title: Treatment with an SLC12A1 antagonist inhibits tumorigenesis in a subset of hepatocellular carcinomas.
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.
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Teng
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Ce
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Jiayong
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: You
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Keyan
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Guoshan
authors.initials: G
authors.lastname: Ding
mesh_terms: D000818:Animals; D002034:Bumetanide / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D030541:Databases, Genetic; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D064466:Solute Carrier Family 12, Member 1 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C578714:SLC12A1 protein, human; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064466:Solute Carrier Family 12, Member 1; D002034:Bumetanide
keywords: Bumetanide; HCC; SLC12A1; cancer outlier profile analysis; liver cancer