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FXYD6: a novel therapeutic target toward hepatocellular carcinoma.

ABSTRACT: FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na(+)/K(+)-ATPase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma (HCC) and enhances the migration and proliferation of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na(+)/K(+)-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

SUBMITTER: Gao Q

PROVIDER: S-EPMC4085285 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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FXYD6: a novel therapeutic target toward hepatocellular carcinoma.

Gao Qian Q Chen Xiongfei X Duan Hongxia H Wang Zhaoqing Z Feng Jing J Yang Dongling D Song Lina L Zhou Ningxin N Yan Xiyun X

Protein & cell 20140410 7

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na(+)/K(+)-ATPase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma (HCC) and enhances the migration and proliferation of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na(+)/K(+)-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blo ...[more]

PMID: 24715268

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Project description:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States, with a median survival period of approximately 10 months. There is an urgent need for the development of effective targeted therapies for the treatment of HCC. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) signaling is implicated in the progression of many cancers, although its specific contribution to the progression of HCC is not yet well understood. Analysis of The Cancer Genome Atlas HCC gene expression data sets and IHC analysis of HCC tissue microarray revealed that HCC tumors had elevated expression of PELP1 compared with normal tissues, and high expression of PELP1 is associated with unfavorable survival outcomes. Suppression of PELP1 expression using short hairpin RNA significantly reduced the cell viability, clonogenicity, and invasion of HCC cells. Importantly, SMIP34, a first-in-class small-molecule inhibitor targeting PELP1, effectively decreased the cell viability, clonogenic survival, and invasiveness of HCC cells. Gene expression analysis using RNA sequencing revealed that PELP1 knockdown cells exhibited a decrease in c-Myc, E2F, and other oncogenic pathways related to HCC. Mechanistic studies showed that SMIP34 treatment impaired the Rix complex, a critical component of ribosomal biogenesis, in HCC cells. Furthermore, the knockdown or pharmacologic inhibition of PELP1 significantly decelerated the HCC tumor growth in xenograft models. In summary, our study findings indicate that PELP1 could serve as a promising target for therapeutic intervention in HCC.SignificanceHCC is one of the leading causes of cancer fatalities in the United States. Effective targeted therapeutics for HCC are urgently needed. In this study, we show that PELP1 proto-oncogene is crucial to HCC progression and that PELP1 inhibition reduced HCC cell proliferation in vitro and in vivo. Our results imply that PELP1-targeted drugs like SMIP34 may be useful as new therapeutic agents for HCC treatment.

Project description:BackgroundHepatocellular 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.Patients and methods54 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.ResultsA 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.ConclusionOur 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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FXYD6: a novel therapeutic target toward hepatocellular carcinoma.

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FXYD6: a novel therapeutic target toward hepatocellular carcinoma.

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