4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice.
4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice.
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DOI：
10.1002/hep.27396
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发表时间：
2015-01
期刊：
影响因子：
13.5
通讯作者：
Chen, Xin
中科院分区：
文献类型：
--
作者：
Wang, Chunmei;Cigliano, Antonio;Jiang, Lijie;Li, Xiaolei;Fan, Biao;Pilo, Maria G.;Liu, Yan;Gui, Bing;Sini, Marcella;Smith, Jeffrey W.;Dombrowski, Frank;Calvisi, Diego F.;Evert, Matthias;Chen, Xin
小鼠肝脏中AKT和Ras的活化形式（AKT/Ras）的伴随表达通过mTORC 1途径的强烈活化导致快速肿瘤发展。mTORC 1通过调节p70 S6 K/RPS 6和4 EBP 1/eIF 4 E级联发挥作用。这些级联反应如何促进肝癌发生仍不清楚。在这里，我们表明，通过雷帕霉素抑制RPS 6通路有效地抑制了，而4 EBP 1A 4（4 EBP 1的非磷酸化形式）阻断4 EBP 1/eIF 4 E级联反应，显著延迟了AKT/Ras诱导的肝癌发生。联合应用雷帕霉素和4 EBP 1A 4可完全抑制AKT/Ras肝癌的发生。在AKT/Ras过表达的肝脏中，通过消融mTORC 1的主要亚基Raptor，成功地再现了这种强烈的抗肿瘤作用。此外，我们证明了eIF 4 E的过度表达，其活性被4 EBP 1特异性抑制的原癌基因，与活化的Ras合作导致HCC的发展。从机制上讲，我们鉴定了ENTPD 5/AK 1/CMPK 1轴和线粒体生物合成途径作为AKT/Ras和Ras/eIF 4 E肝脏以及人HCC细胞系和组织中4 EBP 1/eIF 4 E级联的靶点。完全抑制mTORC 1是抑制小鼠中由AKT和Ras原癌基因诱导的肝癌发展所必需的。mTORC 1效应子RPS 6和eIF 4 E在AKT/Ras肝癌发生过程中发挥着不同的作用。这些新发现可能为人类肝细胞癌的创新疗法开辟道路。
Concomitant expression of activated forms of AKT and Ras in the mouse liver (AKT/Ras) leads to rapid tumor development via strong activation of the mTORC1 pathway. mTORC1 functions via regulating p70S6K/RPS6 and 4EBP1/eIF4E cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of RPS6 pathway via Rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras induced hepatocarcinogenesis. Combined treatment with Rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong anti-neoplastic effect was successfully recapitulated by ablating Raptor, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the protooncogene whose activity is specifically inhibited by 4EBP1, resulted in HCC development in cooperation with activated Ras. Mechanistically, we identified the ENTPD5/AK1/CMPK1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues. Complete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras protooncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human hepatocellular carcinoma.
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影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
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Bruix, Jordi
影响因子：
8
作者：
Martineau, Y.;Azar, R.;Pyronnet, S.
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Pyronnet, S.
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作者：
Guertin, David A.;Sabatini, David M.
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Sabatini, David M.
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254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P