Abstract
NKX6.3 transcription factor is known to be an important regulator in gastric mucosal epithelial differentiation. The present study aimed to investigate whether NKX6.3 acts as an essential tumor suppressor in gastric carcinogenesis. Absent or reduced protein expression and decreased DNA copy number and mRNA transcript of the NKX6.3 gene were frequently observed in gastric cancers. Overexpression of NKX6.3 in AGSNKX6.3 and MKN1NKX6.3 cells markedly arrested cell proliferation by inhibiting cell cycle progression and induced apoptosis through both death receptor- and mitochondrial-pathways. In addition, stable NKX6.3 transfectants increased the expression of gastric differentiation markers, including SOX2 and Muc5ac, and decreased the expression of intestinal differentiation markers, CDX2 and Muc2. In ChIP-cloning and sequencing analyses, NKX6.3 coordinated a repertoire of target genes, some of which are clearly associated with cell cycle, differentiation and death. In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter. Furthermore, there was a positive correlation between NKX6.3 and GKN1 expression in non-cancerous gastric mucosae. Thus, these data suggest that NKX6.3 may control the fate of gastric mucosal cells and function as a gastric tumor suppressor.
Highlights
The gastrointestinal epithelium is characterized by a very high cellular turnover rate, which leads to epithelial renewal every 3-5 days, and apoptosis is a key regulator of this turnover [1]
AGS, MKN1, MKN28 and MKN45 gastric cancer cells showed no expression of the NKX6.3 protein, whereas its marked expression was detected in AGS cells transiently transfected with NKX6.3 (Figure 1B), confirming tissue data and suggesting a role for NKX6.3 as a tumor suppressor
To further identify the mechanism underlying NKX6.3 inactivation in gastric cancers, DNA copy number and mRNA transcript levels of the NKX6.3 gene were examined by real-time QPCR and real-time RT-polymerase chain reaction (PCR), respectively
Summary
The gastrointestinal epithelium is characterized by a very high cellular turnover rate, which leads to epithelial renewal every 3-5 days, and apoptosis is a key regulator of this turnover [1]. Post-mitotic cells migrate up or down from the neck region toward the gland and differentiate into a variety of cell types [2]. NKX6.3, a third member of the NKX6 subfamily of NKX gene, is expressed in the epithelium of the most distal stomach and eventually segregates to the lower/base region of www.impactjournals.com/oncotarget the gastric unit [6, 7]. Since NKX6.3 is expressed in post-mitotic differentiated migrant cells of gastric units and loss of heterozygosity at chromosome 8p11 has been frequently detected [7, 8], we hypothesized that alteration of the NKX6.3 gene may lead to abnormal differentiation and homeostatic imbalance of gastric mucosal epithelium and may eventually cause gastric cancer
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