Gegotek Agnieszka, Niklinski Jacek, Charkiewicz Radoslaw, Bielawska Katarzyna, Kozlowski Miroslaw, Skrzydlewska Elzbieta
Medical University of Bialystok, Department of Analytical Chemistry, Poland.
Medical University of Bialystok, Department of Clinical Molecular Biology, Poland.
Free Radic Biol Med. 2014 Oct;75 Suppl 1:S31. doi: 10.1016/j.freeradbiomed.2014.10.761. Epub 2014 Dec 10.
Lung cancer development is characterized by oxidative stress that leads to the oxidative modifications of cellular components, including phospholipid and protein. Lipid peroxidation products may be involved in intracellular signaling pathways or in the activity of transcription factors (Nrf2). Therefore, the aim of this study has been to evaluate the relationship between the level of reactive aldehydes and the activity of the transcription factor and a comparison of these parameters in different histological types and stages of non-small cell lung cancer. Lung cancer tissues and tissues without morphological changes were received during operation from patients with squamous cell lung carcinoma (SqCC), lung adenocarcinoma (AC) and large cell lung carcinoma (LCC). In the tissue homogenates the level of reactive aldehydes [4-HNE, MDA, 4-ONE] was determined by GCMS, while Nrf2 and its activators/inhibitors were evaluated by Western immunobloting. Tumor tissues showed several times higher reactive aldehydes level and those changes were accompanied by overexpression of Nrf2. The highest increase of 4-HNE and MDA level was observed in the SqCC and it was correlated with the highest increase in Nrf2 expression. Moreover, the aldehydes level and Nrf2 phosphorylation were significantly higher in the stage I than in the stage II. The level of Nrf2 inhibitor - Bach1 was lower in all histological types of tumor, but in AC was the most reduced, what is correlated with the lowest level of reactive aldehydes. The highest expression of p62 and p21 - Nrf2 activators was observed also in adenocarcinoma of the lung. However, the level of another Nrf2 activator - KAP1 was decreased in all histological types of tumor. Additionally, the cJun amount in the tumor tissue was increased, whereas reduction of its phosphorylated form in AC and LCC was observed. Understanding the relation between reactive aldehydes level and the Nrf2 activity may be applied in anticancer therapies.
肺癌的发展以氧化应激为特征,氧化应激会导致细胞成分(包括磷脂和蛋白质)发生氧化修饰。脂质过氧化产物可能参与细胞内信号通路或转录因子(Nrf2)的活性调节。因此,本研究的目的是评估反应性醛水平与转录因子活性之间的关系,并比较这些参数在不同组织学类型和分期的非小细胞肺癌中的差异。在手术过程中,从鳞状细胞肺癌(SqCC)、肺腺癌(AC)和大细胞肺癌(LCC)患者处获取肺癌组织和无形态学改变的组织。通过气相色谱-质谱联用(GCMS)测定组织匀浆中反应性醛[4-羟基壬烯醛(4-HNE)、丙二醛(MDA)、4-氧代壬烯醛(4-ONE)]的水平,同时通过蛋白质免疫印迹法评估Nrf2及其激活剂/抑制剂。肿瘤组织中反应性醛水平高出数倍,且这些变化伴随着Nrf2的过表达。在SqCC中观察到4-HNE和MDA水平升高最为显著,且与Nrf2表达的最高增加相关。此外,I期的醛水平和Nrf2磷酸化显著高于II期。Nrf2抑制剂Bach1在所有组织学类型的肿瘤中水平均较低,但在AC中降低最为明显,这与反应性醛的最低水平相关。在肺腺癌中也观察到p62和p21(Nrf2激活剂)的最高表达。然而,另一种Nrf2激活剂KAP1在所有组织学类型的肿瘤中水平均降低。此外,肿瘤组织中cJun的量增加,而在AC和LCC中观察到其磷酸化形式减少。了解反应性醛水平与Nrf2活性之间的关系可能应用于抗癌治疗。
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