NKX6-3, a transcription factor, is a crucial regulator in gastric mucosal epithelial differentiation [2,5]. It is associated with multiple pathways, such as those related to amyloid-β (Aβ) production, cell cycle, DNA repair, and Wnt/β-catenin and Rho-GTPase signaling. It plays a significant role in maintaining gastric epithelial homeostasis and is important for preventing gastric carcinogenesis [1-8]. Genetic models, like KO/CKO mouse models, can be valuable in studying its functions.

Depletion of NKX6-3 in gastric epithelial cells leads to various detrimental effects. It increases cell death, Aβ peptide oligomer production, and the expression of related proteins such as ApoE and Bace1, resulting in gastric mucosal atrophy [1]. It also causes mitotic defects, genomic instability, accelerated cell cycle progression, and abnormal mitotic figure formation, contributing to gastric carcinogenesis [3,4]. Moreover, NKX6-3 depletion leads to abnormal expression of CDX2 and SOX2, which are required for gastric-to-intestinal transdifferentiation, and activates AICDA/APOBEC family, causing genetic mutations in gastric epithelial cells [5,6]. In addition, NKX6-3 depletion impairs DNA replication and repair regulation, leading to copy number alterations of various genes [4].

In conclusion, NKX6-3 is essential for maintaining gastric epithelial cell homeostasis, regulating differentiation, and preventing gastric carcinogenesis. Studies using KO/CKO mouse models (hypothetical in this case as not specifically mentioned in the references) would further elucidate its role in these processes. The findings from loss-of-function experiments in gastric epithelial cells highlight its importance in understanding gastric diseases like atrophic gastritis and gastric cancer [1-8].

References:

1. Yoon, Jung Hwan, Lee, Yeon Soo, Kim, Olga, Nam, Suk Woo, Park, Won Sang. . NKX6.3 protects against gastric mucosal atrophy by downregulating β-amyloid production. In World journal of gastroenterology, 25, 330-345. doi:10.3748/wjg.v25.i3.330. https://pubmed.ncbi.nlm.nih.gov/30686901/

2. Yoon, Jung Hwan, Choi, Won Suk, Kim, Olga, Lee, Jung Young, Park, Won Sang. . NKX6.3 controls gastric differentiation and tumorigenesis. In Oncotarget, 6, 28425-39. doi:10.18632/oncotarget.4952. https://pubmed.ncbi.nlm.nih.gov/26314965/

3. Yoon, Jung Hwan, Kim, Jeong-Kyu, Eun, Jung Woo, Nam, Suk Woo, Park, Won Sang. 2025. NKX6.3 modulation of mitotic dynamics and genomic stability in gastric carcinogenesis. In Cell communication and signaling : CCS, 23, 35. doi:10.1186/s12964-025-02030-4. https://pubmed.ncbi.nlm.nih.gov/39833908/

4. Yoon, Jung Hwan, Eun, Jung Woo, Ashktorab, Hassan, Nam, Suk Woo, Park, Won Sang. 2021. Depletion of NK6 Homeobox 3 (NKX6.3) causes gastric carcinogenesis through copy number alterations by inducing impairment of DNA replication and repair regulation. In Oncogenesis, 10, 85. doi:10.1038/s41389-021-00365-4. https://pubmed.ncbi.nlm.nih.gov/34893582/

5. Yoon, Jung H, Choi, Sung S, Kim, Olga, Lee, Jung Y, Park, Won S. 2016. Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation. In Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 29, 194-208. doi:10.1038/modpathol.2015.150. https://pubmed.ncbi.nlm.nih.gov/26743476/

6. Yoon, Jung Hwan, Kim, Olga, Eun, Jung Woo, Nam, Suk Woo, Park, Won Sang. 2018. Multiple genetic mutations caused by NKX6.3 depletion contribute to gastric tumorigenesis. In Scientific reports, 8, 17609. doi:10.1038/s41598-018-35733-5. https://pubmed.ncbi.nlm.nih.gov/30514953/