Grhl2 reduces invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer

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.

miR-93 and PTEN: Key regulators of doxorubicin-resistance and EMT in breast cancer

“…EMT has been observed in the majority of tumors (37,38), and emerging evidence also indicates that it may be involved in drug resistance in certain types of cancer cells (7,39), including breast cancer (40,41). In the present study, the observed morphological changes and the upregulation of EMT-related genes in miR-93-overexpressing MCF-7 cells indicated that miR-93 participates in EMT in breast cancer cells.…”

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

“…GRHL2 suppresses EMT and has an expression pattern inversely correlated with that of ZEB1 in numerous cancers (Chen et al, 2016;Chung et al, 2016;Nishino et al, 2017;Paltoglou et al, 2017;Pan et al, 2017;Quan et al, 2014;Werner et al, 2013;Xiang et al, 2017). The miR-200 family of microRNAs, including MIR141, MIR200A, MIR200B, MIR200C and MIR429, along with MIR205, bind to the ZEB1 and ZEB2 mRNAs and inhibit their translation (Gregory et al, 2008).…”

Epithelial–mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease

“…Given that genetic mutations in hTERT may predispose for IPF (Tsakiri et al, ; Alder et al, ), GRHL2 may be dysregulated in IPF progression. Consistent with its role in lung development, GRHL2 can (a) inhibit EMT‐inducing transcription factor ZEB1 directly, and is inhibited during TGFβ‐mediated EMT (Cieply et al, ; Xiang et al, ), (b) induce epithelial gene expression signature during cancer progression (Xiang et al, ), and (c) maintain collective migration in non–small‐cell lung cancer (NSCLC) H1975 cells that display a stable hybrid E/M phenotype (Jolly et al, ).…”