Dataset Information

Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT.

ABSTRACT: The Elongator is a complex with multiple subunits (Elp1-Elp6) which promotes transcript elongation and protein translation. In this study, we investigated the effects of Elongator on the migration and invasion of HCC cells as well as the underlying mechanisms. We showed that overexpression of Elp3 or Elp4 promoted the migration and invasion of HCC cells, which was abolished when either Elp3 or Elp4 was silenced. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 were enhanced by phosphorylation of AKT. Elongator-driven migration and invasion and the expression of MMP-2 and MMP-9 were reduced in HCC cells treated with AKT inhibitor LY294002. Depletion of Elp3 also reduced the phosphorylation of AKT induced by growth factors. In vivo assay of lung metastasis in mice demonstrated that overexpression of Elp3 increased tumor nodules metastatic to lung. Importantly, Elp3 was up-regulated in human HCC tissues, which was correlated with the phosphorylation of AKT and expression of MMP-2. Collectively, these results suggested that Elongator activated migration and invasion of HCC cells by promoting the expression of MMP-2 and MMP-9 through the PI3K/AKT signaling pathway. Our work suggests that Elongator might be a potential marker which promotes the metastasis of HCC.

SUBMITTER: Xu Y

PROVIDER: S-EPMC5968844 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT.

Xu Yi Y Zhou Wei W Ji Yuan Y Shen Jian J Zhu Xiaxia X Yu Huijun H Guo Jingchun J Pang Zhi Z Wei Wenxiang W

International journal of biological sciences 20180405 5

The Elongator is a complex with multiple subunits (Elp1-Elp6) which promotes transcript elongation and protein translation. In this study, we investigated the effects of Elongator on the migration and invasion of HCC cells as well as the underlying mechanisms. We showed that overexpression of Elp3 or Elp4 promoted the migration and invasion of HCC cells, which was abolished when either Elp3 or Elp4 was silenced. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 were enhanced by phos ...[more]

PMID: 29805303

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Project description:Dickkopf-1 (DKK1), an inhibitor of the most frequently impaired signaling pathway in hepatocellular carcinoma (HCC), the Wnt/beta-catenin pathway, seems to fulfill contradictory functions in the process of tumorigenesis, acting either as an oncogenic promoter of metastasis or as a tumor suppressor. Elevated serum levels of DKK1 have been reported in HCC; however, little is known about its functional significance. In the current study, we treated HepG2/C3A and PLC/PRF/5 with the recombinant protein DKK1. Cytotoxicity was first determined by the WST-8 assay. AFP expression was measured at both the mRNA and protein levels. Expression of the oncogenes MYC, CCND1, hTERT, and MDM2 and the tumor suppressor genes TP53, P21 and RB was assessed. Western blot analysis of non-phosphorylated ?-catenin and Sanger sequencing were performed to explain the functional differences between the two cell lines. Subsequently, inflammation, migration and invasion were evaluated by qPCR, ELISA, the Boyden chamber assay, zymography, and MMP-2 and MMP-9 western blot analysis. Knockdown of DKK1 and TGF-?1 were also performed. Our results suggest that DKK1 exerts an oncogenic effect on HepG2/C3A cell line by upregulating the expression of oncogenes and downregulating that of tumor suppressor genes, whereas the opposite effect was demonstrated in PLC/PRF/5 cells. This differential impact of DKK1 can be explained by the mutations that affect the canonical Wnt pathway that were detected in exon 3 of the CTNNB1 gene in the HepG2 cell line. We further confirmed that DKK1 promotes inflammation, tumor invasion and migration in both cell types. The canonical pathway was not responsible for the DKK1 proinvasive effect, as indicated by the active ?-catenin levels in the two cell lines upon DKK1 treatment. Interestingly, knockdown of TGF-?1 negatively affected the DKK1 proinvasive effect. Taken together, DKK1 appears to facilitate tumor invasion and migration through TGF- ?1 by remodeling the tumor microenvironment and inducing inflammation. This finding endorses the relevance of TGF-?1 as a therapeutic target.

Dataset Information

Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT.

Publications

Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT.

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