Twist1-mediated 4E-BP1 regulation through mTOR in non-small cell lung cancer
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Tangfeng Lv1,2,*, Qian Wang1,3,*, Meghan Cromie1, Hongbing Liu2, Song Tang1, Yong Song2, Weimin Gao1
1Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Lubbock, Texas 79416, United States of America
2Department of Respiratory Medicine, Jinling Hospital, Nanjing, Jiangsu 210002, China
3Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
*These authors have contributed equally to this work
Yong Song, e-mail: email@example.com
Weimin Gao, e-mail: firstname.lastname@example.org
Keywords: Twist1, epithelial-mesenchymal transition, phosphorylated 4E-binding protein 1, phosphorylated mammalian target of rapamycin, non-small cell lung cancer
Received: May 21, 2015 Accepted: July 31, 2015 Published: August 12, 2015
Twist1 overexpression corresponds with poor survival in non-small cell lung cancer (NSCLC), but the underlining mechanism is not clear. The objective of the present study was to investigate the tumorigenic role of Twist1 and its related molecular mechanisms in NSCLC. Twist1 was overexpressed in 34.7% of NSCLC patients. The survival rate was significantly lower in patients with high Twist1 expression than low expression (P < 0.05). Twist1 expression levels were higher in H1650 cells, but relatively lower in H1975 cells. H1650 with stable Twist1 knockdown, H1650shTw, demonstrated a significantly slower rate of wound closure; however, H1975 with stable Twist1 overexpression, H1975Over, had an increased motility velocity. A significant decrease in colony number and size was observed in H1650shTw, but a significant increase in colony number was found in H1975Over (P < 0.05). Tumor growth significantly decreased in mice implanted with H1650shTw compared to H1650 (P < 0.05). 4E-BP1 and p53 gene expressions were increased, but p-4E-BP1 and p-mTOR protein expressions were decreased in H1650shTw. However, 4E-BP1 gene expression was decreased, while p-4E-BP1 and p-mTOR protein expressions were increased in H1975Over. p-4E-BP1 was overexpressed in 24.0% of NSCLC patients. Survival rate was significantly lower in patients with high p-4E-BP1 expression than low p-4E-BP1 (P < 0.01). A significant correlation was found between Twist1 and p-4E-BP1 (P < 0.01). A total of 13 genes in RT-PCR array showed significant changes in H1650shTw. Altogether, Twist1 is correlated with p-4E-BP1 in predicting the prognostic outcome of NSCLC. Inhibition of Twist1 decreases p-4E-BP1 expression possibly through downregulating p-mTOR and increasing p53 expression in NSCLC.
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