Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology.

Carmelo Moscatello,Giordano Spacco,Luca Savino,Pasquale Simeone,Raffaella Muraro,Roberto Cotellese,Gitana Maria Aceto,Gabriella Mincione,Emira D’Amico,Paola Lanuti,Maria Carmela Di Marcantonio

doi:10.3390/cells11050822

Carmelo Moscatello, Giordano Spacco + Show 9 more

Open Access

https://doi.org/10.3390/cells11050822

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Journal: Cells	Publication Date: Feb 26, 2022
Citations: 8	License type: CC BY 4.0

Affiliation: University of Chieti-Pescara

Abstract

Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, the molecular mechanisms concerning the role of oxidative stress remain elusive. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyperactivation of mitogen-activated protein kinase (MAPK) and PI3K/Akt, which mediate ErbB signaling. Increased levels of 8-oxoG DNA adducts have been detected in the early stages of thyroid cancer. These DNA lesions are efficiently recognized and removed by the base excision repair (BER) pathway initiated by 8-oxoG glycosylase1 (OGG1). This study investigated the relationships between the EGFR and OGG1-BER pathways and their mutual regulation following oxidative stress stimulus by H2O2 in human thyrocytes. We clarified the modulation of ErbB receptors and their downstream pathways (PI3K/Akt and MAPK/ERK) under oxidative stress (from H2O2) at the level of gene and protein expression, according to the mechanism defined in a human non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the results obtained by gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/PTC rearrangement (TPC-1). Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and OGG1-BER pathways in normal thyroid cells (while this is dysregulated in the TPC-1 cells). Gene expression data also delineated that MUTYH gene could play a physiological role in crosstalk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall, our data on OGG1 protein expression suggest that it was physiologically regulated in response to oxidative modulation of ErbB, and that these might be dysregulated in the signaling pathway involving AKT in the progression of thyroid malignancies with RET/PTC rearrangements.

Highlights

Over the last 30 years, the incidence rate of thyroid cancer has steadily increased by2.4 times [1,2] and papillary thyroid carcinoma (PTC) represents the most common histological type, with a frequency around 80% of cases [1]
Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and oxoG glycosylase1 (OGG1)-base excision repair (BER) pathways in normal thyroid cells
Our data on OGG1 protein expression suggest that it was physiologically regulated in response to oxidative modulation of ErbB, and that these might be dysregulated in the signaling pathway involving AKT in the progression of thyroid malignancies with RET/PTC rearrangements

Summary

Introduction

Over the last 30 years, the incidence rate of thyroid cancer has steadily increased by2.4 times [1,2] and papillary thyroid carcinoma (PTC) represents the most common histological type, with a frequency around 80% of cases [1]. Carcinogenesis and tumor progression in the thyroid gland are a phenotypic expression of a complex molecular interaction based on the connection between gene predisposition, environmental factors, and lifestyle, the effects of which influence thyroid hormone metabolism and oxidative DNA damage [3,4]. Oxidative damage has been suggested to promote tumor initiation and progression by increasing mutation rates and activating oncogenic pathways. On the other hand, based on its strong oxidative power, H2O2, could be responsible for the high level of oxidative DNA damage as observed in thyroid cancer tissue; it is considered a second messenger able to activate several signaling pathways [9,10]. Oxidative DNA lesions have been detected in advanced stages of thyroid cancer, suggesting their contribution to tumor progression [4]. There has been a growing interest in studying the role of oxidative stress in cancer initiation/progression and therapeutic response [11]. H2O2 is a signaling molecule involved in both the regulation of cell proliferation and apoptosis [10]

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