Tissue Expresion of the Genes Mutyh and Ogg1 in Patients With Sporadic Colorectal Cancer

Nascimento, Enzo Fabrício Ribeiro; Ribeiro, Marcelo Lima; Magro, Daniéla Oliveira; Carvalho, J.C.T.; Kanno, Danilo Toshio; Coy, Cláudio Saddy Rodrigues

doi:10.1590/0102-6720201700020005

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…In sporadic CRC, unrepaired 8-oxo-dG adducts induce mutations in proto-oncogenes, such as KRAS and tumor suppressor genes and, also, both MUTYH and hOGG1 were found to be downregulated in neoplastic human colon tissues compared to adjacent tissues [78]. The concerted action of MUTYH and hOGG1 is illustrated in Figure 1.…”

Section: Sporadic Colorectal Cancermentioning

confidence: 97%

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Vodička

Urbanová

Makovický

et al. 2020

IJMS

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Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

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Section: Sporadic Colorectal Cancermentioning

confidence: 97%

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Vodička

Urbanová

Makovický

et al. 2020

IJMS

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“…Recent research also suggests that patients with colorectal cancer have lower MUTYH expression in cancer tissues compared with normal tissues (19). Meanwhile, the MUTYH gene was found to present reduced expression in more advanced stages of colorectal cancer, and lower MUTYH expression may contribute to worse patient prognosis (12). In the present study, the association of MUTYH with CDDP resistance in ESCC cells was analyzed.…”

Section: Downregulation Of Mutyh Contributes To Cisplatin-resistance Of Esophageal Squamous Cell Carcinoma Cells By Promoting Twist-mediamentioning

confidence: 76%

“…MUTYH is a key component of the system of base excision repair (BER), which is able to remove the oxidized bases paired erroneously, thereby ensuring the maintenance of DNA integrity (10,11). It has been confirmed by experimental evidence that MUTYH has an important role in various cancer types; it was reported that modification of the tissue expression of MUTYH is associated with the elevated risk of development of various cancer types, such as colorectal cancer, lung cancer, esophageal carcinoma, thyroid cancer and head and neck cancer (12)(13)(14)(15)(16)(17). Mutations in MUTYH reduce BER effectiveness and predisposition to cancer (17,18).…”

Section: Downregulation Of Mutyh Contributes To Cisplatin-resistance Of Esophageal Squamous Cell Carcinoma Cells By Promoting Twist-mediamentioning

confidence: 94%

Downregulation of MUTYH contributes to cisplatin‑resistance of esophageal squamous cell carcinoma cells by promoting Twist‑mediated EMT

et al. 2019

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Acquired resistance to cisplatin (CDDP) in esophageal squamous cell carcinoma (ESCC) remains a major challenge in cancer therapy. Although progress has been made in identifying the mechanisms responsible for resistance to CDDP, the underlying mechanisms of resistance in ESCC are still not entirely understood. In the present study, a CDDP-resistant ESCC cell line EC109/CDDP was established by culturing parental EC109 cells in increasing concentrations of CDDP, and it was demonstrated that MutY homolog (MUTYH), a critical base excision repair gene, was significantly downregulated in the resistant EC109/CDDP cells compared with that noted in the parental cells. Ectopic expression of MUTYH by transient transfection of pcDNA3.1-MUTYH plasmid significantly enhanced the CDDP-mediated inhibitory effect on resistant cell proliferation and induction of apoptosis, while silencing of MUTYH by transiently transfecting MUTYH-targeted siRNA in parental cells led to decreased sensitivity to CDDP as demonstrated by MTT assay, suggesting the crucial involvement of MUTYH in CDDP resistance. Further experiments demonstrated that the CDDP-resistant cells went through epithelial-mesenchymal transition (EMT) driven by its master regulator Twist, and MUTYH overexpression significantly reduced the Twist expression level and reversed the phenotype of EMT as detected by western blot analysis and RT-qPCR assays, suggesting that downregulation of MUTYH contributed to the Twist-mediated EMT. Moreover, it was observed that the effect of MUTYH on Twist was also associated with its degradation in addition to transcription. MUTYH acted as a positive regulator of reactive oxygen species (ROS) that showed a low level in resistant cells via flow cytometry assay, as demonstrated by increased ROS production in response to MUTYH overexpression. Reduced ROS by using N-acetylcysteine led to a decrease in proteasome activity and sequentially inhibited the degradation of Twist. In conclusion, the present data demonstrated that EMT activation mediated by MUTYH downregulation, by both enhancing Twist transcription and blocking its degradation, is one of the mechanisms for acquisition of CDDP resistance in ESCC.

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“…The main mechanism involved in the removal and repair of oxidized DNA bases with the involvement of lesion-specific DNA glycosylases is base excision repair (BER) [ 10 , 11 , 12 ]. Additionally, both MUTYH and hOGG1 were found to be downregulated in malignant human colon tissues in comparison with adjacent tissues [ 13 ]. The role of BER glycosylases in the transition from early adenoma to CRC has clearly been documented on hereditary syndromes MUTYH -associated polyposis (MAP) and NTHL1 -associated tumor syndrome (NATS) [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases MUTYH and hOGG1 in Colorectal Cancer Patients

Kavec

Urbanová

Makovický

et al. 2022

IJMS

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Oxidative stress, oxidative DNA damage and resulting mutations play a role in colorectal carcinogenesis. Impaired equilibrium between DNA damage formation, antioxidant status, and DNA repair capacity is responsible for the accumulation of genetic mutations and genomic instability. The lesion-specific DNA glycosylases, e.g., hOGG1 and MUTYH, initiate the repair of oxidative DNA damage. Hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome) with germline mutations causing a loss-of-function in base excision repair glycosylases, serve as straight forward evidence on the role of oxidative DNA damage and its repair. Altered or inhibited function of above glycosylases result in an accumulation of oxidative DNA damage and contribute to the adenoma-adenocarcinoma transition. Oxidative DNA damage, unless repaired, often gives rise G:C > T:A mutations in tumor suppressor genes and proto-oncogenes with subsequent occurrence of chromosomal copy-neutral loss of heterozygosity. For instance, G>T transversions in position c.34 of a KRAS gene serves as a pre-screening tool for MUTYH-associated polyposis diagnosis. Since sporadic colorectal cancer represents more complex and heterogenous disease, the situation is more complicated. In the present study we focused on the roles of base excision repair glycosylases (hOGG1, MUTYH) in colorectal cancer patients by investigating tumor and adjacent mucosa tissues. Although we found downregulation of both glycosylases and significantly lower expression of hOGG1 in tumor tissues, accompanied with G>T mutations in KRAS gene, oxidative DNA damage and its repair cannot solely explain the onset of sporadic colorectal cancer. In this respect, other factors (especially microenvironment) per se or in combination with oxidative DNA damage warrant further attention. Base excision repair characteristics determined in colorectal cancer tissues and their association with disease prognosis have been discussed as well.

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Tissue Expresion of the Genes Mutyh and Ogg1 in Patients With Sporadic Colorectal Cancer

Cited by 10 publications

References 32 publications

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Downregulation of MUTYH contributes to cisplatin‑resistance of esophageal squamous cell carcinoma cells by promoting Twist‑mediated EMT

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases MUTYH and hOGG1 in Colorectal Cancer Patients

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