NKX6.3 controls gastric differentiation and tumorigenesis

// Jung Hwan Yoon 1,* , Won Suk Choi 1,* , Olga Kim 1 , Sung Sook Choi 2 , Eun Kyung Lee 3 , Suk Woo Nam 1,4 , Jung Young Lee 1,4 and Won Sang Park 1,4 1 Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea 2 College of Pharmacy, Sahmyook University, Hwarangro, Nowon-gu, Seoul, South Korea 3 Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea 4 Department of Functional RNomics Reasearch Center, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Won Sang Park, email: // Keywords : NKX6.3, differentiation, cell proliferation, cell death, stomach Received : April 03, 2015 Accepted : June 28, 2015 Published : July 22, 2015 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 AGS NKX6.3 and MKN1 NKX6.3 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.