miR-1262 suppresses gastric cardia adenocarcinoma via targeting oncogene ULK1

Yan Zheng; Mengyu Xie; Nasha Zhang; Jiandong Liu; Yemei Song; Liqing Zhou; Ming Yang

doi:10.7150/jca.46971

miR-1262 suppresses gastric cardia adenocarcinoma via targeting oncogene ULK1

J Cancer. 2021 Jan 1;12(4):1231-1239. doi: 10.7150/jca.46971. eCollection 2021.

Authors

Yan Zheng^{1

2

3}, Mengyu Xie⁴, Nasha Zhang², Jiandong Liu², Yemei Song², Liqing Zhou⁵, Ming Yang^{2

4}

Affiliations

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.

Abstract

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: ULK1; gastric cardia adenocarcinoma; genetic polymorphism; miR-1262; tumor suppressor.