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.
摘要：
甲状腺疾病具有复杂和多因素的病因。尽管对与恶性转变有关的信号进行了大量研究，关于氧化应激作用的分子机制仍然难以捉摸。基于其强大的氧化能力，H2O2可能是在癌性甲状腺组织中观察到的高水平氧化DNA损伤和丝裂原活化蛋白激酶（MAPK）和PI3K/Akt的过度活化的原因。它介导ErbB信号。在甲状腺癌的早期阶段已检测到8-oxoGDNA加合物的水平升高。这些DNA损伤通过由8-oxoG糖基化酶1（OGG1）启动的碱基切除修复（BER）途径被有效识别和去除。这项研究调查了人甲状腺细胞中H2O2氧化应激刺激后EGFR和OGG1-BER途径之间的关系及其相互调节。我们阐明了在氧化应激（来自H2O2）下，ErbB受体及其下游途径（PI3K/Akt和MAPK/ERK）在基因和蛋白质表达水平上的调节，根据人类非病理细胞系统中定义的机制，Nthy-ori3-1.稍后，根据正常细胞中基因表达聚类分析获得的结果，我们评估了甲状腺乳头状癌与RET/PTC重排(TPC-1)模型的关系失调.我们的观察结果表明，H2O2应激可能会在正常甲状腺细胞中诱导ErbB和OGG1-BER途径之间的生理交叉调节（而在TPC-1细胞中这种调节异常）。基因表达数据还描述了MUTYH基因可以在ErbB和BER途径之间的串扰中起生理作用，并且该功能在癌细胞中丢失。总的来说,我们对OGG1蛋白表达的数据表明，它是生理调节的响应ErbB的氧化调节，并且这些可能在涉及AKT的信号通路中失调，参与RET/PTC重排的甲状腺恶性肿瘤的进展。
