Relationship: 2069



Chronic ROS leads to Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion

Upstream event


Chronic ROS

Downstream event


Sustained tissue damage / macrophage activation/ porcupine-induced Wnt secretion

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Chronic reactive oxygen species leading to human treatment-resistant gastric cancer adjacent Moderate Moderate

Taxonomic Applicability


Sex Applicability


Life Stage Applicability


Key Event Relationship Description


ROS production causes the tissue damage (Gao, Zhou, Lin, Paus, & Yue, 2019).. ROS production is involved in Wnt-driven tumorigenesis (Myant et al., 2013).

Injury causes the Porcupine-induced Wnt secretion (Saha et al., 2016).

Evidence Supporting this KER


Biological Plausibility


Sustained ROS increase caused by/causes DNA damage, which will alter several signaling pathways including Wnt signaling. Macrophages accumulate into injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion. ROS stimulate inflammatory factor production and Wnt/beta-catenin signaling (Vallée & Lecarpentier, 2018).

Empirical Evidence


Production of ROS by DNA double-strand break causes the tissue damages (Gao et al., 2019).

ROS signaling induces Wnt/beta-catenin signaling(Pérez, Taléns-Visconti, Rius-Pérez, Finamor, & Sastre, 2017).

Uncertainties and Inconsistencies


The balance of ROS signaling is important, and dual effects of ROS should be taken in consideration. The ROS may enhance Wnt/beta-catenin proliferating pathways to promote tumorigenesis, while ROS may disrupt tumor progression by different pro-apoptotic mechanisms (Pérez et al., 2017). It is also known that Wnt signaling induces ROS signaling (Cheung et al., 2016). Wnt/beta-catenin signaling control by ROS needs to be further investigated (Caliceti, Nigro, Rizzo, & Ferrari, 2014).

Quantitative Understanding of the Linkage


Response-response Relationship


ROS induces inflammatory responses (Bhattacharyya, Chattopadhyay, Mitra, & Crowe, 2014). Oxidant induces ROS generation and p38 MAPK activation in macrophages (Conway & Kinter, 2006). ROS induce tissue damage in cardiac myocytes (Miller & Cheung, 2016; Yang et al., 2006).



For the colony formation assay, cells were treated with 400 microM/L H2O2 for 1 week, where the medium was changed every three days (Wang et al., 2019).

Known modulating factors


GPX2, an activator of Wnt/beta-catenin signaling, is identified as a key regulator of intracellular H2O2 levels and an inhibitor of apoptosis (Wang et al., 2019).

Known Feedforward/Feedback loops influencing this KER


The reduction in ROS levels in the human serum albumin-treated cerebral ischemia/reperfusion-induced injury may be mediated by Wnt/beta-catenin signaling (Tang, Shen, Zhang, Yang, & Liu, 2019).

Domain of Applicability




Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S. E. (2014). Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiological reviews, 94(2), 329-354. doi:10.1152/physrev.00040.2012

Caliceti, C., Nigro, P., Rizzo, P., & Ferrari, R. (2014). ROS, Notch, and Wnt signaling pathways: crosstalk between three major regulators of cardiovascular biology. BioMed research international, 2014, 318714-318714. doi:10.1155/2014/318714

Cheung, E. C., Lee, P., Ceteci, F., Nixon, C., Blyth, K., Sansom, O. J., & Vousden, K. H. (2016). Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes & development, 30(1), 52-63. doi:10.1101/gad.271130.115

Conway, J. P., & Kinter, M. (2006). Dual role of peroxiredoxin I in macrophage-derived foam cells. The Journal of biological chemistry, 281(38), 27991-28001. doi:10.1074/jbc.M605026200

Gao, Q., Zhou, G., Lin, S.-J., Paus, R., & Yue, Z. (2019). How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models. Experimental dermatology, 28(4), 413-418. doi:10.1111/exd.13846

Miller, B. A., & Cheung, J. Y. (2016). TRPM2 protects against tissue damage following oxidative stress and ischaemia-reperfusion. The Journal of physiology, 594(15), 4181-4191. doi:10.1113/JP270934

Myant, K. B., Cammareri, P., McGhee, E. J., Ridgway, R. A., Huels, D. J., Cordero, J. B., . . . Sansom, O. J. (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell stem cell, 12(6), 761-773. doi:10.1016/j.stem.2013.04.006

Pérez, S., Taléns-Visconti, R., Rius-Pérez, S., Finamor, I., & Sastre, J. (2017). Redox signaling in the gastrointestinal tract. Free radical biology & medicine, 104, 75-103. doi:10.1016/j.freeradbiomed.2016.12.048

Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature Communications, 7, 13096-13096. doi:10.1038/ncomms13096

Tang, Y., Shen, J., Zhang, F., Yang, F.-Y., & Liu, M. (2019). Human serum albumin attenuates global cerebral ischemia/reperfusion-induced brain injury in a Wnt/β-Catenin/ROS signaling-dependent manner in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 115, 108871-108871. doi:10.1016/j.biopha.2019.108871

Vallée, A., & Lecarpentier, Y. (2018). Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis. Frontiers in immunology, 9, 745-745. doi:10.3389/fimmu.2018.00745

Wang, Y., Cao, P., Alshwmi, M., Jiang, N., Xiao, Z., Jiang, F., . . . Li, S. (2019). GPX2 suppression of H(2)O(2) stress regulates cervical cancer metastasis and apoptosis via activation of the β-catenin-WNT pathway. OncoTargets and therapy, 12, 6639-6651. doi:10.2147/OTT.S208781

Yang, K. T., Chang, W. L., Yang, P. C., Chien, C. L., Lai, M. S., Su, M. J., & Wu, M. L. (2006). Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death & Differentiation, 13(10), 1815-1826. doi:10.1038/sj.cdd.4401813