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Na+/K+-ATPase ?1 subunit, a novel therapeutic target for hepatocellular carcinoma.

ABSTRACT: We aimed to identify the expression patterns of Na+/K+-ATPase (NKA) ? subunits in human hepatocellular carcinoma (HCC) samples and evaluate these subunits as potential targets for HCC treatment. The mRNA expression profiles of NKA ? subunits in human HCC samples were analyzed. We found that the mRNA expression for NKA ?1 subunit (ATP1A1) was higher than that for other NKA ? subunits. Also, ATP1A1 gene expression was markedly higher in HCC samples than in adjacent nontumor tissue samples. Western blotting data suggested that 6 of 14 (43%) HCC samples had elevated ATP1A1 protein expression. Furthermore, knockdown of ATP1A1 expression in human HCC HepG2 and MHCC97H cells markedly reduced their proliferation in vitro and suppressed the tumorigenicity of MHCC97H cells in vivo. Downregulation of ATP1A1 expression resulted in cell-cycle arrest at G2/M phase and apoptosis in HepG2 cells as well as decreased migration in Hep3B cells. We further validated that ATP1A1 downregulation caused intracellular accumulation of reactive oxygen species. Pretreatment with N-acetyl cysteine blocked cell-growth inhibition induced by ATP1A1 downregulation. Collectively, these data suggested that targeting ATP1A1 is a novel approach to the treatment of HCC.

SUBMITTER: Zhuang L

PROVIDER: S-EPMC4695053 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Na+/K+-ATPase α1 subunit, a novel therapeutic target for hepatocellular carcinoma.

Zhuang Liping L Xu Litao L Wang Peng P Jiang Yan Y Yong Pan P Zhang Chenyue C Zhang Haibin H Meng Zhiqiang Z Yang Peiying P

Oncotarget 20150901 29

We aimed to identify the expression patterns of Na+/K+-ATPase (NKA) α subunits in human hepatocellular carcinoma (HCC) samples and evaluate these subunits as potential targets for HCC treatment. The mRNA expression profiles of NKA α subunits in human HCC samples were analyzed. We found that the mRNA expression for NKA α1 subunit (ATP1A1) was higher than that for other NKA α subunits. Also, ATP1A1 gene expression was markedly higher in HCC samples than in adjacent nontumor tissue samples. Western ...[more]

PMID: 26334094

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Project description:Hepatocellular carcinoma (HCC) is a global health problem. Its incidence and mortality are increasing. Exploring novel therapeutic targets against HCC is important and urgent. We here explored the expression and potential function of Gαi2 (G protein subunit alpha i2) in HCC. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database shows that the number of Gαi2 transcripts in HCC tissues is significantly higher than that in the normal liver tissues. Moreover, Gαi2 overexpression in HCC correlates with poor prognosis of the patients. Gαi2 mRNA and protein expression are also elevated in local HCC tissues and different human HCC cells. In patient-derived primary HCC cells and immortalized HepG2 cells, Gαi2 silencing (by targeted shRNA) or knockout (KO, by the dCas9-sgRNA method) largely suppressed cell proliferation and motility, while inducing cell cycle arrest and caspase-apoptosis activation. Moreover, Gαi2 silencing or KO-induced reactive oxygen species (ROS) production and oxidative injury in primary and HepG2 HCC cells. Whereas different antioxidants ameliorated Gαi2-shRNA-induced anti-HCC cell activity. Using a lentiviral construct, Gαi2 overexpression further augmented proliferation and motility of primary and immortalized HCC cells. Further studies revealed that the binding between the transcription factor early growth response zinc finger transcription factor 1 (EGR1) and Gαi2 DNA promoter was significantly increased in HCC tissues and cells. In vivo, intratumoral injection of Gαi2 shRNA adeno-associated virus significantly hindered HCC xenograft growth in nude mice. Moreover, the growth of Gαi2-KO HCC xenografts in the nude mice was remarkably slow. Gαi2 depletion, oxidative injury, and apoptosis induction were detected in Gαi2-silenced or Gαi2-KO HCC xenografts. Together, overexpressed Gαi2 is required for HCC cell growth in vitro and in vivo, representing as a novel and promising diagnosis marker and therapeutic target of HCC.

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Na+/K+-ATPase ?1 subunit, a novel therapeutic target for hepatocellular carcinoma.

Publications

Na+/K+-ATPase α1 subunit, a novel therapeutic target for hepatocellular carcinoma.

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