Abstract
In the tumor progression, transforming growth factor β1 (TGFβ1) plays a critical role in tumorigenesis as well as metastasis. It is known that high plasma level of TGFβ1 in patients with advanced non-small cell lung cancer (NSCLC) is correlated with poor prognostics. In addition, the generation of cancer stem-like cells is associated with metastasis, drug resistance, and tumor recurrence, which also lead to poor outcomes in NSCLC patients. However, it remains unclear how TGFβ1 promotes NSCLC cells to acquire stem-like properties and accelerate tumor metastasis. In our study, we found that short term TGFβ1 treatment resulted in a significant epithelial-mesenchymal transition (EMT) morphological change in TGFβ1–sensitive NSCLC cells but not in insensitive cells. Western blotting confirmed increased Vimentin and reduced E-Cadherin protein expression after TGFβ1 treatment in A549, NCI-H1993, and NCI-H358 cells. TGFβ1 incubation dramatically decreased in vitro cell proliferation and increased cell invasion in TGFβ1–sensitive NSCLC cells but not in NCI-H1975, NCI-H1650, and HCC827 cells. Moreover, TGFβ1 was able to enhance the mRNA expression of Oct4, Nanog and Sox2 and drastically increased anchorage-independent colony formation in TGFβ1–sensitive NSCLC cells, suggesting the acquisition of cancer stem-like properties. Interestingly, we found that vascular endothelial growth factor receptor 3 (VEGFR3) mRNA expression was significantly elevated in TGFβ1–sensitive NSCLC cells compared to insensitive cells. And TGFβ1 was capable of inducing VEGF-C gene expression. Pharmacological blocking TGFβ type I receptor kinase (ALK5) significantly inhibited TGFβ1-induced VEGF-C expression. Silencing of ALK5 by siRNA also dramatically reduced TGFβ1-induced VEGF-C expression in TGFβ1–sensitive NSCLC cells. Therefore, TGFβ1 contributes for NSCLC metastasis through promoting EMT, generation of high invasive cancer cells with stem-like properties, and increasing VEGF-C expression. Blocking TGFβ pathway is a potential therapeutic target in human non-small cell lung cancer.
Highlights
non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide with 5-year overall survival rate of around 16% for decades [1, 2]
We demonstrated that transforming growth factor β1 (TGFβ1) can induce epithelial-mesenchymal transition (EMT) and promote the acquisition of cancer stem-like properties in a group of TGFβ1-sensitive NSCLC cells with upregulation of vascular endothelial growth factor receptor 3 (VEGFR3) expression
The reduction of TGFβR1 expression showed virtually the same result as the inhibitor LY2157299 (Fig 4D). These results suggest that TGFβ1 pathway is likely involved in the upregulation of Vascular endothelial growth factor (VEGF)-C expression in TGFβ1 sensitive NSCLC cells
Summary
NSCLC is one of the deadliest cancers worldwide with 5-year overall survival rate of around 16% for decades [1, 2]. TGFβ is a critical tumor suppressor of epithelial cell proliferation and primary tumorigenesis. It is known as a positive contributor of tumor progression and metastasis because many studies demonstrated that TGFβ can induce EMT in certain types of cancer cells [3]. One is that TGFβ induces EMT via Smad protein mediated TGFβ type I receptor kinase (ALK-5) activation, which facilitates cell motility. Certain types of cancer cells induced to undergo EMT showed stem cell-like properties, such as self-renewal and tumor formation. In certain NSCLC cells, we observed similar results of TGFβ1-induced EMT and generation of lung cancer stem-like cells. We aimed to identify the mechanisms through which TGFβ1 activates and sustains prometastatic process
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