Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.
Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.
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DOI：
10.1016/j.ccell.2017.10.011
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发表时间：
2017-12-11
期刊：
影响因子：
50.3
通讯作者：
Karin M
中科院分区：
文献类型：
--
作者：
Todoric J;Antonucci L;Di Caro G;Li N;Wu X;Lytle NK;Dhar D;Banerjee S;Fagman JB;Browne CD;Umemura A;Valasek MA;Kessler H;Tarin D;Goggins M;Reya T;Diaz-Meco M;Moscat J;Karin M
尽管癌性KRAS表达，恶性前胰腺上皮内瘤变1 （PanIN1）病变很少成为完全恶性胰腺导管腺癌（PDAC）。慢性胰腺炎、腺泡细胞损伤和/或有缺陷的自噬等危险因素增加PDAC发生可能性的分子机制尚不清楚。我们发现，应激KrasG12D腺泡细胞中自噬底物p62/SQSTM1的积累与人类细胞和小鼠恶性肿瘤的PDAC发展和维持有关。p62的积累通过控制nrf2介导的MDM2的诱导来促进肿瘤的进展，MDM2通过p53依赖和独立的机制来消除阻止分化的腺泡细胞转化为增生性导管祖细胞的检查点。靶向MDM2可能有助于预防高危人群的PDAC发展。Todoric等人证明，在致癌KRAS的背景下，胰腺炎诱导的自噬底物p62/SQSTM1的积累促进了胰腺导管腺癌的进展。这种p62功能依赖于nrf2驱动的MDM2诱导，以及p53依赖和独立的MDM2活性。
Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors such as chronic pancreatitis, acinar cell damage and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals. Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.
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影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Jean-Paul, De La O.;Emerson, Lyska L.;Murtaugh, L. Charles
通讯作者：
Murtaugh, L. Charles
DOI：
10.1073/pnas.93.24.13943
发表时间：
1996-11-26
影响因子：
11.1
作者：
Chan, KM;Lu, RH;Kan, YW
通讯作者：
Kan, YW
影响因子：
50.3
作者：
Guerra C;Collado M;Navas C;Schuhmacher AJ;Hernández-Porras I;Cañamero M;Rodriguez-Justo M;Serrano M;Barbacid M
通讯作者：
Barbacid M
影响因子：
29.4
作者：
Jensen, JN;Cameron, E;Jensen, J
通讯作者：
Jensen, J