FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/β-catenin signalling

Abstract

Background:FAT4, a cadherin-related protein, was shown to function as a tumour suppressor; however, its role in human gastric cancer remains largely unknown. Here, we investigated the role of FAT4 in gastric cancer and examined the underlying molecular mechanisms.Methods:The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT–PCR in relation to the clinicopathological characteristics of gastric cancer patients. The effects of FAT4 silencing on cell proliferation, migration, and invasion were assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay, and migration and invasion assays in gastric cancer cell lines in vitro and in a mouse xenograft model in vivo.Results:Downregulation of FAT4 expression in gastric cancer tissues compared with adjacent normal tissues was correlated with lymph-node metastasis and poor survival. Knockdown of FAT4 promoted the growth and invasion of gastric cancer cells via the activation of Wnt/β-catenin signalling, and induced epithelial-to-mesenchymal transition (EMT) in gastric cancer cells, as demonstrated by the upregulation and downregulation of mesenchymal and epithelial markers. Silencing of FAT4 promoted tumour growth and metastasis in a gastric cancer xenograft model in vivo.Conclusions:FAT4 has a tumour suppressor role mediated by the modulation of Wnt/β-catenin signalling, providing potential novel targets for the treatment of gastric cancer.

miR‐107 regulates growth and metastasis of gastric cancer cells via activation of the PI3K‐AKT signaling pathway by down‐regulating FAT4

“…In addition, upregulating FAT4 could inhibit the GC cells proliferation and suppress the growth of xenograft tumor in nude mice, which was similar to the results of down-regulating miR-107. Cai et al 29 demonstrated that down-regulation of FAT4 could promote the growth, EMT of GC cells via activation of Wnt/βactin signaling. EMT is an vital mechanism of tumor cell invasion and metastasis, with the declining of E-cadherin and increasing of N-cadherin, vimentin in its process.…”

Hypoxic microenvironment promotes proliferation and invasion of non-small cell lung cancer A549 Cells through Wnt/β-catenin signaling pathway

“…When Wnt signal pathway is activated by the stimuli to cells, Wnt ligand, binding with the Frizzled/LRP receptor, can activate the Dsh through phosphorylation, thereby isolating the β-catenin from APC/Ax -in/GSK-3β; the accumulation of β-catenin would further enter the nuclear to combine with the TCF/LEF complex, thereby activating the transcription of downstream target genes, through which Wnt signal pathway can regulate various biological events, like cell proliferation, apoptosis, mobility and differentiation [20,21]. Research has reported the close correlations of β-catenin with the development and progression of a variety of tumors, including liver cancer [22], gastric cancer [23] and lung cancer [24]. All these studies have shown that β-catenin is highly expressed in the above tumor tissues.…”

Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

“…This analysis indicated that these candidates may have a putative role in development or progression of human lung cancer. Moreover, some of these of the candidates, such as DLC1 (36), FAT4 (37), and FAS (28), are well-known tumor suppressors.…”