J Cancer 2021; 12(4):1231-1239. doi:10.7150/jca.46971 This issue
1. Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
2. Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
3. Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
4. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
5. Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu, China.
Gastric cardia adenocarcinoma (GCA) is one of two main gastric cancer subtypes and has its own epidemiological, pathogenic and clinical characteristics. Genetic polymorphisms locating in a microRNA (miRNA) gene enhancer could transcriptionally regulates miRNA expression via impacting binding of transcriptional factors. It is still unclear how miR-1262 and a potential regulatory rs12740674 polymorphism mapping to a strong enhancer region of miR-1262 contribute to GCA development. We genotyped miR-1262 rs12740674 in two independent case-control sets consisting of 1,024 GCA patients and 1,118 controls, and found that the rs12740674 CT or TT genotype carriers had a 0.69-fold decreased risk to develop GCA compared to the CC genotype carriers (95% confidence interval=0.57-0.84, P=2.1×10-4). In the genotype-phenotype correlation analyses of 21 pairs of GCA-normal tissues, the rs12740674 CT or TT genotype was associated with significantly increased levels of miR-1262. Cell proliferation, wound healing and transwell assays elucidated that miR-1262 is a novel GCA tumor suppressor. Consistently, a significantly down-regulated level of miR-1262 exists in GCA specimens compared to normal tissues. Furthermore, multiple lines of evidences indicated that oncogene ULK1 is the target gene of miR-1262 in GCA. Our findings demonstrate miR-1262 transcriptionally modulated by an enhancer genetic variant suppresses GCA via targeting oncogene ULK1. Our data highlight miR-1262 as a promising diagnostic marker and therapeutic target for GCA.
Keywords: miR-1262, gastric cardia adenocarcinoma, tumor suppressor, genetic polymorphism, ULK1