Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice.
Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice.
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DOI：
10.1126/scisignal.2002739
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发表时间：
2012-03-27
影响因子：
7.3
通讯作者：
Manning BD
中科院分区：
文献类型：
--
作者：
Menon S;Yecies JL;Zhang HH;Howell JJ;Nicholatos J;Harputlugil E;Bronson RT;Kwiatkowski DJ;Manning BD
哺乳动物雷帕霉素靶标 (mTOR) 复合物 1 (mTORC1) 是一种营养敏感蛋白激酶，在许多人类癌症中异常激活。然而，正常组织中 mTORC1 信号传导失调是否会导致癌症风险尚不清楚。在这里，我们重点关注肝细胞癌，因为它是一种与影响 mTORC1 的环境因素（包括饮食影响）有明显联系的癌症。 mTORC1 抑制成分 Tsc1 的基因消除会导致 mTORC1 信号传导持续升高，这种效应类似于肥胖对该通路的影响。我们发现肝脏特异性敲除 Tsc1 的小鼠会发展为具有异质组织学和生化特征的散发性肝细胞癌。在该小鼠模型中自发发展为肝细胞癌之前，伴随着该癌症的主要病因发生了一系列已知的病理变化，包括肝损伤、炎症、坏死和再生。慢性 mTORC1 信号传导导致未解决的内质网应激和自噬缺陷，从而导致肝细胞损伤和肝细胞癌的发展。因此，我们证明了 mTORC1 在致癌作用中以前未被认识到的作用，这可能代表了癌症风险与饮食等环境因素之间的关键分子联系。
The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient sensitive protein kinase that is aberrantly activated in many human cancers. However, whether dysregulation of mTORC1 signaling in normal tissues contributes to cancer risk is unknown. Here, we focused on hepatocellular carcinoma because it is a cancer with clear links to environmental factors that affect mTORC1, including dietary influences. Genetic ablation of the mTORC1 inhibitory component Tsc1 results in constitutively elevated mTORC1 signaling, an effect similar to that of obesity on this pathway. We found that mice with liver-specific knockout of Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological and biochemical features. The spontaneous development of hepatocellular carcinoma in this mouse model was preceded by a series of pathological changes known to accompany the primary etiologies of this cancer, including liver damage, inflammation, necrosis, and regeneration. Chronic mTORC1 signaling caused unresolved endoplasmic reticulum stress and defects in autophagy, which contributed to hepatocyte damage and hepatocellular carcinoma development. Therefore, we demonstrate a previously unrecognized role for mTORC1 in carcinogenesis, perhaps representing a key molecular link between cancer risk and environmental factors, such as diet.
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影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
50.3
作者：
Haybaeck J;Zeller N;Wolf MJ;Weber A;Wagner U;Kurrer MO;Bremer J;Iezzi G;Graf R;Clavien PA;Thimme R;Blum H;Nedospasov SA;Zatloukal K;Ramzan M;Ciesek S;Pietschmann T;Marche PN;Karin M;Kopf M;Browning JL;Aguzzi A;Heikenwalder M
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Heikenwalder M
影响因子：
9.7
作者：
Bouchard, Michael J.;Navas-Martin, Sonia
通讯作者：
Navas-Martin, Sonia
影响因子：
16
作者：
Düvel K;Yecies JL;Menon S;Raman P;Lipovsky AI;Souza AL;Triantafellow E;Ma Q;Gorski R;Cleaver S;Vander Heiden MG;MacKeigan JP;Finan PM;Clish CB;Murphy LO;Manning BD
通讯作者：
Manning BD
影响因子：
13.5
作者：
Boyault, Sandrine;Rickman, David S.;Zucman-Rossi, Jessica
通讯作者：
Zucman-Rossi, Jessica