Treatment with an SLC12A1 antagonist inhibits tumorigenesis in a subset of hepatocellular carcinomas

// Fei Teng 1, * , Meng Guo 1, * , Fang Liu 1, * , Ce Wang 2 , Jiayong Dong 1 , Lei Zhang 1 , You Zou 1 , Rui Chen 1 , Keyan Sun 1 , Hong Fu 1 , Zhiren Fu 1 , Wenyuan Guo 1 , Guoshan Ding 1 1 Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China 2 Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China * These authors have contributed equally to this work Correspondence to: Guoshan Ding, email: dingguoshanmail@163.com Wenyuan Guo, email: gwyuan7502@aliyun.com Keywords: HCC, liver cancer, SLC12A1, cancer outlier profile analysis, Bumetanide Received: October 02, 2015     Accepted: July 06, 2016     Published: July 18, 2016 ABSTRACT A central aim in cancer research is to identify genes with altered expression patterns in tumor specimens and their potential role in tumorigenesis. Most types of tumors, including hepatocellular carcinoma (HCC), are heterogeneous in terms of genotype and phenotype. Thus, traditional analytical methods like the t-test fail to identify all oncogenes from expression profiles. In this study, we performed a meta-Cancer Outlier Profile Analysis (meta-COPA) across six microarray datasets for HCC from the GEO database. We found that gene SLC12A1 was overexpressed in the Hep3B cell line, compared with five other HCC cell lines and L02 cells. We also found that the upregulation of SLC12A1 was mediated by histone methylation within its promoter region, and that SLC12A1 is a positive regulator of the WNK1/ERK5 pathway. Consistent with in vitro results, treatment with the SLC12A1 antagonist Bumetanide delayed tumor formation and reduced Hep3B cell tumor size in mouse xenografts. In summary, our research reveals a novel subset of HCCs that are sensitive to SLC12A1 antagonist treatment, thereby offering a new strategy for precision HCC treatment.