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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.

miR-1262 suppresses gastric cardia adenocarcinoma via targeting oncogene ULK1