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Review
. 2021 Feb 4;10(2):116.
doi: 10.3390/biology10020116.

Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

Francisco Perez-Dominguez  1 , Diego Carrillo-Beltrán  1 , Rancés Blanco  1 , Juan P Muñoz  2 , Grettell León-Cruz  3 , Alejandro H Corvalan  4 , Ulises Urzúa  5 , Gloria M Calaf  2   6 , Francisco Aguayo  7
Affiliations
Review

Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

Francisco Perez-Dominguez et al. Biology (Basel). .

Abstract

Pirin is an oxidative stress (OS) sensor belonging to the functionally diverse cupin superfamily of proteins. Pirin is a suggested quercetinase and transcriptional activator of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Its biological role in cancer development remains a novel area of study. This review presents accumulating evidence on the contribution of Pirin in epithelial cancers, involved signaling pathways, and as a suggested therapeutic target. Finally, we propose a model in which Pirin is upregulated by physical, chemical or biological factors involved in OS and cancer development.

Keywords: cancer; epithelial; pirin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Secondary Pirin structure (Homo sapiens). Yellow: Protein Data Bank (PDB) structure known for this area; Green: Beta strands; Blue: Helix; Orange: Turn. Red: Fe2+/3+ binding site. Data extracted from Uniprot Consortium [16].
Figure 2
Figure 2
Pirin functional association network. Filled nodes represent proteins with predicted 3D structures. Edges color, Purple: experimentally determined; light blue: association in curated databases; green: co-mentioned in PubMed abstracts (STRING V11.0, full STRING network, confidence 0.900) [39]. Abbreviations: WASF2: Wiskott—Aldrich syndrome protein family member 2; PSMA7: proteasome subunit alpha type-7; RAC1: Ras-related C3 botulinum toxin substrate 1; NCK1: cytoplasmic protein; NCKAP1: Nck-associated protein 1; ABL2: Abelson tyrosine-protein kinase 2.
Figure 3
Figure 3
PIR transcripts expression in head and neck cancers (TCGA, n = 604) stratified by ISH testing for human papillomavirus (p = 0.02028, Welch’s t-test). Raw data were extracted from University of California, Santa Cruz (ena.ucsc.edu). UCSC Xena functional genomics explorer (https://xenabrowser.net) [96].
Figure 4
Figure 4
PIR transcript expression in human cancer (TCGA, n = 10071). p < 0.0001, Welch’s ANOVA test. Raw data were extracted from University of California, Santa Cruz (ena.ucsc.edu). UCSC Xena functional genomics explorer (https://xenabrowser.net) [96].
Figure 5
Figure 5
Model of Pirin-mediated tumor activation by viruses or environmental factors in epithelial cells. (1) HPV integrates into the host genome, overexpressing viral oncogenes (i.e., E7). (2) E7 promotes EGFR/PI3K/AKT activation and NRF2 recruitment into the PIR promoter leading to PIR expression. (3) Environmental factors such as cigarette smoke or UV radiation through reactive oxygen species (ROS) generation promote NRF2 recruitment into the PIR promoter. (4) Overexpressed Pirin (Fe3+ status) binds nuclear p65 promoting expression of κB genes. EGFR (epidermal growth factor receptor), PI3K (phosphoinositide 3-kinase), NRF2 (nuclear factor erythroid 2-related factor 2), ROS (reactive oxygen species), NF-κB (nuclear factor kappa B), EMT (epithelial–mesenchymal transition).
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