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EDG2 enhanced the progression of hepatocellular carcinoma by LPA/PI3K/AKT/ mTOR signaling.

ABSTRACT: HCC is the leading type of the malignant liver tumors with the unsatisfied prognosis. Liver resection has been considered as the predominant curative therapy, however, the post-surgical prognostic evaluation remains an urgent problem and the mechanism of HCC metastases has not been understood completely. EDG2 has been found to accelerate tumor progression through mediating different cell pathways, however, it remains unclear about the role of EDG2 on hepatocarcinogenesis. Here, EDG2 expression was found increased notably in HCC tissues by immunohistochemistry compared with adjacent liver tissues and comparison of survival curves revealed that EDG2 upregulation in HCC tissues was associated with the worse prognosis after liver resection. The positive correlation between EDG2 up-regulation and EMT was observed in HCC samples. Furthermore, EDG2 over-expression in HCC cells brought the typical EMT characteristics including up-regulation of Vimentin, Fibronectin and N-cadherin, suppression of E-cadherin, and enhanced cell migration and invasion capacities. Knockdown of EDG2 reversed the EMT phenotype in HCC cells. The in vivo experiments also identified the oncogenic role of EDG2 on HCC growth. The mechanistic studies elucidated that EDG2 enhanced mTOR phosphorylation via PI3K/AKT signaling and consequently induced EMT of HCC cells. Moreover, EDG2 was found to promote cell viability and proliferation of HCC cell through PI3K/AKT/mTOR/Skp2/p27Kip1 signaling. Taken together, the data here demonstrated EDG2 was a potential predictor for HCC patients receiving liver resection and accelerated HCC progression via regulating EMT driven by PI3K/AKT/mTOR signaling.

SUBMITTER: Xu M

PROVIDER: S-EPMC5630400 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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EDG2 enhanced the progression of hepatocellular carcinoma by LPA/PI3K/AKT/ mTOR signaling.

Xu Meng M Liu Zhikui Z Wang Cong C Yao Bowen B Zheng Xin X

Oncotarget 20170802 39

HCC is the leading type of the malignant liver tumors with the unsatisfied prognosis. Liver resection has been considered as the predominant curative therapy, however, the post-surgical prognostic evaluation remains an urgent problem and the mechanism of HCC metastases has not been understood completely. EDG2 has been found to accelerate tumor progression through mediating different cell pathways, however, it remains unclear about the role of EDG2 on hepatocarcinogenesis. Here, EDG2 expression w ...[more]

PMID: 29029500

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Project description:BackgroundHepatocellular carcinoma (HCC) is the most common pathological type of liver cancer. Valosin-containing protein (VCP) is a member of the AAA-ATPase family associated with multiple molecular functions and involved in tumor metastasis and prognosis. However, the role of VCP in HCC progression is still unclear.MethodsWe examined the expression of VCP in HCC using the RNA sequencing and microarray data from public databases and measured it in clinical samples and cell lines by western blot, and immunohistochemistry (IHC). We also evaluated the correlation between VCP and clinical features. The VCP-interacting proteins were identified by co-immunoprecipitation combined with mass spectrometry (CoIP/MS). The underlying molecular mechanisms were investigated using in vitro and in vivo models of HCC.ResultsWe found that VCP expression is significantly increased in tumor tissues and is associated with advanced TNM stages and poorer prognosis in HCC patients. In vitro analyses revealed that VCP overexpression promoted HCC cell proliferation, migration, and invasion via PI3K/AKT/mTOR pathway activation. Conversely, VCP knockdown resulted in the reverse phenotypes. In vivo studies indicated that up-regulated VCP expression accelerated tumor growth in a subcutaneous HCC model. The D1 domain of VCP and A box of HMGB1 were identified as the critical regions for their interaction, and D1 area was required for the tumor-promoting effects induced by VCP expression. VCP enhanced the protein stability of HMGB1 by decreasing its degradation via ubiquitin-proteasome process. Inhibition of HMGB1 markedly attenuated VCP-mediated HCC progression and downstream activation of PI3K/AKT/mTOR signals.ConclusionCollectively, these findings demonstrate that VCP is a potential prognostic biomarker in HCC and exhibits oncogenic roles via PI3K/AKT/mTOR pathway activation. HMGB1 played an essential role in VCP-mediated HCC progression, indicating that VCP and HMGB1 are potential therapeutic targets in human HCC.

Dataset Information

EDG2 enhanced the progression of hepatocellular carcinoma by LPA/PI3K/AKT/ mTOR signaling.

Publications

EDG2 enhanced the progression of hepatocellular carcinoma by LPA/PI3K/AKT/ mTOR signaling.

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