FXYD6: a novel therapeutic target toward hepatocellular carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Gao Q
PROVIDER: S-EPMC4085285 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Hepatocellular carcinoma (HCC) is a major global health problem and its treatment options have been limited. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor important for various cellular processes. Overexpression and constitutive activation of STAT3 have been frequently found in HCC and associated with poor prognosis. Ample evidence has shown that STAT3 plays pivotal roles in the initiation, progression, metastasis and immune suppression of HCC. Thus, STAT3 has attracted attention as a novel therapeutic target in HCC. Clinical trials have investigated STAT3-targeted therapeutics either as monotherapy or in combination with chemotherapeutic agents, immune checkpoint inhibitors and alternative targeted drugs. Some of these studies have yielded encouraging results. Particularly, napabucasin-a cancer stemness inhibitor targeting STAT3-driven gene transcription-has stood out with its promising clinical efficacy and safety profile. Nonetheless, clinical investigations of STAT3-targeted therapies in HCC are limited and more efforts are strongly urged to evaluate their clinical performance in HCC. Here, we provide a comprehensive review of the roles of STAT3 in HCC and follow by comprehensive analysis of STAT3 targeted strategies.
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Project description:The development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study, we tested the hypothesis that COP1 blockade by short interfering RNA (siRNA)-mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53-null Hep3B cells were resistant. Microarray expression analysis revealed that the antiproliferative effects of COP1 blockade were driven by a common subset of molecular alterations including a p53-associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic acid-lipid particles suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC.
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Project description:CircRNA, a kind of tissue specific and covalently closed circular non-coding RNA is very abundant in eukaryocyte. Generally, circRNA is generated by back-splicing of protein-coding genes' pre-mRNA. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Due to the characteristics of poor prognosis and high recurrence, the pathogenesis of HCC is highly concerned by researchers worldwide. Recent studies demonstrated that numerous circRNAs were differentially expressed in HCC tissues and normal liver tissues, which is closely related with the development and prognosis of HCC. However, the mechanism of circRNA in HCC remains unclear. In this review, we summarized the abnormal expressions of circRNAs in HCC, discussed its role, and potential mechanisms, and tried to explore the prospective values of circRNA in the diagnosis, therapy, and prognosis of HCC.
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Project description:Hepatocellular carcinoma (HCC) is one of the most common types of cancer. The novel sensitive biomarkers and therapeutic targets are urgently needed for the early diagnosis of HCC and improvement of clinical outcomes. Glia maturation factor-β (GMFB) is a growth and differentiation factor for both glia and neurons and has been found to be tightly involved in inflammation and neurodegeneration conditions. In our study, the expression level of GMFB was significantly up-regulated in patients with HCC and positively co-expression with tumor node metastases (TNM) stage and histopathological grade of HCC. The high expression level of GMFB was remarkably associated with poor overall survival, which mainly occurred in males rather than females. Multivariate analysis revealed GMFB to be an independent prognostic factor for overall survival in patients with HCC. Results of Gene Ontology (GO) and KEGG pathways analysis showed that down-regulation of pathways related to protein translation and mitochondria function were enriched. Protein-protein interaction analysis revealed the central role of mitochondria protein in HCC. The downregulation of genes involved in glycolysis and gluconeogenesis was observed among the co-expression genes of GMFB. Knockdown of GMFB in Hep3B significantly inhibited proliferation, migration, and invasion of Hep3B cells, and also downregulated the expression levels of some of metal matrix proteinase (MMP), increased mtDNA copy number and loss of mitochondrial transmembrane potential. GMFB influences the malignancy rate of HCC possibly through regulation of the expression of MMPs, mtDNA function and glycolysis. We proposed that GMFB was a promising HCC diagnostic and prognostic biomarker and therapeutic target in HCC.
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Project description:BACKGROUND:Hepatocellular carcinoma (HCC) is a major threat to public health. However, few effective therapeutic strategies exist. We aimed to identify potentially therapeutic target genes of HCC by analyzing three gene expression profiles. METHODS:The gene expression profiles were analyzed with GEO2R, an interactive web tool for gene differential expression analysis, to identify common differentially expressed genes (DEGs). Functional enrichment analyses were then conducted followed by a protein-protein interaction (PPI) network construction with the common DEGs. The PPI network was employed to identify hub genes, and the expression level of the hub genes was validated via data mining the Oncomine database. Survival analysis was carried out to assess the prognosis of hub genes in HCC patients. RESULTS:A total of 51 common up-regulated DEGs and 201 down-regulated DEGs were obtained after gene differential expression analysis of the profiles. Functional enrichment analyses indicated that these common DEGs are linked to a series of cancer events. We finally identified 10 hub genes, six of which (OIP5, ASPM, NUSAP1, UBE2C, CCNA2, and KIF20A) are reported as novel HCC hub genes. Data mining the Oncomine database validated that the hub genes have a significant high level of expression in HCC samples compared normal samples (t-test, p < 0.05). Survival analysis indicated that overexpression of the hub genes is associated with a significant reduction (p < 0.05) in survival time in HCC patients. CONCLUSIONS:We identified six novel HCC hub genes that might be therapeutic targets for the development of drugs for some HCC patients.
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Project description:Shugoshin-like protein 1 (Sgo1) is an essential protein in mitosis; it protects sister chromatid cohesion and thereby ensures the fidelity of chromosome separation. We found that the expression of Sgo1 mRNA was relatively low in normal tissues, but was upregulated in 82% of hepatocellular carcinoma (HCC), and correlated with elevated alpha-fetoprotein and early disease onset of HCC. The depletion of Sgo1 reduced cell viability of hepatoma cell lines including HuH7, HepG2, Hep3B, and HepaRG. Using time-lapse microscopy, we showed that hepatoma cells were delayed and ultimately die in mitosis in the absence of Sgo1. In contrast, cell viability and mitotic progression of immortalized cells were not significantly affected. Notably, mitotic cell death induced upon Sgo1 depletion was suppressed upon inhibitions of cyclin-dependent kinase-1 and Aurora kinase-B, or the depletion of mitotic arrest deficient-2. Thus, mitotic cell death induced upon Sgo1 depletion in hepatoma cells is mediated by persistent activation of the spindle assembly checkpoint. Together, these results highlight the essential role of Sgo1 in the maintenance of a proper mitotic progression in hepatoma cells and suggest that Sgo1 is a promising oncotarget for HCC.
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Project description:Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. There is an urgent need to develop novel biomarkers for early diagnosis, as well as to identify new drug targets for therapeutic interventions.54 paired HCC samples and 21 normal liver tissues were obtained from West China Hospital of Sichuan University. Informed consent was obtained from all the patients or their relatives prior to analysis, and the project was approved by the Institutional Ethics Committee of Sichuan University. Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)-based proteomics was employed to profile the differentially expressed proteins between a HepG2 human hepatoma cell line and an immortal hepatic cell line L02. Validation of PGAM1 expression was performed by semi-quantitative RT-PCR, immunoblot and immunohistochemistry using clinical samples. shRNA expressing plasmids specifically targeting PGAM1 were designed and constructed by GenePharma Corporation (Shanghai, China), and were utilized to silence expression of PGAM1 in vitro and in vivo. Cell proliferation was measured by a combination of colony formation assay and Ki67 staining. Apoptosis was examined by flow cytometry and TUNEL assay.A total of 63 dysregulated proteins were identified, including 51 up-regulated proteins, and 12 down-regulated proteins (over 2-fold, p < 0.01). Phosphoglycerate mutase 1 (PGAM1) was found markedly upregulated. Clinico-pathological analysis indicated that overexpression of PGAM1 was associated with 66.7% HCC, and strongly correlated with poor differentiation and decreased survival rates (p < 0.01). shRNAs-mediated repression of PGAM1 expression resulted in significant inhibition in liver cancer cell growth both in vitro and in vivo.Our studies suggested that PGAM1 plays an important role in hepatocarcinogenesis, and should be a potential diagnostic biomarker, as well as an attractive therapeutic target for hepatocellular carcinoma.
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Project description:Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene-specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.
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