] Jeha S,Luo XN,Beran M,Kantarjian H,Atweh GF.Antisense RNA inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells.Cancer Res 1996;56(6):1445-50.
[45] Wang X,Chen Y,Han QB,Chan CY,Wang H,Liu Z,Cheng CH,Yew DT,Lin MC,He ML,Xu HX,Sung JJ,Kung HF.Proteomic identification of molecular targets of gambogic acid:role of stathmin in hepatocellular carcinoma.Proteomics 2009;9(2):242-53.
[46] Alli E,Yang JM,Hait WN.Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53.Oncogene 2007;26(7):1003-12.
[47] Jemal A,Siegel R,Ward E,Murray T,Xu J,Smigal C,Thun MJ.Cancer statistics,2006.CA Cancer J Clin 2006;56(2):106-30.
[48] Borja-Cacho D,Jensen EH,Saluja AK,Buchsbaum DJ,Vickers SM.Molecular targeted therapies for pancreatic cancer.Am J Surg 2008;196(3):430-41.
[49]Subramaniam M,Hefferan TE,Tau K,Peus D,Pittelkow M,Jalal S,Riggs BL,Roche P,Spelsberg TC.Tissue,cell type,and breast cancer stage-specific expression of a TGF-beta inducible early transcription factor gene.J Cell Biochem 1998;68(2):226-36.
[50]Fautsch MP,Vrabel A,Subramaniam M,Hefferen TE,Spelsberg TC,Wieben ED.TGFbeta-inducible early gene(TIEG)also codes for early growth response alpha(EGRalpha):evidence of multiple transcripts from alternate promoters.Genomics 1998;51(3):408-16.
[51]Blok LJ,Grossmann ME,Perry JE,Tindall DJ.Characterization of an early growth response gene,which encodes a zinc finger transcription factor,potentially involved in cell cycle regulation.Mol Endocrinol 1995;9(11):1610-20.
[52]Yajima S,Lammers CH,Lee SH,Hara Y,Mizuno K,Mouradian MM.Cloning and characterization of murine glial cell-derived neurotrophic factor inducible transcription factor(MGIF).J Neurosci 1997;17(22):8657-66.
[53]Cook T,Gebelein B,Belal M,Mesa K,Urrutia R.Three conserved transcriptional repressor domains are a defining feature of the TIEG subfamily of Sp1-like zinc finger proteins.J Biol Chem 1999;274(41):29500-4.
[54]Eid MA,Kumar MV,Iczkowski KA,Bostwick DG,Tindall DJ.Expression of early growth response genes in human prostate cancer.Cancer Res 1998;58(11):2461-8.
[55]Chen GG,Xu H,Lee JF,Subramaniam M,Leung KL,Wang SH,Chan UP,Spelsberg TC.15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway.Int J Cancer 2003;107(5):837-43.
[56]Antonello D,Moore PS,Zamboni G,Falconi M,Scarpa A.Absence of mutations in the transforming growth factor-beta inducible early gene 1,TIEG1,in pancreatic cancer.Cancer Lett 2002;183(2):179-83.
[57]Reinholz MM,An MW,Johnsen SA,Subramaniam M,Suman VJ,Ingle IN,Roche PC,Spelsberg TC.Differential gene expression of TGF beta inducible early gene(TIEG),Smad7,Smad2 and Bardl in normal and malignant breast tissue.Breast Cancer Res Treat 2004;86(1):75-88.
[58] Shiraishi K,Okita K,Kusano N,Harada T,Kondoh S,Okita S,Ryozawa S,Ohmura R,Noguchi T,Iida Y,Akiyama T,Oga A,Fukumoto Y,Furuya T,Kawauchi S,Sasaki K.A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver,biliary tract and pancreas.Oncology 2001;60(2):151-61.
[59] Schleger C,Arens N,Zentgraf H,Bleyl U,Verbeke C.Identification of frequent chromosomal aberrations in ductal adenocarcinoma of the pancreas by comparative genomic hybridization(CGH).J Pathol 2000;191(1):27-32.
[60] Sato N,Mizumoto K,Nakamura M,Maehara N,Minamishima YA,Nishio S,Nagai E,Tanaka M.Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells.Cancer Genet Cytogenet 2001;126(1):13-9.
[61] lancu-Rubin C,Atweh GF.p27(Kipl)and stathmin share the stage for the first time.Trends Cell Biol 2005;15(7):346-8.
[62] lacobuzio-Donahue CA,Maitra A,Shen-Ong GL,van Heek T,Ashfaq R,Meyer R,Walter K,Berg K,Hollingsworth MA,Cameron JL,Yeo CJ,Kern SE,Goggins M,Hruban RH.Discovery of novel tumor markers of pancreatic cancer using global gene expression technology.Am J Pathol 2002;160(4):1239-49.
[63] Teraoka H,Sawada T,Nishihara T,Yashiro M,Ohira M,Ishikawa T,Nishino H,Hirakawa K.Enhanced VEGF production and decreased immunogenicity induced by TGF-beta 1 promote liver metastasis of pancreatic cancer.Br J Cancer 2001;85(4):612-7.
[64] Bender H,Wang Z,Schuster N,Krieglstein K.TIEG1 facilitates transforming growth factor-beta-mediated apoptosis in the oligodendroglial cell line OLI-neu.J Neurosci Res 2004;75(3):344-52.
[65] Kleeff J,Ishiwata T,Maruyama H,Friess H,Truong P,Buchler MW,Falb D,Korc M.The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer.Oncogene 1999;18(39):5363-72.
[66]Nakano Y,Tanno S,Koizumi K,Nishikawa T,Nakamura K,Minoguchi M,Izawa T,Mizukami Y,Okumura T,Kohgo Y.Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.Br J Cancer 2007;96(3):457-63.
[67]Kunnumakkara AB,Guha S,Krishnan S,Diagaradjane P,Gelovani J,Aggarwal BB.Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation,angiogenesis,and inhibition of nuclear factor-kappaB-regulated gene products.Cancer Res 2007;67(8):3853-61.
[68]Yu C,Zhang X,Sun G,Guo X,Li H,You Y,Jacobs JL,Gardner K,Yuan D,Xu Z,Du Q,Dai C,Qian Z,Jiang K,Zhu Y,Li QQ,Miao Y.RNA interference-mediated silencing of the polo-like kinase 1 gene enhances chemosensitivity to gemcitabine in pancreatic adenocarcinoma cells.J Cell Mol Med 2008;12(6A):2334-49.
[69]Chen Y,Lin MC,Wang H,Chan CY,Jiang L,Ngai SM,Yu J,He ML,Shaw PC,Yew DT,Sung JJ,Kung HF.Proteomic analysis of EZH2 downstream target proteins in hepatocellular carcinoma.Proteomics 2007;7(17):3097-104.
[70]Mistry SJ,Bank A,Atweh GF.Targeting stathmin in prostate cancer.Mol Cancer Ther 2005;4(12):1821-9.
[71]Johnsen JI,Aurelio ON,Kwaja Z,Jorgensen GE,Pellegata NS,Plattner R,Stanbridge EJ,Cajot JF.p53-mediated negative regulation of stathmin/Op18 expression is associated with G(2)/M cell-cycle arrest.Int J Cancer 2000;88(5):685-91.
[72]lancu C,Mistry SJ,Arkin S,Atweh GF.Taxol and anti-stathmin therapy:a synergistic combination that targets the mitotic spindle.Cancer Res 2000;60(13):3537-41.
[1] Subramaniam M,Harris SA,Oursler MJ,Rasmussen K,Riggs BL,Spelsberg TC.Identification of a novel TGF-beta regulated gene encoding a putative zinc finger protein in human osteoblasts.Nucleic Acids Res 1995;23(23):4907-12.
[2] Hefferan TE,Subramaniam M,Khosla S,Riggs BL,Spelsberg TC.Cytokine-specific induction of the TGF-beta inducible early gene(TIEG):regulation by specific members of the TGF-beta family.J Cell Biochem 2000;78(3):380-90.
[3] Fautsch MP,Vrabel A,Rickard D,Subramaniam M,Spelsberg TC,Wieben ED.Characterization of the mouse TGFbeta-inducible early gene(TIEG):conservation of exon and transcriptional regulatory sequences with evidence of additional transcripts.Mamm Genome 1998;9(10):838-42.
[4] Cook T,Gebelein B,Belal M,Mesa K,Urrutia R.Three conserved transcriptional repressor domains are a defining feature of the TIEG subfamily of Sp1-like zinc finger proteins.J Biol Chem 1999;274(41):29500-4.
[5] Chrisman HR,Tindall DJ.Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha.DNA Cell Biol 2003;22(3):187-99.
[6] Cook T,Urrutia R.TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth.Am J Physiol Gastrointest Liver Physiol 2000;278(4):G513-21.
[7] Subramaniam M,Hawse JR,Johnsen SA,Spelsberg TC.Role of TIEG1 in biological processes and disease states.J Cell Biochem 2007;102(3):539-48.
[8] Blok LJ,Grossmann ME,Perry JE,Tindall DJ.Characterization of an early growth response gene,which encodes a zinc finger transcription factor,potentially involved in cell cycle regulation.Mol Endocrinol 1995;9(11):1610-20.
[9] Wang Z,Peters B,Klussmann S,Bender H,Herb A,Krieglstein K.Gene structure and evolution of Tieg3,a new member of the Tieg family of proteins.Gene 2004;325:25-34.
[10] Johnsen SA,Subramaniam M,Monroe DG,Janknecht R,Spelsberg TC.Modulation of transforming growth factor beta(TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta-inducible early gene-1 by human seven in absentia homologue.J Biol Chem 2002;277(34):30754-9.
[11] Ou XM,Chen K,Shih JC.Dual functions of transcription factors,transforming growth factor-beta-inducible early gene(TIEG)2 and Sp3,are mediated by CACCC element and Spl sites of human monoamine oxidase(MAO)B gene.J Biol Chem 2004;279(20):21021-8.
[12] Pearson R,Fleetwood J,Eaton S,Crossley M,Bao S.Kriippel-like transcription factors:a functional family.Int J Biochem Cell Biol 2008;40(10):1996-2001.
[13] Hefferan TE,Reinholz GG,Rickard DJ,Johnsen SA,Waters KM,Subramaniam M,Spelsberg TC.Overexpression of a nuclear protein,TIEG,mimics transforming growth factor-beta action in human osteoblast cells.J Biol Chem 2000;275(27):20255-9.
[14] Chalaux E,Lopez-Rovira T,Rosa JL,Pons G,Boxer LM,Bartrons R,Ventura F.A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell death in epithelial Mv1Lu cells.FEBS Lett 1999;457(3):478-82.
[15] Tachibana I,Imoto M,Adjei PN,Gores GJ,Subramaniam M,Spelsberg TC,Urrutia R.Overexpression of the TGFbeta-regulated zinc finger encoding gene,TIEG,induces apoptosis in pancreatic epithelial cells.J Clin Invest 1997;99(10):2365-74.
[16] Ribeiro A,Bronk SF,Roberts PJ,Urrutia R,Gores GJ.The transforming growth factor beta(1)-inducible transcription factor TIEG1,mediates apoptosis through oxidative stress.Hepatology 1999;30(6):1490-7.
[17] Johnsen SA,Subramaniam M,Janknecht R,Spelsberg TC.TGFbeta inducible early gene enhances TGFbeta/Smad-dependent transcriptional responses.Oncogene 2002;21(37):5783-90.
[18] Subramaniam M,Hefferan TE,Tau K,Peus D,Pittelkow M,Jalal S,Riggs BL,Roche P,Spelsberg TC.Tissue,cell type,and breast cancer stage-specific expression of a TGF-beta inducible early transcription factor gene.J Cell Biochem 1998;68(2):226-36.
[19]Eid MA,Kumar MV,Iczkowski KA,Bostwick DG,Tindall DJ.Expression of early growth response genes in human prostate cancer.Cancer Res 1998;58(11):2461-8.
[20]Chen GG,Xu H,Lee JF,Subramaniam M,Leung KL,Wang SH,Chan UP,Spelsberg TC.15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway.Int J Cancer 2003;107(5):837-43.
[21]Antonello D,Moore PS,Zamboni G,Falconi M,Scarpa A.Absence of mutations in the transforming growth factor-beta inducible early gene 1,TIEG1,in pancreatic cancer.Cancer Lett 2002;183(2):179-83.
[22]Reinholz MM,An MW,Johnsen SA,Subramaniam M,Suman VJ,Ingle JN,Roche PC,Spelsberg TC.Differential gene expression of TGF beta inducible early gene(TIEG),Smad7,Smad2 and Bard1 in normal and malignant breast tissue.Breast Cancer Res Treat 2004;86(1):75-88.
[23]Jiang L,Chen Y,Chan CY,Wang X,Lin L,He ML,Lin MC,Yew DT,Sung J J,Li JC,Kung HF.Down-regulation of stathmin is required for TGF-beta inducible early gene 1 induced growth inhibition of pancreatic cancer cells.Cancer Lett 2009;274(1):101-8.
[24]Mitsumoto M,Mitsumoto A,Demple B.Nitric oxide-mediated upregulation of the TGF-beta-inducible early response gene-1(TIEG1)in human fibroblasts by mRNA stabilization independent of TGF-beta.Free Radic Biol Med 2003;34(12):1607-13.
[25]Partin JV,Anglin IE,Kyprianou N.Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.Br J Cancer 2003;88(10):1615-21.
[26]Jin W,Qu LF,Min P,Chen S,Li H,Lu H,Hou YT.Identification of genes responsive to apoptosis in HL-60 cells.Acta Pharmacol Sin 2004;25(3):319-26.
[27]Chen Y,Lin MC,Wang H,Chan CY,Jiang L,Ngai SM,Yu J,He ML,Shaw PC,Yew DT,Sung JJ,Kung HF.Proteomic analysis of EZH2 downstream target proteins in hepatocellular carcinoma.Proteomics 2007;7(17):3097-104.
[28] Chen Y,Lin MC,Yao H,Wang H,Zhang AQ,Yu J,Hui CK,Lau GK,He ML,Sung J,Kung HF.Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin.Hepatology 2007;46(1):200-8.
[29] Wang X,Chen Y,Han QB,Chan CY,Wang H,Liu Z,Cheng CH,Yew DT,Lin MC,He ML,Xu HX,Sung JJ,Kung HF.Proteomic identification of molecular targets of gambogic acid:role of stathmin in hepatocellular carcinoma.Proteomics 2009;9(2):242-53.
[30] Alli E,Yang JM,Hait WN.Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53.Oncogene 2007;26(7):1003-12.
[31] Rana S,Maples PB,Senzer N,Nemunaitis J.Stathmin 1:a novel therapeutic target for anticancer activity.Expert Rev Anticancer Ther 2008;8(9):1461-70.
[32] Bensamoun SF,Hawse JR,Subramaniam M,Ilharreborde B,Bassillais A,Benhamou CL,Fraser DG,Oursler MJ,Amadio PC,An KN,Spelsberg TC.TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture.Bone 2006;39(6):1244-51.
[33] Subramaniam M,Gorny G,Johnsen SA,Monroe DG,Evans GL,Fraser DG,Rickard DJ,Rasmussen K,van Deursen JM,Turner RT,Oursler MJ,Spelsberg TC.TIEG1 null mouse-derived osteoblasts are defective in mineralization and in support of osteoclast differentiation in vitro.Mol Cell Biol 2005;25(3):1191-9.
[34] Rajamannan NM,Subramaniam M,Abraham TP,Vasile VC,Ackerman MJ,Monroe DG,Chew TL,Spelsberg TC.TGFbeta inducible early gene-1(TIEG1)and cardiac hypertrophy:Discovery and characterization of a novel signaling pathway.J Cell Biochem 2007;100(2):315-25.
[35] Wang J,Xu N,Feng X,Hou N,Zhang J,Cheng X,Chen Y,Zhang Y,Yang X.Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure.Circ Res 2005;97(8):821-8.
[36] Tsubone T,Moran SL,Subramaniam M,Amadio PC,Spelsberg TC,An KN.Effect of TGF-beta inducible early gene deficiency on flexor tendon healing.J Orthop Res 2006;24(3):569-75.
[37]Bensamoun SF,Tsubone T,Subramaniam M,Hawse JR,Boumediene E,Spelsberg TC,An KN,Amadio PC.Age-dependent changes in the mechanical properties of tail tendons in TGF-beta inducible early gene-1 knockout mice.J Appl Physiol 2006;101(5):1419-24.