Induction of SOCS3 by liver X receptor suppresses the proliferation of hepatocellular carcinoma cells.
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ABSTRACT:
SUBMITTER: Xiong H
PROVIDER: S-EPMC5609985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Suppressor of cytokine signaling 3 (SOCS3) is regarded as a vital repressor in the liver carcinogenesis mainly by inhibiting signal transducer and activator of transcription 3 (STAT3) activity. Farnesoid X Receptor (FXR), highly expressed in liver, has an important role in protecting against hepatocellular carcinoma (HCC). However, it is unclear whether the tumor suppressive activity of FXR involves the regulation of SOCS3. In the present study, we found that activation of FXR by its specific agonist GW4064 in HCC cells inhibited cell growth, induced cell cycle arrest at G1 phase, elevated p21 expression and repressed STAT3 activity. The above anti-tumor effects of FXR were dramatically alleviated by knockdown of SOCS3 with siRNA. Reporter assay revealed that FXR activation enhanced the transcriptional activity of SOCS3 promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay displayed that FXR directly bound to IR9 DNA motif within SOCS3 promoter region. The in vivo study in nude mice showed that treatment with FXR ligand GW4064 could decelerate the growth of HCC xenografts, up-regulate SOCS3 and p21 expression and inhibit STAT3 phosphorylation in the xenografts. These results suggest that induction of SOCS3 may be a novel mechanism by which FXR exerts its anti-HCC effects, and the FXR-SOCS3 signaling may serve as a new potential target for the prevention/treatment of HCC.
| S-EPMC4741476 | biostudies-literature
Project description:Dimethyl fumarate (DMF) is generally used to treat psoriasis and multiple sclerosis. In the present study, we aimed to investigate the effects of DMF on hepatocellular carcinoma progression and its mechanism of action. In vitro, cell viability was examined using CCK-8 assay; cell cycle was analyzed by flow cytometry; angiogenesis was detected using tube formation assay; and autophagic flux assay results were examined using fluorescence microscopy. We also used western blotting to explore the potential mechanisms. In vivo, tumor xenograft experiment was performed with nude mice, and liver function, renal function, and routine blood counts were assessed using biochemical tests. Dimethyl fumarate inhibited tumor growth and angiogenesis in hepatocellular carcinoma, both in vitro and in vivo. Dimethyl fumarate decreased autophagy in hepatocellular carcinoma cells. Treatment with DMF activated SOCS3, which led to repression of JAK1 and STAT3 phosphorylation. DMF inhibited cell proliferation, angiogenesis, and autophagy via activation of the SOCS3/JAK1/STAT3 signaling pathway. This finding may provide a novel approach for the treatment of hepatocellular carcinoma.
| S-EPMC6731444 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths. Previous studies have suggested that mu-opioid receptor (MOR), a member of the opioid receptor family, is involved in the pathogenesis of HCC. However, the mechanism by which MOR regulates the biological behavior of HCC is still poorly understood. To address this problem, in this study, we investigated the role of MOR in the proliferation of HCC cell lines and the underlying mechanism. First, RT-PCR, western-blot and immunohistochemistry revealed higher expression of MOR in HCC cells and tissue than in non-tumor cells or adjacent tissue, and elevated expression of MOR was associated with jeopardized survival of HCC patients, as demonstrated by bioinformatic databases. Knockdown of MOR by specific siRNA attenuated the proliferation and migration of HCC cells and this effect could be reversed by rescue experiments, confirming the essential role of MOR in the proliferation of HCC. Moreover, results of colony formation assay, CCK8 test, flow cytometry and western blot suggested that a monoclonal antibody (mAb) specifically against MOR could inhibit proliferation of HepG2 and Huh7 cells via the MOR-CD147-p53-MAPK pathway, and the interaction between MOR and CD147 was verified by immunofluorescence colocalization and co-IP analysis. The mAb against MOR also enhanced the cisplatin-induced apoptosis of HCC cells by downregulating p-ERK, Bcl-2 and upregulating Bax. Taken together, these results suggest that MOR could regulate the proliferation of HCC cells in a CD147-p53-MAPK dependent manner. MOR possesses the potential to be a therapeutic target to treat HCC.
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Project description:BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2-/-) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.
| S-EPMC8157759 | biostudies-literature
Project description:The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to stimuli. Among NLRs, NLRP3 senses the widest array of stimuli. NLRP3 inflammasome plays an important role in the development of many cancer types. However, Whether NLRP3 inflammasome plays an important role in the process of hepatocellular carcinoma (HCC) is still unknown. Here, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, against HCC cells and the underlying mechanisms were investigated. Luteoloside significantly inhibited the proliferation of HCC cells in vitro and in vivo. Live-cell imaging and transwell assays showed that the migration and invasive capacities of HCC cells, which were treated with luteoloside, were significantly inhibited compared with the control cells. The inhibitory effect of luteoloside on metastasis was also observed in vivo in male BALB/c-nu/nu mouse lung metastasis model. Further studies showed that luteoloside could significantly reduce the intracellular reactive oxygen species (ROS) accumulation. The decreased levels of ROS induced by luteoloside was accompanied by decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by luteoloside resulted in inhibition of IL-1β. Thus, luteoloside exerts its inhibitory effect on proliferation, invasion and metastasis of HCC cells through inhibition of NLRP3 inflammasome. Our results indicate that luteoloside can be a potential therapeutic agent not only as an adjuvant therapy for HCC, but also, in the control and prevention of metastatic HCC.
| S-EPMC3935965 | biostudies-literature
Project description:Epithelial membrane protein-3 (EMP3), a typical member of the epithelial membrane protein (EMP) family, is epigenetically silenced in some cancer types, and has been proposed to be a tumor suppressor gene. However, its effects on tumor suppression are controversial and its roles in development and malignancy of hepatocellular carcinoma (HCC) remain unclear. In the present study, we found that EMP3 was highly expressed in the tumorous tissues comparing to the matched normal tissues, and negatively correlated with differentiated degree of HCC patients. Knockdown of EMP3 significantly reduced cell proliferation, arrested cell cycle at G1 phase, and inhibited the motility and invasiveness in accordance with the decreased expression and activity of urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9) in HCC cells. The in vivo tumor growth of HCC was effectively suppressed by knockdown of EMP3 in a xenograft mouse model. The EMP3 knockdown-reduced cell proliferation and invasion were attenuated by inhibition of phosphatidylinositol 3-kinase (PI3K) or knockdown of Akt, and rescued by overexpression of Akt in HCC cells. Clinical positive correlations of EMP3 with p85 regulatory subunit of PI3K, p-Akt, uPA, as well as MMP-9 were observed in the tissue sections from HCC patients. Here, we elucidated the tumor progressive effects of EMP3 through PI3K/Akt pathway and uPA/MMP-9 cascade in HCC cells. The findings provided a new insight into EMP3, which might be a potential molecular target for diagnosis and treatment of HCC.
| S-EPMC4741495 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells.
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Project description:Chronic liver inflammation and injuries play a critical role in development of hepatocellular carcinoma (HCC). Parkinson disease (autosomal recessive, early onset) 7, encoding PARK7 protein (also called DJ-1), plays important roles in many carcinogenesis processes and is essential in modulating inflammation. However, whether DJ-1 is involved in HCC development remains largely unknown. To determine the effect of DJ-1 on HCC development, we accessed the correlation of hepatic DJ-1 expression with overall survival (OS) and TNM stage in 96 HCC patients and found a significant inverse correlation between DJ-1 expression and OS. By adopting a classic diethylnitrosamine (DEN)-induced murine HCC model, DJ-1 knockout (KO) mice displayed reduced tumorigenesis and cell proliferation, accompanied by decreased hepatic inflammation and IL-6/STAT3 activation. Furthermore, after an acute DEN challenge, DJ-1 KO mice showed significant decreases in liver injury, hepatocyte proliferation and DNA damage. In a human HCC cell line (MHCC-97L), cancer cell proliferation was induced by overexpression of DJ-1 and is related to oncogenic signaling of MAPKs and AKT. Induction of DJ-1 may serve as a novel regulator for HCC cell proliferation and HCC development possibly through enhanced MAPK signaling and inflammation.
| S-EPMC5352417 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) remains an intractable disease despite numerous advancements made in the available treatments over recent decades. Therefore, investigation of the underlying pathogenesis of HCC is urgently required. Our previous microarray result showed that SCIN was generally downregulated in 23 paired tumor/normal tissues. Reverse transcription-quantitative PCR, western blotting and immunohistochemistry were performed in the present study in order to detect the expression of scinderin (SCIN). Lentivirus-mediated gene delivery was used in order to produce SCIN-manipulated cell lines. MTT and crystal violet assays were performed in order to investigate cell growth, and fluorescence-activated cell sorting analysis was used in order to determine cell cycle distribution. SCIN was downregulated in HCC samples, and low SCIN expression predicted the poor prognosis of patients with HCC. Notably, SCIN may have the potential to serve as an independent risk factor for overall survival (3-year overall survival rate of 28.6 and 10.3% in high SCIN expression and low SCIN expression groups, respectively) and disease-free survival (3-year recurrence rate of 71.4 and 84.6% in high SCIN expression and low SCIN expression groups, respectively) in HCC. SCIN inhibited HCC cell proliferation both in vitro and in subcutaneous tumor formation assay. Furthermore, SCIN decreased the levels of phosphorylated STAT3, thereby downregulating cyclin A1 levels in HCC cells. The results of the present study demonstrate the tumor suppressive role of SCIN in HCC, providing a candidate strategy to treat this disease.
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Project description:Studies have shown that swertiamarin (STM) has multiple biological activities, but its anti-tumour effects and molecular mechanisms are still unclear. The present research aimed to validate the STM's impacts on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells, and to study its potential mechanism. Two HCC cell lines were treated with STM. Tumour growth was observed by the mouse tumour xenografts model. HCC cell lines stably expressing T-cell lymphomas 1 (FRAT1) were generated by lentivirusmediated overexpression. Cell viability, proliferation, migration, and invasion were observed using Cell Counting Kit-8 (CCK8), the xCELLigence Real-Time Cell Analyzer system (RTCA), and transwell analysis, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to observe the expression of FRAT1 and proteins related to the Wnt/?-catenin signalling pathway. Tumour growth was inhibited by STM in vivo. STM suppressed the proliferation, migration, and invasion of HCC cells. STM negatively regulated FRAT1 expression, whereas overexpressed FRAT1 blocked the anti-tumour function of STM. The results revealed that STM suppressed the FRAT1/Wnt/?-catenin signalling pathway. The findings of this study provide new insights into investigation of therapeutic strategies against HCC.
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