Abstract
Background
Increased levels of oxidative stress/cell inflammation contribute to colorectal cancer
(CRC) onset. Nuclear factor-erythroid 2-related factor 2 (Nrf2) and its controlled
growth factor erv1-like (Gfer) gene regulate redox‐sensitive and anti-inflammatory
mechanisms, respectively, which can contribute to promoting cancer development.
Aim
We evaluated Nrf2 and Gfer RNA expression and Nrf2 protein expression in colon mucosa
in order to establish their possible involvement in the early stage of CRC.
Methods
Forty subjects were enrolled after a histological evaluation of their colon biopsies.
They included 20 subjects with a sporadic colorectal adenoma (SpCA group) and 20 without
precancerous lesions (controls). Biopsy samples were processed for gene expression
analysis and protein expression, using Real-time PCR and immunofluorescence confocal
microscopy, respectively.
Results
Nrf2 and Gfer mRNA expression were significantly reduced (p=0.007 and p<0.003, respectively)
in SpCA tissues compared to normal mucosa from controls. Furthermore, immunofluorescence
analysis confirmed a relevant reduction of Nrf2 in SpCA tissue compared to normal
tissue from controls.
Conclusions
Our data confirm the hypothesis that Nrf2 and Gfer expression may be involved in the
initial hits contributing to the multistep process of colon carcinogenesis. Further
larger studies are needed to confirm if Nrf2 and Gfer are potential risk/prognostic
factors for cancer development.
Keywords
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References
- Oxidative damage in sporadic colorectal cancer: molecular mapping of base excision repair glycosylases in colorectal cancer patients.Int J Mol Sci. 2020; 21: 2473-2493
- Epidemiology and risk factors of colorectal cancer in China.Chin J Cancer Res. 2020; 32: 729-741
- Precancerous colorectal lesions (Review).Int J Oncol. 2013; 43: 973-984
- Precancerous lesions in colorectal cancer.Gastroenterol Res Pract. 2013; 2013457901
- Non-polypoid colorectal neoplasms: Classification, therapy and follow-up.World J Gastroenterol. 2015; 21: 5149-5157
- The role of oxidative stress and its counteractive utility in colorectal cancer (CRC).Cancers (Basel). 2020; 12: 3336-3369
- Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy.Antioxid Redox Signal. 2012; 16: 1295-1322
- Simultaneous activation of Nrf2 and elevation of dietary and endogenous antioxidant chemicals for cancer prevention in humans.J Am Coll Nutr. 2016; 35: 175-184
- Tissue expression of the genes MUTYH and OGG1 in patients with sporadic colorectal cancer.Arq Bras Cir Dig. 2017; 30: 98-102
- Oxidative stress in melanocyte senescence and melanoma transformation.Eur J Cell Biol. 2014; 93: 36-41
- Argyrophilic nucleolar organizer regions (AgNORs) as malignancy biomarkers in colorectal neoplasms.Clin Ter. 2001; 152: 91-93
- Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals.Cancer Lett. 2017; 387: 95-105
- ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS.Proc Natl Acad Sci USA. 2010; 107: 4153-4158
- ROS, stress-activated kinases and stress signaling in cancer.EMBO Rep. 2002; 3: 420-425
- ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.Nat Rev Mol Cell Biol. 2007; 8: 813-824
- Reactive oxygen species: a breath of life or death?.Clin Cancer Res. 2007; 13: 789-794
- Hydrogen peroxide sensing and signaling.Mol Cell. 2007; 26: 1-14
- Oxidatively damaged DNA and its repair in colon carcinogenesis.Mutat Res. 2012; 736: 82-92
- Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma.Laryngoscope Investig Otolaryngol. 2021; 6: 699-707
- Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study.World J Gastroenterol. 2013; 19: 4325-4333
- Global colorectal cancer burden in 2020 and projections to 2040.Transl Oncol. 2021; : 101174
- ERβ expression in normal, adenomatous and carcinomatous tissues of patients with familial adenomatous polyposis.Scand J Gastroenterol. 2010; 45: 1320-1328
- Tumor evolution: Linear, branching, neutral or punctuated?.Biochim Biophys Acta. 2017; 1867: 151-161
- New insights into the earliest stages of colorectal tumorigenesis.Exp Rev Gastroenterol Hepatol. 2017; 11: 723-729
- Molecular pathways in colorectal cancer.J Gastroenterol Hepatol. 2012; 27: 1423-1431
- Oncogene induced Nrf2 transcription promotes ROS detoxification and tumorigenesis.Nature. 2011; 475: 106-109
- Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation.Cell Death Dis. 2014; 5: e1183
- Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells.Oncol Lett. 2015; 10: 1287-1292
- Colorectal cancer.Lancet. 2014; 383 (-02): 1490
- The dual roles of NRF2 in cancer.Trends Mol Med. 2016; 22: 578-593
- Chronic ulcerative colitis and colorectal cancer.Cancer Lett. 2014; 345: 235-241
- Oxidative stress and oxidative damage in carcinogenesis.Toxicol Pathol. 2010; 38: 96-109
- Molecular mechanisms of Nrf2-mediated antioxidant response.Mol Carcinog. 2009; 48: 91-104
- Targeting carcinogen metabolism by dietary cancer preventive compounds.Curr Cancer Drug Targets. 2007; 7: 416-424
- Direct and indirect antioxidant properties of inducers of cytoprotective proteins.Mol Nutr Food Res. 2008; 52: S128-S138
- Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.Biochem Pharmacol. 2008; 76: 1485-1489
- When NRF2 talks, who's listening?.Antioxid Redox Signal. 2010; 13: 1649-1663
- Nrf2 knockout enhances intestinal tumorigenesis in Apc(min/+) mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation.Mol Carcinog. 2014; 53: 77-84
- Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis.Cancer Res. 2006; 66: 11580-11584
- Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer.Cancer Prevent Res (Philadelphia, Pa.). 2008; 1: 187-191
- Decreased expression of the augmenter of liver regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells.Cell Death Dis. 2012; 3: e289
- Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration.Mol Med. 2013; 19: 237-244
- Augmenter of liver regeneration, a protective factor against ROS-induced oxidative damage in muscle tissue of mitochondrial myopathy affected patients.Int J Biochem Cell Biol. 2013; 45: 2410-2419
- Reactive oxygen species and colorectal cancer.J Cell Physiol. 2018; 233: 5119-5132
- Protective effect of augmenter of liver regeneration on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells.Free Radic Res. 2009; 43: 865-875
- Human augmenter of liver regeneration is important for hepatoma cell viability and resistance to radiation-induced oxidative stress.Free Radic Biol Med. 2009; 47: 1057-1066
- Augmenter of liver regeneration (ALR) is a novel biomarker of hepatocellular stress/inflammation: in vitro, in vivo and in silico studies.Mol Med. 2013; 18: 1421-1429
- Knockdown of augmenter of liver regeneration in HK-2 cells inhibits inflammation response via the mitogen-activated protein kinase signaling pathway.Inflamm Res. 2015; 64: 453-462
- The role of PIAS3, p-STAT3 and ALR in colorectal cancer: new translational molecular features for an old disease.Eur Rev Med Pharmacol Sci. 2020; 24: 10496-10511
- Clinical implications of augmenter of liver regeneration in cancer: a systematic review.Anticancer Res. 2017; 37: 3379-3383
- Augmenter of liver regeneration gene expression in human colon cancer cell lines and clinical tissue samples.J BUON. 2015; 20: 84-91
Article info
Publication history
Published online: February 21, 2022
Accepted:
January 20,
2022
Received:
August 23,
2021
Identification
Copyright
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.