JAK/STAT/SOCS信号通路在mda-7/IL-24旁观者效应中的作用
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摘要
第一部分复制缺陷型腺病毒介导IL-24对肝癌裸鼠的促凋亡作用
目的：用复制缺陷型腺病毒介导的IL-24基因(Interleukin-24)治疗肝癌裸鼠移植瘤,探索基因治疗用于肝癌的新方法。
方法：构建携带人IL-24/mda-7基因的非复制性腺病毒载体(Ad.mda-7)及裸鼠肝癌模型,1周后当裸鼠肿瘤生长直径约为5～6mm时,计为第0天,将裸鼠随机分为3组,每组8只。(1)空白对照组：肝癌裸鼠模型的腹腔内注射生理盐水0.3ml,1/d,共3次。(2)阴性对照组(Ad.vec组)：Ad.vec肿瘤内局部多点注射,每只裸鼠共注入3×1010vp。(3)基因治疗组(Ad.mda-7组)：Ad.mda-7肿瘤内局部多点注射,每只裸鼠共注入3×1010vp。共计3个实验组对肝癌细胞裸鼠移植瘤进行治疗,观察各组裸鼠生存时间及肿瘤体积的变化,并对各组瘤体组织进行TUNEL检测。
结果：成功构建了非复制性腺病毒mda-7/IL-24载体并能实现体内表达,基因治疗组(Ad.mda-7)裸鼠平均生存时间为61.4±1.67d,与其它2组相比生存期明显延长(P<0.01)；基因治疗组(Ad.mda-7)治疗后36d的抑癌率为45.96%,显著高于阴性对照组(Ad.vec)的11.63%(P<0.01)；基因治疗组(Ad.mda-7)肿瘤组织中肿瘤细胞凋亡指数为25.7%±3.1%,与另两组相比差异有统计学意义(P<0.05)。
结论：复制缺陷型腺病毒介导mda-7/IL-24对肝癌裸鼠模型具有明显的抗肿瘤作用,其主要作用机制与mda-7/IL-24促进肿瘤组织中肝癌细胞凋亡有关。
第二部分重组人IL-24细胞因子对肝癌细胞株的选择性抗肿瘤作用
目的：观察重组人mda-7/IL-24细胞因子(rhIL-24)对肝癌细胞株HepG2的生物学作用,为肝癌的基因治疗提供理论基础。
方法：将重组人mda-7/IL-24细胞因子(rhIL-24)干预正常肝细胞株L02、肝癌细胞株HepG2和人肺癌细胞株A549。通过RT-PCR方法观察各细胞株膜表面IL-24细胞因子受体链(IL-20R1/IL-20R2和IL-22R/IL-20R2)的表达状态,采用四甲基偶氮唑蓝染色法(MTT)观察rhIL-24对肝癌细胞的生长抑制和杀伤作用,荧光染料CFSE检测rhIL-24对肝癌细胞及正常肝细胞增殖的影响,再用Annexin-V和PI双染后流式细胞仪检测rhIL-24对肝癌细胞的凋亡诱导作用,以及利用PI单染法流式细胞仪检测rhIL-24对细胞周期的影响。
结果：(1)RT-PCR检测表明正常肝细胞L-02膜表面IL-20R1(+)IL-20R2(+)IL-22R1(+),肝癌细胞系HepG2膜表面IL-20R1(-)IL-20R2(+)IL-22R1(+)；(2)160nmol/L rhIL-24能促进正常肝细胞L-02增殖(P<0.05),且随着浓度增加,细胞增殖速度也增加(P<0.05)；却可以抑制肝癌细胞的增殖,差异具有统计学意义(P<0.01); (3)CFSE法测定细胞增殖的实验发现160noml/L rhIL-24干预肝癌细胞HepG2后主要起到阻滞细胞增殖的作用,而对正常肝细胞则能起到促进细胞增殖的作用,与相应对照组比较差异具有统计学意义(P<0.05)；(4)高浓度rhIL-24能使正常肝细胞和肝癌细胞阻滞于G0/G1期,且显著降低细胞中S期的比例；(5)160nmol/L rhIL-24干预各细胞系48h后,经流式细胞仪检测发现HepG2组细胞凋亡率显著上升,与L-02组相比差异具有统计学意义(P<0.01)；而L-02组细胞凋亡率则没有显著变化(P>0.05)。
结论：人MDA-7/IL-24蛋白具有强大的旁观者效应,高浓度rhIL-24细胞因子可以诱导肝癌细胞凋亡,达到有效的抗肿瘤效果。
第三部分JAK/STAT通路协同SOCS3对重组人IL-24选择性抗肿瘤作用的调控
目的：探讨重组人mda-7/IL-24细胞因子(rhIL-24)对肝癌细胞株HepG2的旁观者效应机制,并深入研究rhIL-24特异性作用于肝癌细胞的选择性机理。
方法：用高浓度重组人mda-7/IL-24细胞因子(rhIL-24)干预正常肝细胞株L02和肝癌细胞株HepG2。通过western-blot蛋白印迹检测rhIL-24干预后,正常肝细胞和肝癌细胞内不同时间点总STAT1、总STAT3、磷酸化STAT1、磷酸化STAT3以及JAK/STAT信号通路下游信号分子Bax、caspase-3、P53蛋白的表达变化,同时通过RT-PCR方法观察各细胞株在rhIL-24处理后,SOCS家族mRNA表达变化。之后,设计相应的化学修饰siRNA干预SOCS家族表达最强者,再用Annexin-V和PI双染后流式细胞仪检测siRNA干预后rhIL-24对正常肝细胞和肝癌细胞的作用。
结果：(1) rhIL-24干预后,正常肝细胞和肝癌细胞内不同时间点总STAT1或是总STAT3的含量并无显著性差异(P>0.05), pSTAT1在正常肝细胞或是肝癌细胞中被激活,且含量较pSTAT3的含量稍低,但差异无显著统计学意义(P>0.05)；(2)高浓度rhIL-24处理后的正常肝细胞中Bax和caspase-3蛋白的表达随时间的延长而逐渐下降(P<0.05),但P53蛋白的表达不断增加(P<0.05)；而在肝癌细胞中Bax和·caspase-3蛋白的表达则随着干预时间的推移,表达量不断增加(P<0.05),但是P53蛋白的表达量则同样呈上升趋势(P<0.05); (3) 160nmol/L rhIL-24干预后,肝癌细胞HepG2中几乎没有SOCS1, SOCS3, CIS mRNA的表达,但在正常肝细胞L-02中却可以检测到少量的SOCS1 mRNA表达,以及显著的SOCS3 mRNA的表达；(4)当siRNA-SOCS3干预8h后,不仅HepG2组凋亡细胞的比例显著增加(P<0.01),更重要的是,L-02细胞也发生了大量细胞凋亡的现象,总凋亡比例从4.35%增加到35.26%,差异具有显著统计学意义(P<0.01)。
结论：SOCS3可能通过抑制已经激活的JAK/STAT信号通路,从而保护正常肝细胞免于高浓度rhIL-24对细胞的凋亡诱导作用,进而使得rhIL-24具有显著的选择性旁观者抗肿瘤效应。
Apoptosis-inducing effects on hepatocellular carcinoma in nude mice by replication-incompetent adenovirus vector-mediated mda-7/IL-24
Objective:To study the apoptosis-inducing effects after the treatment of replication-incompetent adenovirus vector-mediated mda-7/IL-24 on hepatocellular carcinoma in nude mice.
Methods:The recombinant replication-incompetent adenovirus vector carrying melanoma differentiation-associated gene-7 (Ad.mda-7) was constructed. The xenograft tumors were established by subcutaneous (sc) injection of 1×105 HCC cells suspended in serum-free saline into the hind legs. When the diameter of the tumors reached 5-6 mm (day 0), animals were randomized into three treatment groups as follows:blank control (saline injection; n= 8), negative control (3×1010 vp in three fractions on days 1,3, and 5; n=8), Admda7 (3×1010 vp in three fractions on days 1,3, and 5; n=8). Their antitumor effects on the average volume of the tumor and the survival rate of the mice were observed in each group and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining was performed after administration of different substances in every group in vivo.
Results:Recombinant replication-incompetent adenovirus vector carrying mda-7/IL-24 was constructed successfully. The mice treated with Ad.mda-7 had significantly longer survival time (61.4±1.67d) and greater tumor inhibition compare to other two groups (P<0.01). In the group treated with Ad.mda-7, apoptosis index was 25.7%±3.1%. There is significant difference between Ad.mda-7 group and the other two control group (P<0.05).
Conclusion:Ad.mda-7 has stronger antitumor potency on metastastic hepatocellular carcinoma mouse model. The mechanism of this antitumor effect is related to tumor cells apoptosis-inducing.
The specific antitumor activity of recombinant human IL-24 against hepatocellular carcinoma cells in vitro
Objective:To investigate the biological effect of MDA-7/IL-24 protein on the hepatocellular carcinoma HepG2 cells in vitro.
Methods:Treated normal liver L-02 cells, human hepatocellular carcinoma HepG2 cells and human non-small-cell lung carcinoma A549 cells with the recombinant human mda-7/IL-24 cytokines. The mRNA expression of IL-24 receptor complex (IL-20R1/IL-20R2 and IL-22R/IL-20R2) in three kinds of cells was confirmed by RT-PCR. MTT assay and CFSE assay were used to study tumor cell proliferation in vitro. Annexin-V/PI staining was studied to indicate the apoptosis effect. And the flow cytometry was used to assess the cell cycle.
Results:(1) RT-PCR analysis showed that normal liver cell L-02 membrane surface IL-20R1 (+) IL-20R2 (+) IL-22R1 (+), hepatocellular carcinoma cell line HepG2 membrane surface IL-20R1 (-) IL-20R2 (+) IL-22R1 (+); (2) 160nmol/L rhIL-24 could promote normal liver L-02 cell proliferation (P<0.05), and with the concentration of rhIL-24, rate of the cell proliferation also increased (P<0.05). However, it can inhibit hepatocellular carcinoma cell growth. There were significant difference (P<0.01); (3) cell proliferation was blocked after treated hepatocellular carcinoma cells HepG2 with 160noml/L rhIL-24 which was detected by CFSE, while the cell proliferation was promoted after treatment in normal liver cells, and there were significant difference compared with the corresponding control group (P<0.05); (4) normal liver cells and hepatocellular carcinoma cells were arrested in G0/G1 phase after treated with high concentrations of rhIL-24. there was significantly decrease in the proportion of cells in S phase; (5) Apoptosis rate increased significantly after treated with 160nmol/L rhIL-24 for 48h later in HepG2 cells group compared with the L-02 cells group determined by flow cytometry (P<0.01); while the L-02 cell apoptosis rate did not change significantly (P>0.05).
Conclusions:Our studies suggested that human MDA-7/IL-24 protein exerts a significant bystander effect, and cell apoptosis can be induced by high concentrations of rhIL-24 in hepatocellular carcinoma cells.
Essential role of JAK/STAT/SOCS3 signal pathways in selective anti-tumor effect induced by rhIL-24/MDA-7
Objective:To investigate the mechanisms of the selective bystander effect of recombinant human MDA-7/IL-24 cytokines (rhIL-24) on hepatocellular carcinoma cell line HepG2.
Methods:Normal liver cell line L02 and hepatocellular carcinoma cell line HepG2 were treated with high concentrations of recombinant human MDA-7/IL-24 cytokines (rhIL-24). Western-blot was used to detected the protein expressions of total STAT1, total STAT3, phosphorylated STAT1, phosphorylated STAT3 and the JAK/STAT signaling pathway downstream signal molecule Bax, caspase-3, P53 after the intervention to normal liver cells and hepatocellular carcinoma cells with high concentrations of rhIL-24 at different time points. SOCS family mRNA expressions were determined by RT-PCR method after the treatment with rhIL-24 in defferent cell lines. After that, the appropriate chemically modified siRNA to SOCS family which was expressed highly after interventions of rhIL-24 was designed, and then Annexin-V and PI staining by flow cytometry was used to study the cell apoptosis after siRNA intervention and/or rhIL-24 on normal liver cells and hepatocellular carcinoma cells.
Results:(1) the expressions of the total STAT1 and total STAT3 were no significant difference after the rhIL-24 intervention in normal liver cells and hepatocellular carcinoma cells at different time points (P>0.05), pSTAT1 is activated in normal liver cells or hepatocellular carcinoma cells, and there were the lower contents than the contents of pSTAT3. But the difference was not statistically significant (P>0.05); (2) the expressions of Bax and caspase-3 proteins were decreased with the time extension after treated with high concentrations of rhIL-24 in normal liver cells (P<0.05), but the expression of P53 protein increased (P<0.05); however, the expression of Bax anc caspase-3 protein were increased after intervention in liver cancer cells at different time point (P<0.05), but the expression of P53 protein increased at the same upward trend (P<0.05); (3) there were almost no SOCS1, SOCS3, CIS mRNA expression in hepatocellular carcinoma cells HepG2 after intervention with 160nmol/L rhIL-24. However, small amounts of SOCS1 mRNA expression and significant SOCS3 mRNA expression could be detected in normal liver cells L-02 after the intervention; (4) When intervention with siRNA-SOCS3 8h later, not only HepG2 apoptotic cells was significantly increased (P<0.01), more importantly, cell apoptosis occurred in a large number of normal liver cells L-02. The total percentage of apoptosis increased from 4.35% to 35.26%, and there were significant difference (P<0.01).
Conclusion:SOCS3 may inhibit the activated JAK/STAT signaling pathway, thereby protecting normal liver cells from cell apoptosis induced by high concentrations of rhIL-24, thus making rhIL-24 has significant selective bystander anti-tumor effects.
目的：用复制缺陷型腺病毒介导的IL-24基因(Interleukin-24)治疗肝癌裸鼠移植瘤,探索基因治疗用于肝癌的新方法。
方法：构建携带人IL-24/mda-7基因的非复制性腺病毒载体(Ad.mda-7)及裸鼠肝癌模型,1周后当裸鼠肿瘤生长直径约为5～6mm时,计为第0天,将裸鼠随机分为3组,每组8只。(1)空白对照组：肝癌裸鼠模型的腹腔内注射生理盐水0.3ml,1/d,共3次。(2)阴性对照组(Ad.vec组)：Ad.vec肿瘤内局部多点注射,每只裸鼠共注入3×1010vp。(3)基因治疗组(Ad.mda-7组)：Ad.mda-7肿瘤内局部多点注射,每只裸鼠共注入3×1010vp。共计3个实验组对肝癌细胞裸鼠移植瘤进行治疗,观察各组裸鼠生存时间及肿瘤体积的变化,并对各组瘤体组织进行TUNEL检测。
结果：成功构建了非复制性腺病毒mda-7/IL-24载体并能实现体内表达,基因治疗组(Ad.mda-7)裸鼠平均生存时间为61.4±1.67d,与其它2组相比生存期明显延长(P<0.01)；基因治疗组(Ad.mda-7)治疗后36d的抑癌率为45.96%,显著高于阴性对照组(Ad.vec)的11.63%(P<0.01)；基因治疗组(Ad.mda-7)肿瘤组织中肿瘤细胞凋亡指数为25.7%±3.1%,与另两组相比差异有统计学意义(P<0.05)。
结论：复制缺陷型腺病毒介导mda-7/IL-24对肝癌裸鼠模型具有明显的抗肿瘤作用,其主要作用机制与mda-7/IL-24促进肿瘤组织中肝癌细胞凋亡有关。
第二部分重组人IL-24细胞因子对肝癌细胞株的选择性抗肿瘤作用
目的：观察重组人mda-7/IL-24细胞因子(rhIL-24)对肝癌细胞株HepG2的生物学作用,为肝癌的基因治疗提供理论基础。
方法：将重组人mda-7/IL-24细胞因子(rhIL-24)干预正常肝细胞株L02、肝癌细胞株HepG2和人肺癌细胞株A549。通过RT-PCR方法观察各细胞株膜表面IL-24细胞因子受体链(IL-20R1/IL-20R2和IL-22R/IL-20R2)的表达状态,采用四甲基偶氮唑蓝染色法(MTT)观察rhIL-24对肝癌细胞的生长抑制和杀伤作用,荧光染料CFSE检测rhIL-24对肝癌细胞及正常肝细胞增殖的影响,再用Annexin-V和PI双染后流式细胞仪检测rhIL-24对肝癌细胞的凋亡诱导作用,以及利用PI单染法流式细胞仪检测rhIL-24对细胞周期的影响。
结果：(1)RT-PCR检测表明正常肝细胞L-02膜表面IL-20R1(+)IL-20R2(+)IL-22R1(+),肝癌细胞系HepG2膜表面IL-20R1(-)IL-20R2(+)IL-22R1(+)；(2)160nmol/L rhIL-24能促进正常肝细胞L-02增殖(P<0.05),且随着浓度增加,细胞增殖速度也增加(P<0.05)；却可以抑制肝癌细胞的增殖,差异具有统计学意义(P<0.01); (3)CFSE法测定细胞增殖的实验发现160noml/L rhIL-24干预肝癌细胞HepG2后主要起到阻滞细胞增殖的作用,而对正常肝细胞则能起到促进细胞增殖的作用,与相应对照组比较差异具有统计学意义(P<0.05)；(4)高浓度rhIL-24能使正常肝细胞和肝癌细胞阻滞于G0/G1期,且显著降低细胞中S期的比例；(5)160nmol/L rhIL-24干预各细胞系48h后,经流式细胞仪检测发现HepG2组细胞凋亡率显著上升,与L-02组相比差异具有统计学意义(P<0.01)；而L-02组细胞凋亡率则没有显著变化(P>0.05)。
结论：人MDA-7/IL-24蛋白具有强大的旁观者效应,高浓度rhIL-24细胞因子可以诱导肝癌细胞凋亡,达到有效的抗肿瘤效果。
第三部分JAK/STAT通路协同SOCS3对重组人IL-24选择性抗肿瘤作用的调控
目的：探讨重组人mda-7/IL-24细胞因子(rhIL-24)对肝癌细胞株HepG2的旁观者效应机制,并深入研究rhIL-24特异性作用于肝癌细胞的选择性机理。
方法：用高浓度重组人mda-7/IL-24细胞因子(rhIL-24)干预正常肝细胞株L02和肝癌细胞株HepG2。通过western-blot蛋白印迹检测rhIL-24干预后,正常肝细胞和肝癌细胞内不同时间点总STAT1、总STAT3、磷酸化STAT1、磷酸化STAT3以及JAK/STAT信号通路下游信号分子Bax、caspase-3、P53蛋白的表达变化,同时通过RT-PCR方法观察各细胞株在rhIL-24处理后,SOCS家族mRNA表达变化。之后,设计相应的化学修饰siRNA干预SOCS家族表达最强者,再用Annexin-V和PI双染后流式细胞仪检测siRNA干预后rhIL-24对正常肝细胞和肝癌细胞的作用。
结果：(1) rhIL-24干预后,正常肝细胞和肝癌细胞内不同时间点总STAT1或是总STAT3的含量并无显著性差异(P>0.05), pSTAT1在正常肝细胞或是肝癌细胞中被激活,且含量较pSTAT3的含量稍低,但差异无显著统计学意义(P>0.05)；(2)高浓度rhIL-24处理后的正常肝细胞中Bax和caspase-3蛋白的表达随时间的延长而逐渐下降(P<0.05),但P53蛋白的表达不断增加(P<0.05)；而在肝癌细胞中Bax和·caspase-3蛋白的表达则随着干预时间的推移,表达量不断增加(P<0.05),但是P53蛋白的表达量则同样呈上升趋势(P<0.05); (3) 160nmol/L rhIL-24干预后,肝癌细胞HepG2中几乎没有SOCS1, SOCS3, CIS mRNA的表达,但在正常肝细胞L-02中却可以检测到少量的SOCS1 mRNA表达,以及显著的SOCS3 mRNA的表达；(4)当siRNA-SOCS3干预8h后,不仅HepG2组凋亡细胞的比例显著增加(P<0.01),更重要的是,L-02细胞也发生了大量细胞凋亡的现象,总凋亡比例从4.35%增加到35.26%,差异具有显著统计学意义(P<0.01)。
结论：SOCS3可能通过抑制已经激活的JAK/STAT信号通路,从而保护正常肝细胞免于高浓度rhIL-24对细胞的凋亡诱导作用,进而使得rhIL-24具有显著的选择性旁观者抗肿瘤效应。
Apoptosis-inducing effects on hepatocellular carcinoma in nude mice by replication-incompetent adenovirus vector-mediated mda-7/IL-24
Objective:To study the apoptosis-inducing effects after the treatment of replication-incompetent adenovirus vector-mediated mda-7/IL-24 on hepatocellular carcinoma in nude mice.
Methods:The recombinant replication-incompetent adenovirus vector carrying melanoma differentiation-associated gene-7 (Ad.mda-7) was constructed. The xenograft tumors were established by subcutaneous (sc) injection of 1×105 HCC cells suspended in serum-free saline into the hind legs. When the diameter of the tumors reached 5-6 mm (day 0), animals were randomized into three treatment groups as follows:blank control (saline injection; n= 8), negative control (3×1010 vp in three fractions on days 1,3, and 5; n=8), Admda7 (3×1010 vp in three fractions on days 1,3, and 5; n=8). Their antitumor effects on the average volume of the tumor and the survival rate of the mice were observed in each group and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining was performed after administration of different substances in every group in vivo.
Results:Recombinant replication-incompetent adenovirus vector carrying mda-7/IL-24 was constructed successfully. The mice treated with Ad.mda-7 had significantly longer survival time (61.4±1.67d) and greater tumor inhibition compare to other two groups (P<0.01). In the group treated with Ad.mda-7, apoptosis index was 25.7%±3.1%. There is significant difference between Ad.mda-7 group and the other two control group (P<0.05).
Conclusion:Ad.mda-7 has stronger antitumor potency on metastastic hepatocellular carcinoma mouse model. The mechanism of this antitumor effect is related to tumor cells apoptosis-inducing.
The specific antitumor activity of recombinant human IL-24 against hepatocellular carcinoma cells in vitro
Objective:To investigate the biological effect of MDA-7/IL-24 protein on the hepatocellular carcinoma HepG2 cells in vitro.
Methods:Treated normal liver L-02 cells, human hepatocellular carcinoma HepG2 cells and human non-small-cell lung carcinoma A549 cells with the recombinant human mda-7/IL-24 cytokines. The mRNA expression of IL-24 receptor complex (IL-20R1/IL-20R2 and IL-22R/IL-20R2) in three kinds of cells was confirmed by RT-PCR. MTT assay and CFSE assay were used to study tumor cell proliferation in vitro. Annexin-V/PI staining was studied to indicate the apoptosis effect. And the flow cytometry was used to assess the cell cycle.
Results:(1) RT-PCR analysis showed that normal liver cell L-02 membrane surface IL-20R1 (+) IL-20R2 (+) IL-22R1 (+), hepatocellular carcinoma cell line HepG2 membrane surface IL-20R1 (-) IL-20R2 (+) IL-22R1 (+); (2) 160nmol/L rhIL-24 could promote normal liver L-02 cell proliferation (P<0.05), and with the concentration of rhIL-24, rate of the cell proliferation also increased (P<0.05). However, it can inhibit hepatocellular carcinoma cell growth. There were significant difference (P<0.01); (3) cell proliferation was blocked after treated hepatocellular carcinoma cells HepG2 with 160noml/L rhIL-24 which was detected by CFSE, while the cell proliferation was promoted after treatment in normal liver cells, and there were significant difference compared with the corresponding control group (P<0.05); (4) normal liver cells and hepatocellular carcinoma cells were arrested in G0/G1 phase after treated with high concentrations of rhIL-24. there was significantly decrease in the proportion of cells in S phase; (5) Apoptosis rate increased significantly after treated with 160nmol/L rhIL-24 for 48h later in HepG2 cells group compared with the L-02 cells group determined by flow cytometry (P<0.01); while the L-02 cell apoptosis rate did not change significantly (P>0.05).
Conclusions:Our studies suggested that human MDA-7/IL-24 protein exerts a significant bystander effect, and cell apoptosis can be induced by high concentrations of rhIL-24 in hepatocellular carcinoma cells.
Essential role of JAK/STAT/SOCS3 signal pathways in selective anti-tumor effect induced by rhIL-24/MDA-7
Objective:To investigate the mechanisms of the selective bystander effect of recombinant human MDA-7/IL-24 cytokines (rhIL-24) on hepatocellular carcinoma cell line HepG2.
Methods:Normal liver cell line L02 and hepatocellular carcinoma cell line HepG2 were treated with high concentrations of recombinant human MDA-7/IL-24 cytokines (rhIL-24). Western-blot was used to detected the protein expressions of total STAT1, total STAT3, phosphorylated STAT1, phosphorylated STAT3 and the JAK/STAT signaling pathway downstream signal molecule Bax, caspase-3, P53 after the intervention to normal liver cells and hepatocellular carcinoma cells with high concentrations of rhIL-24 at different time points. SOCS family mRNA expressions were determined by RT-PCR method after the treatment with rhIL-24 in defferent cell lines. After that, the appropriate chemically modified siRNA to SOCS family which was expressed highly after interventions of rhIL-24 was designed, and then Annexin-V and PI staining by flow cytometry was used to study the cell apoptosis after siRNA intervention and/or rhIL-24 on normal liver cells and hepatocellular carcinoma cells.
Results:(1) the expressions of the total STAT1 and total STAT3 were no significant difference after the rhIL-24 intervention in normal liver cells and hepatocellular carcinoma cells at different time points (P>0.05), pSTAT1 is activated in normal liver cells or hepatocellular carcinoma cells, and there were the lower contents than the contents of pSTAT3. But the difference was not statistically significant (P>0.05); (2) the expressions of Bax and caspase-3 proteins were decreased with the time extension after treated with high concentrations of rhIL-24 in normal liver cells (P<0.05), but the expression of P53 protein increased (P<0.05); however, the expression of Bax anc caspase-3 protein were increased after intervention in liver cancer cells at different time point (P<0.05), but the expression of P53 protein increased at the same upward trend (P<0.05); (3) there were almost no SOCS1, SOCS3, CIS mRNA expression in hepatocellular carcinoma cells HepG2 after intervention with 160nmol/L rhIL-24. However, small amounts of SOCS1 mRNA expression and significant SOCS3 mRNA expression could be detected in normal liver cells L-02 after the intervention; (4) When intervention with siRNA-SOCS3 8h later, not only HepG2 apoptotic cells was significantly increased (P<0.01), more importantly, cell apoptosis occurred in a large number of normal liver cells L-02. The total percentage of apoptosis increased from 4.35% to 35.26%, and there were significant difference (P<0.01).
Conclusion:SOCS3 may inhibit the activated JAK/STAT signaling pathway, thereby protecting normal liver cells from cell apoptosis induced by high concentrations of rhIL-24, thus making rhIL-24 has significant selective bystander anti-tumor effects.
引文
1 Shariff MI, Cox IJ, Gomaa AI, Khan SA, Gedroyc W, Taylor-Robinson SD. Hepatocellular carcinoma:current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Expert Rev Gastroenterol Hepatol 2009 Aug; 3(4):353-367.
2 Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995 Dec 21; 11(12):2477-2486.
3 Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB. mda-7/IL-24:multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006 Sep; 111(3):596-628.
4 Lebedeva IV, Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Gupta P, Nemunaitis J, Cunningham C, Yacoub A, Dent P, Fisher PB. mda-7/IL-24:exploiting cancer's Achilles' heel. Mol Ther 2005 Jan; 11(1):4-18.
5 Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM, Chada S. Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther 2004 Apr; 9(4):510-518.
6 Kreis S, Philippidou D, Margue C, Behrmann Ⅰ. IL-24:a classic cytokine and/or a potential cure for cancer? J Cell Mol Med 2008 May 24.
7 Su Z, Emdad L, Sauane M, Lebedeva Ⅳ, Sarkar D, Gupta P, James CD, Randolph A, Valerie K, Walter MR, Dent P, Fisher PB. Unique aspects of mda-7/IL-24 antitumor bystander activity:establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene 2005 Nov 17; 24(51):7552-7566.
8 Su ZZ, Lebedeva Ⅳ, Sarkar D, Gopalkrishnan RV, Sauane M, Sigmon C, Yacoub A, Valerie K, Dent P, Fisher PB. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene 2003 Feb 27; 22(8):1164-1180.
9 Sarkar D, Lebedeva Ⅳ, Gupta P, Emdad L, Sauane M, Dent P, Curiel DT, Fisher PB. Melanoma differentiation associated gene-7 (mda-7)/IL-24:a'magic bullet' for cancer therapy? Expert Opin Biol Ther 2007 May; 7(5):577-586.
10 Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L, Grimm EA, Renauld JC, Kotenko S, Chada S. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003 Aug 15; 63(16):5105-5113.
11 Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, Retter MW, Hill P, Chada S, Grimm EA. The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 2002 Jun 15; 168(12):6041-6046.
12 Su Z, Lebedeva Ⅳ, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, Dent P, Fisher PB. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci U S A 2001 Aug 28; 98(18):10332-10337.
13 Sarkar D, Lebedeva Ⅳ, Su ZZ, Park ES, Chatman L, Vozhilla N, Dent P, Curiel DT, Fisher PB. Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. Cancer Res 2007 Jun 1; 67(11):5434-5442.
14 Zheng M, Bocangel D, Doneske B, Mhashilkar A, Ramesh R, Hunt KK, Ekmekcioglu S, Sutton RB, Poindexter N, Grimm EA, Chada S. Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother 2007 Feb; 56(2):205-215.
15 Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M. mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 2005 May; 11(5):724-733.
16 Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S. Bystander activity of Ad-mda7:human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004 Dec; 10(6):1085-1095.
17 Fisher PB, Sarkar D, Lebedeva IV, Emdad L, Gupta P, Sauane M, Su ZZ, Grant S, Dent P, Curiel DT, Senzer N, Nemunaitis J. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24):novel gene therapeutic for metastatic melanoma. Toxicol Appl Pharmacol 2007 Nov 1; 224(3):300-307.
18 Wang CJ, Xue XB, Yi JL, Chen K, Zheng JW, Wang J, Zeng JP, Xu RH. Melanoma differentiation-associated gene-7, MDA-7/IL-24, selectively induces growth suppression, apoptosis in human hepatocellular carcinoma cell line HepG2 by replication-incompetent adenovirus vector. World J Gastroenterol 2006 Mar 21; 12(11):1774-1779.
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29 Su ZZ, Lebedeva IV, Sarkar D, Emdad L, Gupta P, Kitada S, Dent P, Reed JC, Fisher PB. Ionizing radiation enhances therapeutic activity of mda-7/IL-24:overcoming radiation-and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. Oncogene 2006 Apr 13; 25(16):2339-2348.
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7 Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci U S A 2005 Sep 27; 102(39):14034-14039.
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1 Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB. mda-7/IL-24:multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006 Sep; 111(3):596-628.
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3 Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L, Grimm EA, Renauld JC, Kotenko S, Chada S. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003 Aug 15; 63(16):5105-5113.
4 Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, Retter MW, Hill P, Chada S, Grimm EA. The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 2002 Jun 15; 168(12):6041-6046.
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1 Shariff MI, Cox IJ, Gomaa AI, Khan SA, Gedroyc W, Taylor-Robinson SD. Hepatocellular carcinoma:current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Expert Rev Gastroenterol Hepatol 2009 Aug; 3(4):353-367.
2 Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995 Dec 21; 11(12):2477-2486.
3 Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB. mda-7/IL-24:multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006 Sep; 111(3):596-628.
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14 Zheng M, Bocangel D, Doneske B, Mhashilkar A, Ramesh R, Hunt KK, Ekmekcioglu S, Sutton RB, Poindexter N, Grimm EA, Chada S. Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother 2007 Feb; 56(2):205-215.
15 Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M. mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 2005 May; 11(5):724-733.
16 Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S. Bystander activity of Ad-mda7:human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004 Dec; 10(6):1085-1095.
17 Fisher PB, Sarkar D, Lebedeva IV, Emdad L, Gupta P, Sauane M, Su ZZ, Grant S, Dent P, Curiel DT, Senzer N, Nemunaitis J. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24):novel gene therapeutic for metastatic melanoma. Toxicol Appl Pharmacol 2007 Nov 1; 224(3):300-307.
18 Wang CJ, Xue XB, Yi JL, Chen K, Zheng JW, Wang J, Zeng JP, Xu RH. Melanoma differentiation-associated gene-7, MDA-7/IL-24, selectively induces growth suppression, apoptosis in human hepatocellular carcinoma cell line HepG2 by replication-incompetent adenovirus vector. World J Gastroenterol 2006 Mar 21; 12(11):1774-1779.
19 McKenzie T, Liu Y, Fanale M, Swisher SG, Chada S, Hunt KK. Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells. Surgery 2004 Aug; 136(2):437-442.
20 Tahara I, Miyake K, Hanawa H, Kurai T, Hirai Y, Ishizaki M, Uchida E, Tajiri T, Shimada T. Systemic Cancer Gene Therapy Using Adeno-associated Virus Type 1 Vector Expressing MDA-7/IL24. Mol Ther 2007 Jun 5.
21 Hussain K, El-Serag HB. Epidemiology, screening, diagnosis and treatment of hepatocellular carcinoma. Minerva Gastroenterol Dietol 2009 Jun; 55(2):123-138.
22 Fisher PB. Is mda-7/IL-24 a "magic bullet" for cancer? Cancer Res 2005 Nov 15; 65(22): 10128-10138.
23 Fukazawa T, Matsuoka J, Yamatsuji T, Maeda Y, Durbin ML, Naomoto Y. Adenovirus-mediated cancer gene therapy and virotherapy (Review). Int J Mol Med Jan; 25(1):3-10.
24 Gabitzsch ES, Xu Y, Yoshida LH, Balint J, Amalfitano A, Jones FR. Novel Adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag, Pol, Nef despite the presence of Ad5 immunity. Vaccine 2009 Oct 30; 27(46):6394-6398.
25 Li J, Li H, Zhu L, Song W, Li R, Wang D, Dou K. The adenovirus-mediated linamarase/linamarin suicide system:a potential strategy for the treatment of hepatocellular carcinoma. Cancer Lett Mar 28; 289(2):217-227.
26 Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK, Tang ZY. Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol 2004 Aug; 130(8):460-468.
27 Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE. Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 2004 Jun; 9(6):818-828.
28 Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci U S A 2005 Sep 27; 102(39):14034-14039.
29 Su ZZ, Lebedeva IV, Sarkar D, Emdad L, Gupta P, Kitada S, Dent P, Reed JC, Fisher PB. Ionizing radiation enhances therapeutic activity of mda-7/IL-24:overcoming radiation-and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. Oncogene 2006 Apr 13; 25(16):2339-2348.
30 Yacoub A, Mitchell C, Hong Y, Gopalkrishnan RV, Su ZZ, Gupta P, Sauane M, Lebedeva IV, Curiel DT, Mahasreshti PJ, Rosenfeld MR, Broaddus WC, James CD, Grant S, Fisher PB, Dent P. MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. Cancer Biol Ther 2004 Aug; 3(8):739-751.
1 Fisher PB. Is mda-7/IL-24 a "magic bullet" for cancer? Cancer Res 2005 Nov 15; 65(22): 10128-10138.
2 Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge:immune cells as sources and targets of the IL-10 family members? J Immunol 2002 Jun 1; 168(11):5397-5402.
3 Wang M, Liang P. Interleukin-24 and its receptors. Immunology 2005 Feb; 114(2): 166-170.
4 Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC. Cutting edge:STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 2001 Oct 1; 167(7):3545-3549.
5 Jiang J, Zenewicz LA, San Mateo LR, Lau LL, Shen H. Activation of antigen-specific CD8 T cells results in minimal killing of bystander bacteria. J Immunol 2003 Dec 1; 171(11): 6032-6038.
6 Su Z, Lebedeva Ⅳ, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, Dent P, Fisher PB. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci U S A 2001 Aug 28; 98(18): 10332-10337.
7 Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci U S A 2005 Sep 27; 102(39):14034-14039.
8 Yacoub A, Mitchell C, Brannon J, Rosenberg E, Qiao L, McKinstry R, Linehan WM, Su ZS, Sarkar D, Lebedeva Ⅳ, Valerie K, Gopalkrishnan RV, Grant S, Fisher PB, Dent P. MDA-7 (interleukin-24) inhibits the proliferation of renal carcinoma cells and interacts with free radicals to promote cell death and loss of reproductive capacity. Mol Cancer Ther 2003 Jul; 2(7):623-632.
9 Sarkar D, Lebedeva Ⅳ, Gupta P, Emdad L, Sauane M, Dent P, Curiel DT, Fisher PB. Melanoma differentiation associated gene-7 (mda-7)/IL-24:a 'magic bullet' for cancer therapy? Expert Opin Biol Ther 2007 May; 7(5):577-586.
10 Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S. Bystander activity of Ad-mda7:human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004 Dec; 10(6):1085-1095.
11 Sauane M, Gupta P, Lebedeva IV, Su ZZ, Sarkar D, Randolph A, Valerie K, Gopalkrishnan RV, Fisher PB. N-glycosylation of MDA-7/IL-24 is dispensable for tumor cell-specific apoptosis and "bystander" antitumor activity. Cancer Res 2006 Dec 15; 66(24): 11869-11877.
12 Su Z, Emdad L, Sauane M, Lebedeva IV, Sarkar D, Gupta P, James CD, Randolph A, Valerie K, Walter MR, Dent P, Fisher PB. Unique aspects of mda-7/IL-24 antitumor bystander activity:establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene 2005 Nov 17; 24(51):7552-7566.
13 Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM, Chada S. Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther 2004 Apr; 9(4):510-518.
14 Cunningham CC, Chada S, Merritt JA, Tong A, Senzer N, Zhang Y, Mhashilkar A, Parker K, Vukelja S, Richards D, Hood J, Coffee K, Nemunaitis J. Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma:a phase I study. Mol Ther 2005 Jan; 11(1):149-159.
15 Fisher PB, Gopalkrishnan RV, Chada S, Ramesh R, Grimm EA, Rosenfeld MR, Curiel DT, Dent P. mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene:from the laboratory into the clinic. Cancer Biol Ther 2003 Jul-Aug; 2(4 Suppl 1):S23-37.
16 Tong AW, Nemunaitis J, Su D, Zhang Y, Cunningham C, Senzer N, Netto G, Rich D, Mhashilkar A, Parker K, Coffee K, Ramesh R, Ekmekcioglu S, Grimm EA, van Wart Hood J, Merritt J, Chada S. Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24):biologic outcome in advanced cancer patients. Mol Ther 2005 Jan; 11(1):160-172.
17 Lebedeva IV, Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Gupta P, Nemunaitis J, Cunningham C, Yacoub A, Dent P, Fisher PB. mda-7/IL-24:exploiting cancer's Achilles' heel. Mol Ther 2005 Jan; 11(1):4-18.
18 Dalloul A, Sainz-Perez A. Interleukin-24:a molecule with potential anti-cancer activity and a cytokine in search of a function. Endocr Metab Immune Disord Drug Targets 2009 Dec; 9(4):353-360.
19 Lange C, Thiersch M, Samardzija M, Grimm C. The differential role of Jak/STAT signaling in retinal degeneration. Adv Exp Med Biol; 664:601-607.
20 Yacoub A, Park MA, Gupta P, Rahmani M, Zhang G, Hamed H, Hanna D, Sarkar D, Lebedeva IV, Emdad L, Sauane M, Vozhilla N, Spiegel S, Koumenis C, Graf M, Curiel DT, Grant S, Fisher PB, Dent P. Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells. Mol Cancer Ther 2008 Feb; 7(2):297-313.
21 Pataer A, Chada S, Roth JA, Hunt KK, Swisher SG. Development of Ad-mda7/IL-24-resistant lung cancer cell lines. Cancer Biol Ther 2007 Oct 13; 7(1).
22 Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE. Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 2004 Jun; 9(6):818-828.
23 Zdanov A. Structural features of the interleukin-10 family of cytokines. Curr Pharm Des 2004; 10(31):3873-3884.
24 Murray PJ. The JAK-STAT signaling pathway:input and output integration. J Immunol 2007 Mar 1; 178(5):2623-2629.
25 Sauane M, Gopalkrishnan RV, Lebedeva I, Mei MX, Sarkar D, Su ZZ, Kang DC, Dent P, Pestka S, Fisher PB. Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways. J Cell Physiol 2003 Aug; 196(2):334-345.
26 Su ZZ, Lebedeva IV, Sarkar D, Emdad L, Gupta P, Kitada S, Dent P, Reed JC, Fisher PB. Ionizing radiation enhances therapeutic activity of mda-7/IL-24:overcoming radiation-and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. Oncogene 2006 Apr 13; 25(16):2339-2348.
27 Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D, Zhang G, Sarkar D, Lebedeva IV, Emdad L, Koumenis C, Curiel DT, Grant S, Fisher PB, Dent P. Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther 2008 Feb; 7(2):314-329.
28 Zhou Q, Kwan HY, Chan HC, Jiang JL, Tam SC, Yao X. Blockage of voltage-gated K+ channels inhibits adhesion and proliferation of hepatocarcinoma cells. Int J Mol Med 2003 Feb; 11(2):261-266.
29 Wang CJ, Xue XB, Yi JL, Chen K, Zheng JW, Wang J, Zeng JP, Xu RH. Melanoma differentiation-associated gene-7, MDA-7/IL-24, selectively induces growth suppression, apoptosis in human hepatocellular carcinoma cell line HepG2 by replication-incompetent adenovirus vector. World J Gastroenterol 2006 Mar 21; 12(11):1774-1779.
30 Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB. mda-7/IL-24:multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006 Sep; 111(3):596-628.
1 Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB. mda-7/IL-24:multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006 Sep; 111(3):596-628.
2 Sarkar D, Lebedeva IV, Gupta P, Emdad L, Sauane M, Dent P, Curiel DT, Fisher PB. Melanoma differentiation associated gene-7 (mda-7)/IL-24:a 'magic bullet' for cancer therapy? Expert Opin Biol Ther 2007 May; 7(5):577-586.
3 Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L, Grimm EA, Renauld JC, Kotenko S, Chada S. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003 Aug 15; 63(16):5105-5113.
4 Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, Retter MW, Hill P, Chada S, Grimm EA. The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 2002 Jun 15; 168(12):6041-6046.
5 Su Z, Lebedeva IV, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, Dent P, Fisher PB. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci U S A 2001 Aug 28; 98(18):10332-10337.
6 Zheng M, Bocangel D, Doneske B, Mhashilkar A, Ramesh R, Hunt KK, Ekmekcioglu S, Sutton RB, Poindexter N, Grimm EA, Chada S. Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother 2007 Feb; 56(2):205-215.
7 Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M. mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 2005 May; 11(5):724-733.
8 Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S. Bystander activity of Ad-mda7:human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004 Dec; 10(6):1085-1095.
9 Su Z, Emdad L, Sauane M, Lebedeva IV, Sarkar D, Gupta P, James CD, Randolph A, Valerie K, Walter MR, Dent P, Fisher PB. Unique aspects of mda-7/IL-24 antitumor bystander activity:establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene 2005 Nov 17; 24(51):7552-7566.
10 Inoue S, Shanker M, Miyahara R, Gopalan B, Patel S, Oida Y, Branch CD, Munshi A, Meyn RE, Andreeff M, Tanaka F, Mhashilkar AM, Chada S, Ramesh R. MDA-7/IL-24-based cancer gene therapy:translation from the laboratory to the clinic. Curr Gene Ther 2006 Feb; 6(1):73-91.
11 Chada S, Sutton RB, Ekmekcioglu S, Ellerhorst J, Mumm JB, Leitner WW, Yang HY, Sahin AA, Hunt KK, Fuson KL, Poindexter N, Roth JA, Ramesh R, Grimm EA, Mhashilkar AM. MDA-7/IL-24 is a unique cytokine--tumor suppressor in the IL-10 family. Int Immunopharmacol 2004 May; 4(5):649-667.
12 Deng J, Grande F, Neamati N. Small molecule inhibitors of Stat3 signaling pathway. Curr Cancer Drug Targets 2007 Feb; 7(1):91-107.
13 Kim HS, Lee MS. STAT1 as a key modulator of cell death. Cell Signal 2007 Mar; 19(3): 454-465.
14 Kreis S, Philippidou D, Margue C, Rolvering C, Haan C, Dumoutier L, Renauld JC, Behrmann I. Recombinant interleukin-24 lacks apoptosis-inducing properties in melanoma cells. PLoS ONE 2007; 2(12):e1300.
15 Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006 Apr; 130(4):1117-1128.
16 Shen X, Hong F, Nguyen VA, Gao B. IL-10 attenuates IFN-alpha-activated STAT1 in the liver:involvement of SOCS2 and SOCS3. FEBS Lett 2000 Sep 1; 480(2-3):132-136.
17 Lehner B, Fraser AG, Sanderson CM. Technique review:how to use RNA interference. Brief Funct Genomic Proteomic 2004 Apr; 3(1):68-83.
18 Pellish RS, Nasir A, Ramratnam B, Moss SF. Review article:RNA interference-potential therapeutic applications for the gastroenterologist. Aliment Pharmacol Ther 2008 May; 27(9):715-723.
19 Fjose A, Drivenes O. RNAi and microRNAs:from animal models to disease therapy. Birth Defects Res C Embryo Today 2006 Jun; 78(2):150-171.
20 Bertrand JR, Pottier M, Vekris A, Opolon P, Maksimenko A, Malvy C. Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. Biochem Biophys Res Commun 2002 Aug 30; 296(4):1000-1004.
21 Morris KV, Chan SW, Jacobsen SE, Looney DJ. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 2004 Aug 27; 305(5688):1289-1292.
1 Shariff MI, Cox IJ, Gomaa AI, Khan SA, Gedroyc W, Taylor-Robinson SD. Hepatocellular carcinoma:current trends in worldwide epidemiology, risk factors, diagnosis and therapeutics. Expert Rev Gastroenterol Hepatol 2009 Aug; 3(4):353-367.
2 Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995 Dec 21; 11(12):2477-2486.
3 Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L, Bachelor MA, Grant S, Curiel DT, Dent P, Fisher PB. mda-7/IL-24:multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006 Sep; 111(3):596-628.
4 Lebedeva IV, Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Gupta P, Nemunaitis J, Cunningham C, Yacoub A, Dent P, Fisher PB. mda-7/IL-24:exploiting cancer's Achilles' heel. Mol Ther 2005 Jan; 11(1):4-18.
5 Ramesh R, Ito I, Gopalan B, Saito Y, Mhashilkar AM, Chada S. Ectopic production of MDA-7/IL-24 inhibits invasion and migration of human lung cancer cells. Mol Ther 2004 Apr; 9(4):510-518.
6 Kreis S, Philippidou D, Margue C, Behrmann I. IL-24:a classic cytokine and/or a potential cure for cancer? J Cell Mol Med 2008 May 24.
7 Su Z, Emdad L, Sauane M, Lebedeva IV, Sarkar D, Gupta P, James CD, Randolph A, Valerie K, Walter MR, Dent P, Fisher PB. Unique aspects of mda-7/IL-24 antitumor bystander activity:establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene 2005 Nov 17; 24(51):7552-7566.
8 Su ZZ, Lebedeva IV, Sarkar D, Gopalkrishnan RV, Sauane M, Sigmon C, Yacoub A, Valerie K, Dent P, Fisher PB. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene 2003 Feb 27; 22(8):1164-1180.
9 Sarkar D, Lebedeva IV, Gupta P, Emdad L, Sauane M, Dent P, Curiel DT, Fisher PB. Melanoma differentiation associated gene-7 (mda-7)/IL-24:a 'magic bullet' for cancer therapy? Expert Opin Biol Ther 2007 May; 7(5):577-586.
10 Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch CD, Sieger K, Mumm JB, Stewart AL, Boquoi A, Dumoutier L, Grimm EA, Renauld JC, Kotenko S, Chada S. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2003 Aug 15; 63(16):5105-5113.
11 Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, Mhashilkar AM, Yang XH, Retter MW, Hill P, Chada S, Grimm EA. The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol 2002 Jun 15; 168(12):6041-6046.
12 Su Z, Lebedeva IV, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, Dent P, Fisher PB. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci U S A 2001 Aug 28; 98(18):10332-10337.
13 Sarkar D, Lebedeva IV, Su ZZ, Park ES, Chatman L, Vozhilla N, Dent P, Curiel DT, Fisher PB. Eradication of therapy-resistant human prostate tumors using a cancer terminator virus. Cancer Res 2007 Jun 1; 67(11):5434-5442.
14 Zheng M, Bocangel D, Doneske B, Mhashilkar A, Ramesh R, Hunt KK, Ekmekcioglu S, Sutton RB, Poindexter N, Grimm EA, Chada S. Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10. Cancer Immunol Immunother 2007 Feb; 56(2):205-215.
15 Chada S, Bocangel D, Ramesh R, Grimm EA, Mumm JB, Mhashilkar AM, Zheng M. mda-7/IL24 kills pancreatic cancer cells by inhibition of the Wnt/PI3K signaling pathways: identification of IL-20 receptor-mediated bystander activity against pancreatic cancer. Mol Ther 2005 May; 11(5):724-733.
16 Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D, Zheng M, Grimm EA, Ekmekcioglu S. Bystander activity of Ad-mda7:human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004 Dec; 10(6):1085-1095.
17 Fisher PB, Sarkar D, Lebedeva IV, Emdad L, Gupta P, Sauane M, Su ZZ, Grant S, Dent P, Curiel DT, Senzer N, Nemunaitis J. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24):novel gene therapeutic for metastatic melanoma. Toxicol Appl Pharmacol 2007 Nov 1; 224(3):300-307.
18 Wang CJ, Xue XB, Yi JL, Chen K, Zheng JW, Wang J, Zeng JP, Xu RH. Melanoma differentiation-associated gene-7, MDA-7/IL-24, selectively induces growth suppression, apoptosis in human hepatocellular carcinoma cell line HepG2 by replication-incompetent adenovirus vector. World J Gastroenterol 2006 Mar 21; 12(11):1774-1779.
19 Xue XB, Chen K, Wang CJ, Zheng JW, Yu Y, Peng ZH, Wu ZD. Adenovirus vector expressing mda-7 selectively kills hepatocellular carcinoma cell line Hep3B. Hepatobiliary Pancreat Dis Int 2008 Oct; 7(5):509-514.
20 McKenzie T, Liu Y, Fanale M, Swisher SG, Chada S, Hunt KK. Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu-overexpressing breast cancer cells. Surgery 2004 Aug; 136(2):437-442.
21 Tahara I, Miyake K, Hanawa H, Kurai T, Hirai Y, Ishizaki M, Uchida E, Tajiri T, Shimada T. Systemic Cancer Gene Therapy Using Adeno-associated Virus Type 1 Vector Expressing MDA-7/IL24. Mol Ther 2007 Jun 5.
22 Hussain K, El-Serag HB. Epidemiology, screening, diagnosis and treatment of hepatocellular carcinoma. Minerva Gastroenterol Dietol 2009 Jun; 55(2):123-138.
23 Fisher PB. Is mda-7/IL-24 a "magic bullet" for cancer? Cancer Res 2005 Nov 15; 65(22): 10128-10138.
24 Fukazawa T, Matsuoka J, Yamatsuji T, Maeda Y, Durbin ML, Naomoto Y. Adenovirus-mediated cancer gene therapy and virotherapy (Review). Int J Mol Med Jan; 25(1):3-10.
25 Gabitzsch ES, Xu Y, Yoshida LH, Balint J, Amalfitano A, Jones FR. Novel Adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag, Pol, Nef despite the presence of Ad5 immunity. Vaccine 2009 Oct 30; 27(46):6394-6398.
26 Li J, Li H, Zhu L, Song W, Li R, Wang D, Dou K. The adenovirus-mediated linamarase/linamarin suicide system:a potential strategy for the treatment of hepatocellular carcinoma. Cancer Lett Mar 28; 289(2):217-227.
27 Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK, Tang ZY. Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol 2004 Aug; 130(8):460-468.
28 Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE. Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 2004 Jun; 9(6):818-828.
29 Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P, Fisher PB. Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice. Proc Natl Acad Sci U S A 2005 Sep 27; 102(39):14034-14039.
30 Su ZZ, Lebedeva IV, Sarkar D, Emdad L, Gupta P, Kitada S, Dent P, Reed JC, Fisher PB. Ionizing radiation enhances therapeutic activity of mda-7/IL-24:overcoming radiation-and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. Oncogene 2006 Apr 13; 25(16):2339-2348.
31 Yacoub A, Mitchell C, Hong Y, Gopalkrishnan RV, Su ZZ, Gupta P, Sauane M, Lebedeva IV, Curiel DT, Mahasreshti PJ, Rosenfeld MR, Broaddus WC, James CD, Grant S, Fisher PB, Dent P. MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. Cancer Biol Ther 2004 Aug; 3(8):739-751.
32 Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge:immune cells as sources and targets of the IL-10 family members? J Immunol 2002 Jun 1; 168(11):5397-5402.
33 Wang M, Liang P. Interleukin-24 and its receptors. Immunology 2005 Feb; 114(2): 166-170.
34 Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC. Cutting edge:STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 2001 Oct 1; 167(7):3545-3549.
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