Related Experiment Video
Updated: Sep 23, 2025
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Genomic landscape of chemical-induced lung tumors under Nrf2 different expression levels
Hironori Satoh1,2,3, Yasuhito Arai1, Eisaku Furukawa4
1Division of Cancer Genomics, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.
Abstract:
The transcription factor Nrf2 plays a crucial role in the anti-oxidative stress response, protection of DNA from injury and DNA repair mechanisms. Nrf2 activity reduces cancer initiation, but how Nrf2 affects whole-genome alterations upon carcinogenic stimulus remains unexplored. Although recent genome-wide analysis using next-generation sequencing revealed landscapes of nucleotide mutations and copy number alterations in various human cancers, genomic changes in murine cancer models have not been thoroughly examined. We elucidated the relationship between Nrf2 expression levels and whole exon mutation patterns using an ethyl-carbamate (urethane)-induced lung carcinogenesis model employing Nrf2-deficient and Keap1-kd mice, the latter of which express high levels of Nrf2. Exome analysis demonstrated that single nucleotide and trinucleotide mutation patterns and the Kras mutational signature differed significantly and were dependent on the expression level of Nrf2. The Nrf2-deficient tumors exhibited fewer copy number alterations relative to the Nrf2-wt and Keap1-kd tumors. The observed trend in genomic alterations likely prevented the Nrf2-deficient tumors from progressing into malignancy. For the first time, we present whole-exome sequencing results for chemically-induced lung tumors in the Nrf2 gain or loss of function mouse models. Our results demonstrate that different Nrf2 expression levels lead to distinct gene mutation patterns that underly different oncogenic mechanisms in each tumor genotype.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) influences cancer development by altering gene mutation patterns. Nrf2 levels impact whole-genome changes, affecting lung tumor progression in mice.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is vital for cellular defense against oxidative stress, DNA damage, and repair.
- While Nrf2 inhibits cancer initiation, its precise role in shaping whole-genome alterations during carcinogenesis is not fully understood.
- Previous genome-wide studies focused on human cancers, leaving murine cancer models underexplored regarding genomic changes.
Purpose of the Study:
- To investigate the relationship between Nrf2 expression levels and whole-exome mutation patterns in a chemically induced lung cancer model.
- To analyze how Nrf2 deficiency or overexpression affects genomic alterations during lung carcinogenesis in mice.
Main Methods:
- Utilized a urethane-induced lung carcinogenesis model in mice with Nrf2 deficiency and Keap1 knockdown (high Nrf2 expression).
- Performed whole-exome sequencing to analyze mutation patterns, including single nucleotide and trinucleotide alterations, and copy number changes.
- Compared genomic landscapes between Nrf2-deficient, wild-type, and Keap1-knockdown (high Nrf2) tumors.
Main Results:
- Significant differences in single nucleotide and trinucleotide mutation patterns, as well as the Kras mutational signature, were observed and were dependent on Nrf2 expression levels.
- Nrf2-deficient tumors displayed fewer copy number alterations compared to wild-type and Keap1-knockdown tumors.
- The distinct genomic alteration profiles in Nrf2-deficient tumors may impede their progression to malignancy.
Conclusions:
- This study provides the first whole-exome sequencing data for chemically induced lung tumors in mouse models with altered Nrf2 function.
- Nrf2 expression levels dictate specific gene mutation patterns, influencing distinct oncogenic mechanisms in different tumor genotypes.
- Understanding these Nrf2-dependent genomic alterations is crucial for deciphering varied oncogenic pathways in cancer development.
More Related Videos
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
