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Identification of novel Nrf2 target genes as prognostic biomarkers in colitis-associated colorectal cancer in Nrf2-deficient mice.
Life Sci 2019; :116968LS

Abstract

AIMS

Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers.

MAIN METHODS

The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC.

KEY FINDINGS

In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients.

SIGNIFICANCE

Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.

Authors+Show Affiliations

Department of Biochemistry and Department of Thoracic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China.Department of Pharmacology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, PR China.Department of Biochemistry and Department of Thoracic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China.Department of Biochemistry and Department of Thoracic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China.The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 322000, PR China.Department of Biochemistry and Department of Thoracic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, PR China. Electronic address: xiuwentang@zju.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31628914

Citation

Hammad, Ahmed, et al. "Identification of Novel Nrf2 Target Genes as Prognostic Biomarkers in Colitis-associated Colorectal Cancer in Nrf2-deficient Mice." Life Sciences, 2019, p. 116968.
Hammad A, Zheng ZH, Gao Y, et al. Identification of novel Nrf2 target genes as prognostic biomarkers in colitis-associated colorectal cancer in Nrf2-deficient mice. Life Sci. 2019.
Hammad, A., Zheng, Z. H., Gao, Y., Namani, A., Shi, H. F., & Tang, X. (2019). Identification of novel Nrf2 target genes as prognostic biomarkers in colitis-associated colorectal cancer in Nrf2-deficient mice. Life Sciences, p. 116968. doi:10.1016/j.lfs.2019.116968.
Hammad A, et al. Identification of Novel Nrf2 Target Genes as Prognostic Biomarkers in Colitis-associated Colorectal Cancer in Nrf2-deficient Mice. Life Sci. 2019 Oct 16;116968. PubMed PMID: 31628914.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of novel Nrf2 target genes as prognostic biomarkers in colitis-associated colorectal cancer in Nrf2-deficient mice. AU - Hammad,Ahmed, AU - Zheng,Zhao-Hong, AU - Gao,Yang, AU - Namani,Akhileshwar, AU - Shi,Hong-Fei, AU - Tang,Xiuwen, Y1 - 2019/10/16/ PY - 2019/09/03/received PY - 2019/10/03/revised PY - 2019/10/13/accepted PY - 2019/10/20/entrez PY - 2019/10/20/pubmed PY - 2019/10/20/medline KW - Colitis KW - Colorectal cancer KW - Gene expression KW - Nrf2 KW - Transcription SP - 116968 EP - 116968 JF - Life sciences JO - Life Sci. N2 - AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/31628914/Identification_of_novel_Nrf2_target_genes_as_prognostic_biomarkers_in_colitis-associated_colorectal_cancer_in_Nrf2-deficient_mice L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(19)30895-1 DB - PRIME DP - Unbound Medicine ER -