Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Todoric J

PROVIDER: S-EPMC5730340 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Todoric Jelena J Antonucci Laura L Di Caro Giuseppe G Li Ning N Wu Xuefeng X Lytle Nikki K NK Dhar Debanjan D Banerjee Sourav S Fagman Johan B JB Browne Cecille D CD Umemura Atsushi A Valasek Mark A MA Kessler Hannes H Tarin David D Goggins Michael M Reya Tannishtha T Diaz-Meco Maria M Moscat Jorge J Karin Michael M

Cancer cell 20171116 6

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<sup>G12D</sup> acinar cells is a ...[more]

PMID: 29153842

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Project description:Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend?=?0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR)?=?3.95, 95% confidence intervals (CI)?=?1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR?=?6.53, 95% CI?=?1.31-32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p?=?0.12-0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation.

Dataset Information

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

Publications

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

Similar Datasets

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