Working Paper Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 27 October 2020 / Approved: 27 October 2020 / Online: 27 October 2020 (20:15:19 CET)

How to cite: Moscatello, C.; Di Marcantonio, M.C.; D'Amico, E.; Savino, L.; Spacco, G.; Muraro, R.; Mincione, G.; Cotellese, R.; Aceto, G.M. Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology. Preprints 2020, 2020100561 Moscatello, C.; Di Marcantonio, M.C.; D'Amico, E.; Savino, L.; Spacco, G.; Muraro, R.; Mincione, G.; Cotellese, R.; Aceto, G.M. Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology. Preprints 2020, 2020100561

Abstract

Abstract Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, still remain elusive the molecular mechanisms concerning the role of oxidative stress. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyper-activation of mitogen-activated protein kinase (MAPK), and PI3K/Akt, that 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 relationship 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 non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the obtained results of gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/TPC 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 cross-talk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall our data about OGG1 protein expression suggest that the alternative splicing mechanisms may lead to different protein isoforms, physiologically regulated in response to ErbB modulation, and that these could be dysregulated in the progression of thyroid malignancies with RET/TPC rearrangement.

Subject Areas

Oxidative Stress, ERBBs; OGG1; Base Excision Repair; crosstalk; Thyroid

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