Oxidative Stress and DNA Damage Markers in Colorectal Cancer

Acevedo-León, Delia; Monzó-Beltrán, Lidia; Pérez-Sánchez, Laura; Naranjo-Morillo, Eva; Gómez-Abril, Segundo Ángel; Estañ-Capell, Nuria; Bañuls, Celia; Sáez, Guillermo T.

doi:10.3390/ijms231911664

Cited by 23 publications

(11 citation statements)

References 52 publications

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“…We showed previously that EspF increases the production of ROS and induces the generation of γ-H2AX ( 5 , 41 ), suggesting that signs of oxidative DNA lesions exist during EHEC infection. To explore this hypothesis, we determined the level of 8-oxoG, the most abundant DNA lesion after exposure to oxidative stress, which serves as an oxidative stress biomarker for CRC ( 4 ). Caco-2 cells were incubated with the indicated strains for 6 and 9 h, and a time-dependent increase in ROS levels dependent on EspF was observed.…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative stress and subsequent DNA lesions are considered as a starting point in the development of colitis-associated cancer ( 3 ). 8-Oxoguanine (8-oxoG) and phosphorylated histone H2A variant H2AX are commonly used as biomarkers for oxidative DNA damage and double-strand breaks (DSBs) in colorectal cancer (CRC) ( 4 ). Although the tumorigenic potential of EHEC has been previously discussed ( 5 – 7 ), there is limited evidence of the mechanisms underlying the formation of oxidative DNA lesions.…”

Section: Introductionmentioning

confidence: 99%

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Enterohemorrhagic Escherichia coli effector EspF triggers oxidative DNA lesions in intestinal epithelial cells

Fang,

Fu,

et al. 2024

Infect Immun

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Attaching/effacing (A/E) pathogens induce DNA damage and colorectal cancer by injecting effector proteins into host cells via the type III secretion system (T3SS). EspF is one of the T3SS-dependent effector proteins exclusive to A/E pathogens, which include enterohemorrhagic Escherichia coli . The role of EspF in the induction of double-strand breaks (DSBs) and the phosphorylation of the repair protein SMC1 has been demonstrated previously. However, the process of damage accumulation and DSB formation has remained enigmatic, and the damage response is not well understood. Here, we first showed a compensatory increase in the mismatch repair proteins MutS homolog 2 (MSH2) and MSH6, as well as poly(ADP-ribose) polymerase 1, followed by a dramatic decrease, threatening cell survival in the presence of EspF. Flow cytometry revealed that EspF arrested the cell cycle at the G2/M phase to facilitate DNA repair. Subsequently, 8-oxoguanine (8-oxoG) lesions, a marker of oxidative damage, were assayed by ELISA and immunofluorescence, which revealed the accumulation of 8-oxoG from the cytosol to the nucleus. Furthermore, the status of single-stranded DNA (ssDNA) and DSBs was confirmed. We observed that EspF accelerated the course of DNA lesions, including 8-oxoG and unrepaired ssDNA, which were converted into DSBs; this was accompanied by the phosphorylation of replication protein A 32 in repair-defective cells. Collectively, these findings reveal that EspF triggers various types of oxidative DNA lesions with impairment of the DNA damage response and may result in genomic instability and cell death, offering novel insight into the tumorigenic potential of EspF. IMPORTANCE Oxidative DNA lesions play causative roles in colitis-associated colon cancer. Accumulating evidence shows strong links between attaching/effacing (A/E) pathogens and colorectal cancer (CRC). EspF is one of many effector proteins exclusive to A/E pathogens with defined roles in the induction of oxidative stress, double-strand breaks (DSBs), and repair dysregulation. Here, we found that EspF promotes reactive oxygen species generation and 8-oxoguanine (8-oxoG) lesions when the repair system is activated, contributing to sustained cell survival. However, infected cells exposed to EspF presented 8-oxoG, which results in DSBs and ssDNA accumulation when the cell cycle is arrested at the G2/M phase and the repair system is defective or saturated by DNA lesions. In addition, we found that EspF could intensify the accumulation of nuclear DNA lesions through oxidative and replication stress. Overall, our work highlights the involvement of EspF in DNA lesions and DNA damage response, providing a novel avenue by which A/E pathogens may contribute to CRC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enterohemorrhagic Escherichia coli effector EspF triggers oxidative DNA lesions in intestinal epithelial cells

Fang,

Fu,

et al. 2024

Infect Immun

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“…Our study found that an elevated OBS reduces the risk of secondary metastasis and abdominal pain caused by proximal colon cancer, yet it elevates the risk of secondary metastasis and abdominal pain induced by distal colon cancer. This may be due to the fact that differences in genetic and molecular characteristics of proximal colon cancer result in antioxidants having a more positive effect, such as reducing DNA damage caused by oxidative stress, thereby lowering the risk of metastasis and symptoms induced by the tumor ( 35 ). Some antioxidants may promote the proliferation and metastasis of existing tumor cells at high doses, especially when the tumor cells have adapted to a high oxidative stress environment ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Oxidative balance score: a potential tool for reducing the risk of colorectal cancer and its subsites incidences

Chang,

Li,

Wang

et al. 2024

Front. Endocrinol.

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BackgroundThe Oxidative Balance Score (OBS) is commonly used to assess oxidative stress and provides a comprehensive evaluation of dietary and lifestyle-related exposures. However, there is limited research on the association between OBS and colorectal cancer (CRC), its subsites, and complications. The objective of this study was to assess the relationship between OBS and the risk of CRC, its subsites, and common complications in a large prospective cohort study.MethodsWe included data from 175,808 participants in the UK Biobank data sample repository from 2006 to 2010. We evaluated OBS using a scoring system based on 22 dietary and lifestyle factors. Multiple adjustments, including multivariate Cox proportional hazard regression, gender stratification, subgroup analysis, and sensitivity analysis, were performed to fully explore the relationship between OBS and CRC, its subsites, and complications. The mediation analysis was conducted to investigate whether serum albumin, uric acid, and neutrophil levels mediate the relationship between OBS and CRC.ResultsAfter adjusting for potential confounding factors, a significant negative correlation was found between OBS and the risk of CRC and its subsites (proximal colon cancer, distal colon cancer, and rectal cancer). This correlation was particularly pronounced in male CRC patients. Serum albumin, uric acid, and neutrophil count, which are biomarkers, were found to have a significant mediating effect between OBS and CRC.ConclusionOur study suggests that higher exposure to antioxidants assessed through OBS (diet and lifestyle rich in antioxidants) may decrease the occurrence of CRC and its subsites.

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“…In vitro assays showed that overexpression of ACOX2 leads to decreased cellular lipid content and elevated cellular ROS content in PCa cell lines with upregulated CAT expression. Overcoming the degradation ability of peroxidases such as CAT, the excessive generation of ROS results in oxidative stress 32 and cell cycle arrest 33 . It has been reported that ROS leads to G2/M arrest in cervical carcinoma 34 and colorectal cancer cells 35 .…”

Section: Discussionmentioning

confidence: 99%

ACOX2 Serves as a Favorable Indicator Related to Lipid Metabolism and Oxidative Stress for Biochemical Recurrence in Prostate Cancer

Tan,

Deng,

Cai

et al. 2024

J. Cancer

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Given the heterogeneity of tumors, there is an urgent need for accurate prognostic parameters in prostate cancer (PCa) patients. Lipid metabolism (LM) reprogramming and oxidative stress (OS) play a vital role in the progression of PCa. In this work, we identified five LM-OS-related genes (including ACOX2, PPRAGC1A, PTGS1, PTGS2, and HAO1) associated with the biochemical recurrence (BCR) of PCa. Subsequently, a prognostic signature was established based on these five genes. Kaplan-Meier survival estimates, receiver operating characteristic curves, and relationship analysis between risk score and clinical characters were applied to measure the robustness of the signature in an external cohort. A nomogram of risk score combined with clinical characteristics was constructed for clinical application. Functional enrichment analysis suggested that the underlying mechanism related to the signature included the calcium signaling, lipid transport, and cell cycle signaling pathways. Furthermore, WEE1 inhibitor was identified as a potential agent related to the cell cycle for high-risk patients. The mRNA expression and the prognostic value of the five genes were determined, and ACOX2 was identified as the key gene related to the prognostic signature. The protein expression of ACOX2 was measured in a prostate tissue microarray through an immunohistochemistry assay, confirming the bioinformatics results. By constructing the ACOX2-overexpressing PCa cell lines PC-3 and 22Rv1, the biological function of PCa cells was investigated. The cell viability, colony formation, migration, and invasion ability of PCa cell lines overexpressing ACOX2 were hindered. Decreased cellular lipid content and elevated cellular ROS content were observed in ACOX2-overexpressing PCa cell lines with reduced G2/M phases. In conclusion, this work presents the first prognostic signature specifically focused on LM-OS for PCa. ACOX2 could serve as a favorable indicator for the BCR in PCa. Further experiments are required to identify the potential underlying mechanism.

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Oxidative Stress and DNA Damage Markers in Colorectal Cancer

Cited by 23 publications

References 52 publications

Enterohemorrhagic Escherichia coli effector EspF triggers oxidative DNA lesions in intestinal epithelial cells

Enterohemorrhagic Escherichia coli effector EspF triggers oxidative DNA lesions in intestinal epithelial cells

Oxidative balance score: a potential tool for reducing the risk of colorectal cancer and its subsites incidences

ACOX2 Serves as a Favorable Indicator Related to Lipid Metabolism and Oxidative Stress for Biochemical Recurrence in Prostate Cancer

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