Chen Chung-Yu, Chen Ying-Yin, Chen Jeremy J W, Chen Kuan-Yu, Ho Chao-Chi, Shih Jin-Yuan, Chang Yih-Leong, Yu Chong-Jen, Yang Pan-Chyr
Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Oncotarget. 2017 Jun 28;8(37):61901-61916. doi: 10.18632/oncotarget.18717. eCollection 2017 Sep 22.
Previous studies have suggested that astrocyte-elevated gene-1 (AEG-1) contributes to the mechanisms of resistance to various chemotherapeutics. In this study, we investigated whether AEG-1 expression level correlated with that of thymidylate synthase (TS), as higher TS expression is known to be associated with the resistance to pemetrexed chemotherapy in patients with advanced lung adenocarcinoma. Using pemetrexed-resistant lung adenocarcinoma PC-9 cell line, we demonstrated that transfection of AEG-1 siRNA lowered TS expression and decreased pemetrexed IC value. In contrast, overexpression of AEG-1 was associated with increased expression of TS and higher pemetrexed IC value. Immunohistochemical staining of clinical biopsy samples showed that patients with lower AEG-1 expression had longer overall survival time. Moreover, analysis of repeated biopsy samples revealed that an increase in the TS level from baseline to disease progression was significantly associated with the elevation of AEG-1 expression. In conclusion, our data demonstrated that TS expression might be regulated by AEG-1 and that increased expression of these proteins contributes to lung cancer disease progression and may be associated with the development of resistance to pemetrexed.
先前的研究表明，星形胶质细胞上调基因1（AEG-1）参与了对多种化疗药物的耐药机制。在本研究中，我们调查了AEG-1表达水平是否与胸苷酸合成酶（TS）的表达水平相关，因为已知较高的TS表达与晚期肺腺癌患者对培美曲塞化疗的耐药性有关。使用耐培美曲塞的肺腺癌PC-9细胞系，我们证明转染AEG-1 siRNA可降低TS表达并降低培美曲塞的IC值。相反，AEG-1的过表达与TS表达增加和更高的培美曲塞IC值相关。临床活检样本的免疫组织化学染色显示，AEG-1表达较低的患者总生存时间更长。此外，对重复活检样本的分析表明，从基线到疾病进展TS水平的升高与AEG-1表达的升高显著相关。总之，我们的数据表明TS表达可能受AEG-1调节，这些蛋白质表达的增加促进肺癌疾病进展，并可能与对培美曲塞耐药的发生有关。
