Abstract
Metastasis is one of the typical features of malignancy that significantly increases cancer-related mortality. Recent studies have shown that epithelial–mesenchymal transition (EMT) is closely related to the invasion and migration of cancer cells. Grainyhead-like 2 (Grhl2), a transcription factor, has been reported to be associated with several tumor processes including EMT. In the previous study, we have reported that Grhl2 functioned as a tumor suppressor in proliferation and apoptosis of gastric cancer. Here we aim to explore the effects of Grhl2 on invasion and migration of gastric cancer and further clarify its possible underlying mechanisms. As a result, in both SGC7901 and MKN45 cells, Grhl2 overexpression significantly inhibited the ability of invasion and migration. In addition, preliminary experiments showed that Grhl2 reduces the protein expression of matrix metalloproteinase-2, -7 and -9 (MMP-2, MMP-7 and MMP-9). Most importantly, Grhl2 antagonizes transforming growth factor-β (TGFβ)-induced EMT, and inhibition of TGFβ signaling pathways can restore Grhl2 expression. Finally, the results of subcutaneous xenograft model indicated that Grhl2 suppresses the growth of gastric cancer and reverses EMT process in vivo. Meanwhile, the metastatic tumor model further confirmed the inhibition of Grhl2 on metastasis of gastric cancer. Taken together, our findings proved that Grhl2, functioned as a tumor suppressor, reduces the invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer.
Highlights
Gastric cancer (GC) continues to be an important health threat as the third leading cause of cancer-related death in both sexes worldwide.[1]
We have proved that Grhl[2] inhibits proliferation and promotes apoptosis so that it functioned as a tumor suppressor
Human gastric cancer cell lines SGC7901 and MKN45 were used in this study, and both the cell lines were infected with Grhl[2] expression vector
Summary
Gastric cancer (GC) continues to be an important health threat as the third leading cause of cancer-related death in both sexes worldwide.[1]. Metastasis is one of the typical features of malignancy that significantly increases cancer-related mortality. As far as we know, EMT is a complex pathophysiological process that can be triggered by a variety of soluble factors including epidermal growth factor, hepatocyte growth factor, fibroblast growth factor and transforming growth factor-β (TGFβ). Other stimuli such as hypoxia and adhesion to ECM components can induce EMT.[6] Among these, TGFβ family signaling has a predominant role.[7]
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