Astrocyte-elevated gene-1 confers resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase expression
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Chung-Yu Chen1,2,3, Ying-Yin Chen1, Jeremy J.W. Chen4, Kuan-Yu Chen2, Chao-Chi Ho2, Jin-Yuan Shih2,*, Yih-Leong Chang3,*, Chong-Jen Yu2 and Pan-Chyr Yang2
1Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan
2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
3Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
4Institute of Biomedical Science, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
*These authors have contributed equally to this work
Yih-Leong Chang, email: firstname.lastname@example.org
Jin-Yuan Shih, email: email@example.com
Keywords: lung cancer, pemetrexed, thymidylate synthase, astrocyte elevated gene-1, chemoresistance
Received: March 29, 2017 Accepted: May 03, 2017 Published: June 28, 2017
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 IC50 value. In contrast, overexpression of AEG-1 was associated with increased expression of TS and higher pemetrexed IC50 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.
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