Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.,Cancer Cell

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Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.
Cancer Cell ( IF 50.3 ) Pub Date : 2017-Dec-11 , DOI: 10.1016/j.ccell.2017.10.011
Jelena Todoric ₁ , Laura Antonucci ₂ , Giuseppe Di Caro ₂ , Ning Li ₂ , Xuefeng Wu ₂ , Nikki K Lytle ₃ , Debanjan Dhar ₂ , Sourav Banerjee ₄ , Johan B Fagman ₂ , Cecille D Browne ₂ , Atsushi Umemura ₅ , Mark A Valasek ₆ , Hannes Kessler ₂ , David Tarin ₆ , Michael Goggins ₇ , Tannishtha Reya ₃ , Maria Diaz-Meco ₈ , Jorge Moscat ₈ , Michael Karin ₉

Affiliation

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Departments of Pharmacology and Medicine, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 602-8566 Kyoto, Japan.
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Departments of Medicine (Gastroenterology) and Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.

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 Kras^G12D 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.

中文翻译：

应激激活的 NRF2-MDM2 级联控制胰腺肿瘤进展。

尽管表达致癌 KRAS，但癌前胰腺上皮内瘤变 1 (PanIN1) 病变很少变成完全恶性的胰腺导管腺癌 (PDAC)。慢性胰腺炎、腺泡细胞损伤和/或自噬缺陷等已知危险因素增加 PDAC 发生可能性的分子机制尚不清楚。^{我们发现，应激的 Kras G12D}腺泡细胞中自噬底物 p62/SQSTM1 的积累与人类细胞和小鼠的 PDAC 发育和恶性肿瘤的维持相关。p62 积累通过控制 NRF2 介导的 MDM2 诱导来促进肿瘤进展，MDM2 通过 p53 依赖和独立机制发挥作用，消除阻止分化腺泡细胞转化为增殖性导管祖细胞的检查点。MDM2 靶向可能有助于预防高危个体 PDAC 的发展。

更新日期：2017-11-19

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