Abstract
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.
Highlights
85% of lung cancer cases are classified as non-small cell lung cancer (NSCLC), which is often associated with a serious prognosis [1]
We demonstrated the following: (1) Twist1 overexpression is significantly associated with reduced survival of NSCLC patients; (2) knockdown of Twist1 suppresses cell invasion, clone formation, and in vivo tumor growth, but overexpression of Twist1 enhances cell invasion and clone formation; (3) knockdown of Twist1 suppresses p-4E-BP1 possibly through p-mammalian target of rapamycin (mTOR) inhibition, and Twist1 expression is correlated with p-4E-BP1 expression in NSCLC patients; and (4) a variety of gene expressions are changed after Twist1 knockdown
We examined the expression of Twist1 in lung tissues from 75 NSCLC patients
Summary
85% of lung cancer cases are classified as non-small cell lung cancer (NSCLC), which is often associated with a serious prognosis [1]. Twist overexpression has been frequently found and documented in different types of cancer, including breast cancer [9, 10], gastric cancer [11, 12], hepatocellular carcinoma [13], NSCLC [14,15,16,17], prostate cancer [18, 19], and sarcomas [20], and it is becoming an important diagnostic and prognostic marker for cancer detection and monitoring in patients. MTOR could act as an important regulator for 4E-BP1 phosphorylation, and p-4E-BP1 has been frequently found and/or indicated as a prognostic predictor for poor survival in different cancers such as breast cancer [26], nasopharyngeal carcinoma [27], hilar cholangiocarcinoma [28], gastric cancer [29], and lung cancer [30, 31] The suppression of mTOR activity and the decrease of mTOR phosphorylation have been observed in lung cancer H1299 cells after Twist knockdown [17]. mTOR could act as an important regulator for 4E-BP1 phosphorylation, and p-4E-BP1 has been frequently found and/or indicated as a prognostic predictor for poor survival in different cancers such as breast cancer [26], nasopharyngeal carcinoma [27], hilar cholangiocarcinoma [28], gastric cancer [29], and lung cancer [30, 31]
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