Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss.
Transforming growth factor-beta signaling promotes hepatocarcinogenesis induced by p53 loss.
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DOI：
10.1002/hep.24653
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发表时间：
2012-01
期刊：
影响因子：
13.5
通讯作者：
Grady, William M.
中科院分区：
文献类型：
--
作者：
Morris, Shelli M.;Baek, Ji Yeon;Koszarek, Amanda;Kanngurn, Samornmas;Knoblaugh, Sue E.;Grady, William M.
肝细胞癌（HCC）是由肝细胞中肿瘤抑制基因和/或癌基因失调的积累引起的。 TP53 失活和转化生长因子-β (TGF-β) 信号传导抑制是人类肝癌中最常见的分子事件。因此，我们评估了通过删除 II 型 TGF-β 受体 (Tgfbr2) 导致的 TGF-β 信号失活是否与 Trp53 缺失共同促进 HCC 形成。白蛋白转基因小鼠与 floxed Trp53 和/或 floxed Tgfbr2 小鼠杂交，产生肝脏中缺乏 p53 和/或 Tgfbr2 的小鼠。单独删除Trp53 (Trp53KO)会导致大约41%的小鼠在10月龄时出现肝肿瘤，而单独灭活Tgfbr2 (Tgfbr2KO)不会诱发肝肿瘤。令人惊讶的是，在 p53 缺失的情况下删除 Tgfbr2（Trp53KO；Tgfbr2KO）可使小鼠患肝肿瘤的频率降低至 17% 左右，并延迟肿瘤发病的年龄。有趣的是，Trp53KO 和 Trp53KO;Tgfbr2KO 小鼠同时发生 HCC 和胆管癌，这表明 p53 的缺失（不依赖于 TGF-β）可能通过影响常见的肝干细胞群来影响肝肿瘤的形成。对 p53 缺失情况下 TGF-β 信号传导促进肝肿瘤形成的潜在机制的评估揭示了 Trp53KO 肿瘤的一个子集，其表达的甲胎蛋白水平升高。此外，与来自Trp53KO；Tgfbr2KO小鼠的肿瘤相比，来自Trp53KO小鼠的肿瘤表达增加的TGF-β1水平。在 Trp53KO 小鼠的肿瘤中也检测到磷酸化 Smad3 和 ERK1/2 表达增加，并与 TGF-β 反应基因 Pai1 和 Ctgf 表达增加相关。矛盾的是，TGF-β 信号传导会促进 p53 失活情况下出现的肝肿瘤的形成。
Hepatocellular carcinoma (HCC) results from the accumulation of deregulated tumor suppressor genes and/or oncogenes in hepatocytes. Inactivation of TP53 and inhibition of transforming growth factor-beta (TGF-β) signaling are among the most common molecular events in human liver cancers. Thus, we assessed whether inactivation of TGF-β signaling, by deletion of the TGF-β receptor, type II (Tgfbr2), cooperates with Trp53 loss to drive HCC formation. Albumincre transgenic mice were crossed with floxed Trp53 and/or floxed Tgfbr2 mice to generate mice lacking p53 and/or Tgfbr2 in the liver. Deletion of Trp53 alone (Trp53KO) resulted in liver tumors in approximately 41% of mice by 10 months of age, while inactivation of Tgfbr2 alone (Tgfbr2KO) did not induce liver tumors. Surprisingly, deletion of Tgfbr2 in the setting of p53 loss (Trp53KO;Tgfbr2KO) decreased the frequency of mice with liver tumors to around 17% and delayed the age of tumor onset. Interestingly, Trp53KO and Trp53KO;Tgfbr2KO mice develop both HCC and cholangiocarcinomas, suggesting that loss of p53, independent of TGF-β, may affect liver tumor formation through effects on a common liver stem cell population. Assessment of potential mechanisms through which TGF-β signaling may promote liver tumor formation in the setting of p53 loss revealed a subset of Trp53KO tumors that express increased levels of alpha-fetoprotein. Furthermore, tumors from Trp53KO mice express increased TGF-β1 levels compared to tumors from Trp53KO;Tgfbr2KO mice. Increased phosphorylated Smad3 and ERK1/2 expression was also detected in the tumors from Trp53KO mice and correlated with increased expression of the TGF-β responsive genes, Pai1 and Ctgf. TGF-β signaling paradoxically promotes the formation of liver tumors that arise in the setting of p53 inactivation.
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