Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression.
Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression.
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DOI：
10.1016/j.canlet.2016.05.038
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发表时间：
2016-09-28
期刊：
影响因子：
9.7
通讯作者：
Wands JR
中科院分区：
文献类型：
--
作者：
Huang CK;Aihara A;Iwagami Y;Yu T;Carlson R;Koga H;Kim M;Zou J;Casulli S;Wands JR
转化生长因子β 1（TGFβ1）在胆管癌（CCA）发生和生长中的作用需要进一步明确。我们采用药理学和遗传学方法分别抑制或增强TGFβ1信号传导，并确定所涉及的细胞机制。在大鼠模型中，观察到用短发夹RNA（shRNA）或药物抑制TGFβ1活性抑制CCA发育和生长，而TGFβ1过表达增加CCA肿瘤大小并促进肝内转移。抑制TGFβ1活性可抑制miR-34 a介导的下游靶基因表达，包括细胞周期蛋白D1、CDK 6和c-Met。此外，TGFβ1表达的“敲低”揭示了CCA中p21表达增强的miR-34 a正反馈机制。miR-34 a抑制剂逆转了“敲低”TGFβ1对细胞生长、迁移、细胞周期蛋白D1、CDK 6和c-Met表达的作用，表明TGFβ1介导的作用部分通过miR-34 a信号通路发生。TGFβ1的过度表达与CCA肿瘤的进展有关。本研究提示TGFβ1参与CCA肿瘤的进展，并通过miR-34 a介导的下游级联反应参与，是抑制CCA发育和生长的靶点。
Transforming growth factor beta 1 (TGFβ1) role in cholangiocarcinoma (CCA) initiation and growth requires further definition. We employed pharmacological and genetic approaches to inhibit or enhance TGFβ1 signaling, respectively and determine the cellular mechanisms involved. It was observed that inhibiting TGFβ1 activity with short hairpin RNA (shRNA) or pharmaceutical agents suppressed CCA development and growth, whereas overexpression of TGFβ1 enhanced CCA tumor size and promoted intrahepatic metastasis in a rat model. Suppression of TGFβ1 activity inhibits downstream target gene expression mediated by miR-34a that includes cyclin D1, CDK6, and c-Met. In addition, “knockdown” of TGFβ1 expression revealed a miR-34a positive feedback mechanism for enhanced p21 expression in CCAs. A miR-34a inhibitor reversed the effects of “knocking down” TGFβ1 on cell growth, migration, cyclin D1, CDK6 and c-Met expression, suggesting that TGFβ1 mediated effects occurs in part, through this miR-34a signaling pathway. Overexpression of TGFβ1 was associated with CCA tumor progression. This study suggests that TGFβ1 is involved in CCA tumor progression and participates through miR-34a mediated downstream cascades, and is a target to inhibit CCA development and growth.