Application of IL-6 HGF, TGF beta 1 for a bile duct cancer treatment.

IL-6 HGF、TGF beta 1 在胆管癌治疗中的应用。

• 批准号: 15591450
• 负责人: YOKOMURO Shigeki
• 金额: $ 2.11万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591450/
• 关键词: Cholangiocarcinoma; TGF-β1; IL-6; RNAi; HGF; TGFB1; TGFβ1; 胆管上皮癌; TGFβ_1

AIM : To elucidate the biological effects of transforming growth factor-β1 (TGF-β1) on intrahepatic cholangiocarcinoma (ICC).METHODS : We investigated the effects of TGF-β1 on human ICC cell lines (HuCCT1, MEC, and HuH-28) by monitoring the influences of TGF-β1 on tumor growth and interleukin-6 (IL-6) expression in ICC cells.RESULTS : All three human ICC cell lines produced TGF-β1 and accelerated growth in the presence of TGF-β1 with no apoptotic effect. Studies on HuCCT1 revealed a TGF-β1-induced stimulation of the expression of TGF-β1, as well as a decrease in TGF-β1 mRNA expression induced by neutralizing anti-TGF-β1 antibody. These results indicate that TGF-β1 stimulates the production and function of TGF-β1 in an autocrine fashion. Further, IL-6 secretion was observed in all three cell lines and exhibited an inhibitory response to neutralizing anti-TGF-β1 antibody. Experiments using HuCCT1 revealed a TGF-β1-induced acceleration of IL-6 expression in the protein and mRNA levels. Th … More ese findings demonstrate a functional interaction between TGF-β1 and IL-6. All three cell lines proliferated in the presence of IL-6. In contrast, TGF-β1 induced no growth effect in HuCCT1 with small interfering RNA against a specific cell surface receptor of IL-6 (IL-6Rα) and signal transducer and activator of transcription-3 (STAT3).CONCLUSION : ICC cells produce TGF-β1 and confer a TGF-β1-induced growth effect in an autocrine fashion. TGF-β1 activates IL-6 production, and the functional interaction between TGF-β1 and IL-6 contributes to ICC cell growth by TGF-β1. Background & Aims : Transforming growth factorβ (TGF-β) receptor II (TGF-βRII), which is essential for TGF-β signaling and is involved in the causation or participates in the pathway of various human disorders, is consequently considered a key target for therapeutics and analysis of the pathophysiology associated with disruption of the TGF-β system. In the liver, TGF-β plays an essential role in hepatocyte apoptosis, growth inhibition, and progression of fibrogenesis. There is a critical need to introduce technology involving the TGF-β system, such as RNA interference (RNAi), which has high potential for in vivo therapeutics and analytical activities. Methods : Here, we investigated the effect of short hairpin RNA targeting TGF-βRII in human and mouse cell lines and liver injury mouse models. Results : We demonstrated that short hairpin RNA targeting TGFβRII genes in mouse and human cell lines, and physiologic and morphologic changes in hepatocytes suffering from acute injury are spared by RNAi-mediated gene silencing of the target gene and by suppressing downstream signal transduction. Furthermore, short hairpin RNA targeting TGF-βRII protected mice from life-threatening acute liver failure. Conclusions : Our study suggests the potential use of TGF-βRII tool for TGF-β signaling and gene-specific therapy in human disorders. Less

目的：阐明转化生长因子-β1 (TGF-β1) 对肝内胆管癌 (ICC) 的生物学效应。方法：通过监测 TGF-β1 对 ICC 肿瘤生长和白细胞介素 6 (IL-6) 表达的影响，研究 TGF-β1 对人 ICC 细胞系（HuCCT1、MEC 和 HuH-28）的影响 结果：所有三种人 ICC 细胞系均产生 TGF-β1，并在 TGF-β1 存在的情况下加速生长，但没有凋亡作用。对 HuCCT1 的研究揭示了 TGF-β1 诱导的 TGF-β1 表达刺激，以及中和抗 TGF-β1 抗体诱导的 TGF-β1 mRNA 表达减少。这些结果表明TGF-β1以自分泌方式刺激TGF-β1的产生和功能。此外，在所有三种细胞系中均观察到 IL-6 分泌，并表现出对中和抗 TGF-β1 抗体的抑制反应。使用 HuCCT1 的实验揭示了 TGF-β1 诱导蛋白质和 mRNA 水平上 IL-6 表达的加速。这些发现表明 TGF-β1 和 IL-6 之间存在功能性相互作用。所有三种细胞系在 IL-6 存在下均增殖。相比之下，针对特定细胞表面受体 IL-6 (IL-6Rα) 和信号转导器和转录激活剂 3 (STAT3) 的小干扰 RNA，TGF-β1 在 HuCCT1 中没有诱导生长效应。结论：ICC 细胞产生 TGF-β1，并以自分泌方式赋予 TGF-β1 诱导的生长效应。 TGF-β1 激活 IL-6 的产生，TGF-β1 和 IL-6 之间的功能性相互作用通过 TGF-β1 促进 ICC 细胞生长。背景和目的：转化生长因子β (TGF-β) 受体 II (TGF-βRII) 对于 TGF-β 信号转导至关重要，并参与各种人类疾病的因果关系或途径，因此被认为是治疗和分析与 TGF-β 系统破坏相关的病理生理学的关键靶点。在肝脏中，TGF-β 在肝细胞凋亡、生长抑制和纤维发生进展中发挥重要作用。迫切需要引入涉及 TGF-β 系统的技术，例如 RNA 干扰 (RNAi)，它在体内治疗和分析活动方面具有很高的潜力。方法：在这里，我们研究了靶向 TGF-βRII 的短发夹 RNA 在人和小鼠细胞系以及肝损伤小鼠模型中的作用。结果：我们证明，通过 RNAi 介导的靶基因基因沉默和抑制下游信号转导，可以避免小鼠和人类细胞系中针对 TGFβRII 基因的短发夹 RNA 以及遭受急性损伤的肝细胞的生理和形态变化。此外，针对 TGF-βRII 的短发夹 RNA 可以保护小鼠免受危及生命的急性肝衰竭的影响。结论：我们的研究表明 TGF-βRII 工具在人类疾病的 TGF-β 信号传导和基因特异性治疗中具有潜在用途。较少的

项目成果

Short hairpin RNA modulates transforming growth factor beta signaling in life-threatening liverfailure in mice.

短发夹 RNA 在危及生命的小鼠肝衰竭中调节转化生长因子 β 信号传导。

• 发表时间: 2005
• 期刊: Gastroenterology 129
• 作者: Mizuguchi Y;Yokomuro S;Mishima T;Arima Y;Shimizu T;Kawahigashi Y;Kanda T;Yoshida H;Takizawa T;Tajiri T.
• 通讯作者: Tajiri T.

TGFβ1レセプターII型に対するRNAiとして作用するRNA配列

充当 II 型 TGFβ1 受体 RNAi 的 RNA 序列

• 发表时间: 2004

マウス正常肝内胆管上皮細胞培養の確立"Transforming Growth Factor-β1による胆管上皮細胞増殖抑制"

小鼠正常肝内胆管上皮细胞培养物的建立“转化生长因子-β1抑制胆管上皮细胞增殖”

• 发表时间: 2004
• 期刊: 胆道 18
• 作者: 横室 茂樹