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APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.

ABSTRACT: Background: The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process contributed by the accumulation of molecular alterations. We identified Apelin (APLN) as an outlier gene up-regulated in hepatocellular carcinoma (HCC) through RNA-Seq and microarray analysis. We aimed to investigate its function, mechanism of action and clinical implication in HCC. Methods: Gene expression and clinical implication of APLN were assessed in multiple human HCC cohorts. Ectopic expression and silencing of APLN were performed to determine its function. The therapeutic potential of APLN and its downstream pathway was investigated using in vitro and in vivo models. Results: APLN overexpression was commonly observed in more than 80% of HCCs and independently predicted poorer survival of patients in three independent HCC cohorts. Apelin up-regulation was mediated by active ?-catenin, which binds to the APLN promoter to induce transcription. Ectopic APLN expression in HCC cells promoted cell proliferation, accelerated G1/S progression and inhibited apoptosis, whilst APLN knockdown exerted opposite effects in vitro and inhibited HCC xenograft growth in mice. Mechanistically, APLN activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway via APLN receptor, leading to increased expression of phospho-glycogen synthase kinase 3? (p-GSK3?) and cyclin D1. Pharmacological targeting of APLN by ML221 was safe and effective in inhibiting APLN-PI3K/Akt cascade and HCC growth in vitro and in vivo. Conclusions: Our findings unraveled an oncogenic role of APLN in HCC, and that targeting of APLN might be a promising for HCC treatment. APLN may serve as an independent prognostic factor for HCC patients.

SUBMITTER: Chen H

PROVIDER: S-EPMC6691573 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.

Chen Huarong H Wong Chi-Chun CC Liu Dabin D Go Minnie Y Y MYY Wu Bin B Peng Sui S Kuang Ming M Wong Nathalie N Yu Jun J

Theranostics 20190709 18

<b>Background</b>: The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process contributed by the accumulation of molecular alterations. We identified Apelin (APLN) as an outlier gene up-regulated in hepatocellular carcinoma (HCC) through RNA-Seq and microarray analysis. We aimed to investigate its function, mechanism of action and clinical implication in HCC. Methods: Gene expression and clinical implication of APLN were assessed in multiple human HCC cohorts. Ectopic expression a ...[more]

PMID: 31410213

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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.

Project description:BackgroundThe human ether a-go-go-related gene 1 (HERG1) is involved in tumor progression; however, its role in esophageal squamous cell carcinoma (ESCC) is not well studied. This study investigated HERG1 function in ESCC progression and elucidated the underlying mechanisms.MethodsThe prognostic value of HERG1 was determined by immunohistochemistry in ESCC biopsies. Cell growth and proliferation were analyzed by colony formation and methyl thiazolyl tetrazolium assays. Cell migration and invasion were analyzed by wound healing and Boyden transwell assays. Epithelial-mesenchymal transition (EMT) was evaluated by immunoblotting and quantitative polymerase chain reaction (qPCR). A xenograft mouse model was used to validate the tumorigenic and metastatic roles of HERG1 in vivo.ResultsHERG1 expression was overall higher in ESCC tissues compared to adjacent non-tumor tissues. A retrospective analysis of 349 patients with ESCC (stages I-IV) confirmed increased HERG1 expression was associated with disease progression and higher mortality rate. The overall survival of the patients was significantly worse when their tumors displayed higher HERG1 expression. HERG1 knockdown reduced tumor growth and metastasis in athymic mice. HERG1 affected the proliferation, migration, and invasion of two ESCC cell lines (TE-1 and KYSE-30). Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies. Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression.ConclusionsHERG1 contributes to poor prognosis in patients with ESCC by promoting ESCC cell proliferation, migration, and invasion via TXNDC5 through the PI3K/AKT signaling pathway. Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment.

Dataset Information

APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.

Publications

APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target.

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