Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis: implications for the treatment of human liver cancer.
Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis: implications for the treatment of human liver cancer.
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DOI：
10.4161/cc.25099
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Calvisi DF
中科院分区：
文献类型：
--
作者：
Wang C;Cigliano A;Delogu S;Armbruster J;Dombrowski F;Evert M;Chen X;Calvisi DF
肝细胞癌 (HCC) 是全球癌症相关死亡的主要原因之一，治疗选择有限。 AKT/mTOR 和 Ras/MAPK 通路在人类肝癌发生过程中经常失调。最近，我们建立了一种动物模型，其特征是在小鼠肝脏中共同表达激活形式的 AKT 和 Ras。我们发现 AKT/mTOR 和 Ras/MAPK 级联的同时激活导致 AKT/Ras 小鼠肝脏肿瘤快速发展，主要是通过 mTORC1 诱导。为了进一步明确 mTORC1 级联在 AKT/Ras 诱导的 HCC 发展中的作用，当小肿瘤开始在肝脏中出现时，对 AKT/Ras 小鼠施用 mTORC1 抑制剂雷帕霉素。值得注意的是，雷帕霉素治疗显着延缓了 AKT/Ras 小鼠的肝癌发生。然而，尽管进行了治疗，AKT/Ras 小鼠的肝脏中仍然存在一些微小病变，并在雷帕霉素停药后迅速引发 HCC。从机制上讲，雷帕霉素抑制 mTORC1 和 mTORC2 通路、脂肪生成和糖酵解，从而抑制治疗肝脏的增殖。然而，激活的 ERK 及其下游效应器 Mnk1 和 eIF4E 在残留病灶中强烈上调。同时抑制 AKT/mTOR 和 Ras/MAPK 通路对 AKT/Ras 细胞的体外生长非常不利。该研究表明肝癌发生过程中 AKT/mTOR 和 Ras/MAPK 通路之间存在复杂的相互作用，这对于了解 HCC 发病机制及其预防和治疗具有重要意义。
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, with limited treatment options. AKT/mTOR and Ras/MAPK pathways are frequently deregulated in human hepatocarcinogenesis. Recently, we generated an animal model characterized by the co-expression of activated forms of AKT and Ras in the mouse liver. We found that concomitant activation of AKT/mTOR and Ras/MAPK cascades leads to rapid liver tumor development in AKT/Ras mice, mainly through mTORC1 induction. To further define the role of mTORC1 cascade in AKT/Ras induced HCC development, the mTORC1 inhibitor Rapamycin was administered to AKT/Ras mice at the time when small tumors started to emerge in the liver. Of note, Rapamycin treatment significantly delayed hepatocarcinogenesis in AKT/Ras mice. However, some microscopic lesions persisted in the livers of AKT/Ras mice despite the treatment and rapidly gave rise to HCC following Rapamycin withdrawal. Mechanistically, Rapamycin inhibited mTORC1 and mTORC2 pathways, lipogenesis and glycolysis, resulting in inhibition of proliferation in the treated livers. However, activated ERK and its downstream effectors, Mnk1 and eIF4E, were strongly upregulated in the residual lesions. Concomitant suppression of AKT/mTOR and Ras/MAPK pathways was highly detrimental for the growth of AKT/Ras cells in vitro. The study indicates the existence of a complex interplay between AKT/mTOR and Ras/MAPK pathways during hepatocarcinogenesis, with important implications for the understanding of HCC pathogenesis as well as for its prevention and treatment.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
6.2
作者：
Huynh, Hung
通讯作者：
Huynh, Hung
影响因子：
11.5
作者：
Sahin, F;Kannangai, R;Torbenson, M
通讯作者：
Torbenson, M
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
影响因子：
7.3
作者：
Guertin, David A.;Sabatini, David M.
通讯作者：
Sabatini, David M.