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1.
Nat Metab ; 4(10): 1306-1321, 2022 10.
Article in English | MEDLINE | ID: mdl-36192599

ABSTRACT

Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-ß stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-ß-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression.


Subject(s)
Carcinoma, Hepatocellular , Extracellular Vesicles , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Hepatic Stellate Cells/metabolism , Hexokinase/metabolism , Liver Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Cell Proliferation , Cell Line, Tumor , Extracellular Vesicles/metabolism , Transforming Growth Factor beta/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Tumor Microenvironment
2.
Comput Intell Neurosci ; 2022: 7780756, 2022.
Article in English | MEDLINE | ID: mdl-36262601

ABSTRACT

Salient Object Detection (SOD) simulates the human visual perception in locating the most attractive objects in the images. Existing methods based on convolutional neural networks have proven to be highly effective for SOD. However, in some cases, these methods cannot satisfy the need of both accurately detecting intact objects and maintaining their boundary details. In this paper, we present a Multiresolution Boundary Enhancement Network (MRBENet) that exploits edge features to optimize the location and boundary fineness of salient objects. We incorporate a deeper convolutional layer into the backbone network to extract high-level semantic features and indicate the location of salient objects. Edge features of different resolutions are extracted by a U-shaped network. We designed a Feature Fusion Module (FFM) to fuse edge features and salient features. Feature Aggregation Module (FAM) based on spatial attention performs multiscale convolutions to enhance salient features. The FFM and FAM allow the model to accurately locate salient objects and enhance boundary fineness. Extensive experiments on six benchmark datasets demonstrate that the proposed method is highly effective and improves the accuracy of salient object detection compared with state-of-the-art methods.


Subject(s)
Neural Networks, Computer , Visual Perception , Humans , Attention , Semantics , Benchmarking
3.
Mol Cell ; 78(6): 1192-1206.e10, 2020 06 18.
Article in English | MEDLINE | ID: mdl-32470318

ABSTRACT

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.


Subject(s)
Carrier Proteins/metabolism , Cell-Derived Microparticles/metabolism , Membrane Proteins/metabolism , Thyroid Hormones/metabolism , Adult , Aged , Aged, 80 and over , Animals , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carrier Proteins/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell-Derived Microparticles/genetics , Cell-Derived Microparticles/pathology , Chemokine CCL1/metabolism , Disease Progression , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Macrophages/metabolism , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Middle Aged , Monocytes/metabolism , Prognosis , STAT3 Transcription Factor/metabolism , Thyroid Hormones/genetics , Tumor Microenvironment , Thyroid Hormone-Binding Proteins
4.
Oncogene ; 39(11): 2408-2423, 2020 03.
Article in English | MEDLINE | ID: mdl-31959898

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , RNA, Long Noncoding/metabolism , Animals , Carcinogenesis , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Growth Processes , Cell Line, Tumor , Glycolysis , Hep G2 Cells , Heterografts , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Nuclear Receptor Subfamily 4, Group A, Member 1/agonists , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Phenylacetates/pharmacology , Promoter Regions, Genetic , RNA, Long Noncoding/genetics , Transcriptional Activation , Up-Regulation
5.
Int J Clin Exp Pathol ; 12(9): 3376-3383, 2019.
Article in English | MEDLINE | ID: mdl-31934180

ABSTRACT

Fat mass and obesity-associated protein (FTO) has been well known for a pivotal role in regulation of fat mass, adipogenesis and body weight. In recent years, increasing studies revealed a strong association between FTO and various types of cancer. Its role in human hepatocellular carcinoma, however, remains unclear. We aimed at investigating the expression pattern and clinical significance of FTO in hepatocellular carcinoma. We found that FTO mRNA levels were significantly lower in hepatocellular carcinoma tissues. Immunohistochemical analysis showed the expression of FTO was reduced in the nuclei in hepatocellular carcinoma, and was associated with AFP level (P < 0.001), tumor size (P < 0.001), metastasis (P = 0.025) and vascular invasion (P < 0.001). Patients with decreased FTO expression had a shorter overall and tumor-free survival time (P = 0.004 and P = 0.006) than those with normal FTO expression. Cox's proportional hazard regression model revealed that reduced expression of FTO was a risk factor associated with the prognosis of HCC patients (P = 0.022). These results indicated that decreased FTO expression is correlated with clinicopathological factors, implying that FTO could be a vital predictor of poor outcome in HCC patients and serves as a novel biomarker for HCC.

6.
Nat Commun ; 8: 14420, 2017 02 27.
Article in English | MEDLINE | ID: mdl-28240261

ABSTRACT

Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Gluconeogenesis , Liver Neoplasms/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Phosphoenolpyruvate Carboxykinase (ATP)/metabolism , Sumoylation , Acetylation , Animals , Carcinogenesis/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Down-Regulation/genetics , E1A-Associated p300 Protein/metabolism , Enzyme Stability , Gene Expression Regulation, Neoplastic , Glucose/metabolism , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Methylation , Mice, Inbred C57BL , Mice, Knockout , Models, Biological , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Proteolysis , Snail Family Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Conjugating Enzymes/metabolism
7.
Oncol Lett ; 11(3): 2019-2026, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26998115

ABSTRACT

Natural killer (NK) cells have been demonstrated to inhibit tumor growth. However, the role of NK cells in the inhibition of hepatocellular carcinoma metastasis is not well understood. The present study aimed to investigate the roles that NK cells may serve in inhibiting hepatocellular carcinoma metastasis. The role of isolated NK cells in the inhibition, proliferation, migration and invasion of the hepatoma cell line, MHCC97-H, was examined in vitro. Additionally, the survival rate of NK cells labeled with carboxyfluorescein diacetate-succinimidyl ester was assessed in vivo. An orthotopic implantation model was used to evaluate the role of NK cells in suppressing MHCC97-H cells in vivo. The effect of interleukin (IL)-2 stimulation on the tumor-inhibitory role of the NK cells was measured indirectly by analyzing the expression of various NK cell receptors and activated NK cell markers. It was observed that the NK cells inhibited the proliferation, migration and invasion of the MHCC97-H cells in vitro. Furthermore, the NK cells demonstrated long-term survival in the livers of the nude mice, and inhibited lung metastasis of hepatocellular carcinoma in vivo. However, liver tumor growth was not inhibited by the NK cells. IL-2 was identified to enhance the tumor-inhibitory effect of NK cells. The present study concludes that IL-2 may enhance the antitumor activity of the NK cells, and thereby inhibit the metastases of hepatocellular carcinoma in mice.

8.
Oncotarget ; 6(38): 40940-52, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26517514

ABSTRACT

Chromodomain helicase DNA binding protein 5 (CHD5) acts as a tumor suppressor in many cancers. In the present study, we demonstrated that reduced levels of CHD5 in hepatocellular carcinoma (HCC) tissues were significantly associated with metastasis and poor prognosis. Gain-of-function assays revealed that CHD5 suppressed motility and invasion of HCC cells. Subsequent investigations showed that CHD5 was epigenetically silenced by polycomb repressive complex 2 (PRC2)-mediated the trimethylation of histone H3 at lysine 27 (H3K27me3) in HCC cells. Furthermore, overexpression of CHD5 repressed enhancer of zeste homolog 2 (EZH2) and activated PRC2 target genes, such as p16 and p21. Chromatin immunoprecipitation and luciferase reporter assays also showed that CHD5 and EZH2 bind to each other's promoters and inhibit transcription. These findings uncovered, for the first time, a mutual suppression regulation between CHD5 and EZH2, which may provide new insights into their potential therapeutic significance for HCC.


Subject(s)
Carcinoma, Hepatocellular/genetics , DNA Helicases/genetics , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Nerve Tissue Proteins/genetics , Polycomb Repressive Complex 2/genetics , Blotting, Western , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Cell Movement/genetics , Chi-Square Distribution , DNA Helicases/metabolism , Enhancer of Zeste Homolog 2 Protein , Epigenesis, Genetic , Female , Histones/metabolism , Humans , Kaplan-Meier Estimate , Liver Neoplasms/metabolism , Liver Neoplasms/therapy , Lysine/metabolism , Male , Methylation , Middle Aged , Nerve Tissue Proteins/metabolism , Polycomb Repressive Complex 2/metabolism , Promoter Regions, Genetic/genetics , Protein Binding , Reverse Transcriptase Polymerase Chain Reaction
9.
Oncol Lett ; 9(5): 2199-2204, 2015 May.
Article in English | MEDLINE | ID: mdl-26137040

ABSTRACT

We previously reported the case of a 56-year-old male who underwent surgical treatment for gastric hepatoid adenocarcinoma and splenic metastasis. The present study reports the case of the same patient who underwent successful ex vivo hepatectomy and partial liver autotransplantation. Computed tomography scans demonstrated that the tumor was located in the left and caudate lobes of the liver, with hepatic vein and inferior vena cava involvement, and right portal vein compression. To clarify the association between the vessels and the tumor, a three-dimensional imaging technique was used to reconstruct the liver architecture. During the surgery, the whole liver was removed with the retrohepatic vena cava, which was replaced with a prosthetic graft without a veno-venous bypass; a portacaval shunt for the anhepatic phase was performed simultaneously. The surgery lasted 9 h, and the anhepatic phase lasted 4 h. Blood loss during the surgery was recorded at 1,500 ml. The time taken for recovery was 21 days post-surgery, and at 20 months, the patient was disease-free. To the best of our knowledge, this is the first case of ex vivo liver resection performed for hepatic metastasis of hepatoid adenocarcinoma to be reported.

10.
Mol Med Rep ; 12(3): 4203-4209, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26095787

ABSTRACT

DLC1 has been shown to be downregulated or absent in hepatocellular carcinoma (HCC) and is associated with tumorigenesis and development. However, only a small number of studies have focused on genetic variations of DLC1. The present study performed exon sequencing for the DLC1 gene in HCC tissue samples from 105 patients to identify functional genetic variation of DLC1 and its association with HCC susceptibility, clinicopathological features and prognosis. A novel missense mutation and four non­synonymous single nucleotide polymorphisms (SNPs; rs3816748, rs11203495, rs3816747 and rs532841) were identified. A significant correlation of rs3816747 polymorphisms with HCC susceptibility was identified. Compared to individuals with the GG genotype of rs3816747, those with the GA (odds ratio (OR)=0.486; P=0.037) or GA+AA genotype (OR=0.51; P=0.039) were associated with a significantly decreased HCC risk. Furthermore, patients with the GC+CC genotype of rs3816748, the TC+CC genotype of rs11203495 or the GA+AA genotype of rs3816747 had small­sized tumors compared with those carrying the wild­type genotype. No significant association of DLC1 SNPs with the patients' prognosis was found. These results indicated that genetic variations in the DLC1 gene may confer a risk for HCC.


Subject(s)
Carcinoma, Hepatocellular/genetics , GTPase-Activating Proteins/metabolism , Genetic Variation , Liver Neoplasms/genetics , Tumor Suppressor Proteins/metabolism , Alleles , Amino Acid Sequence , Animals , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Disease-Free Survival , Female , GTPase-Activating Proteins/chemistry , GTPase-Activating Proteins/genetics , Genetic Predisposition to Disease , Genotype , Humans , Kaplan-Meier Estimate , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Odds Ratio , Polymorphism, Single Nucleotide , Prognosis , Sequence Analysis, DNA , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/genetics , alpha-Fetoproteins/analysis
11.
Mol Med Rep ; 12(3): 4250-4258, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26099202

ABSTRACT

Hepatocellular carcinoma (HCC) is the one of most common malignant tumors. The tumor microenvironment has a role in not only supporting growth and survival of tumor cells, but also triggering tumor recurrence and metastasis. Hepatocyte growth factor (HGF), one of the important growth factors in the tumor microenvironment, has an important role in angiogenesis, tumorigenesis and regeneration. However, the exact mechanism by which HGF regulates HCC initiation and development via epigenetic reprogramming has remained elusive. The present study focused on the epigenetic modification and target tumor-suppressive genes of HGF treatment in HCC. Expression profiling and DNA methylation array were performed to investigate the function of HGF and examine global genomic DNA methylation changes, respectively. Integrated analysis of gene expression and DNA methylation revealed potential tumor suppressor genes (TSGs) in HCC. The present study showed the multiple functions of HGF in tumorous and non­tumorous pathways and global genomic DNA methylation changes. HGF treatment upregulated the expression of DNA methyltransferase 1 (DNMT1). Overexpression of DNMT1 in HCC patients correlated with the malignant potential and poor prognosis of HCC. Furthermore, integration analysis of gene expression and DNA methylation changes revealed novel potential tumor suppressor genes TSGs including MYOCD, PANX2 and LHX9. The present study has provided mechanistic insight into epigenetic repression of TSGs through HGF­induced DNA hypermethylation.


Subject(s)
DNA Methylation , Hepatocyte Growth Factor/physiology , Hepatocytes/metabolism , Transcriptome , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , Enzyme Induction , Epigenesis, Genetic , Gene Ontology , Hep G2 Cells , Humans , Liver/enzymology , Liver/pathology , Liver Neoplasms/enzymology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Prognosis
12.
PLoS One ; 10(5): e0121538, 2015.
Article in English | MEDLINE | ID: mdl-25933112

ABSTRACT

Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.


Subject(s)
Antineoplastic Agents/therapeutic use , Autophagy/drug effects , Capsaicin/therapeutic use , Cholangiocarcinoma/drug therapy , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Capsaicin/pharmacology , Cell Line, Tumor , Cholangiocarcinoma/pathology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Humans , Mice, Inbred BALB C , Mice, Nude , Signal Transduction/drug effects
13.
Mol Med Rep ; 12(1): 1421-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25760819

ABSTRACT

Enoyl-coenzyme A hydratase short chain 1 (ECHS1) regulates fatty acid metabolism and is an essential factor in tumor development. The present study aimed to investigate the molecular mechanisms of ECHS1 in hepatocellular carcinogenesis by studying proliferation and survival in ECHS1 knocked-down hepatocellular carcinoma (HCC) cell lines, HepG2 and HuH7. The effect of ECHS1 on tumor development was investigated by tumor transplantation in nude mice, and the signaling pathways involved in the ECHS1-mediated regulation of HCC cell proliferation were identified by western blot analysis. The silencing of ECHS1 suppressed HCC cell proliferation in vitro and suppressed the growth of transplanted tumors in vivo. In addition, the phosphorylation of EGFR and its downstream effectors ERK1/2 and AKT was downregulated in ECHS1 knocked-down cells and tumor tissues. Furthermore, knockdown of ECHS1 in HCC suppressed cyclin D3 and cyclin dependent kinase 6 expression, whilst enhancing p16 and p21 expression. Therefore, ECHS1 may also be involved in cell cycle progression in HCC cells. These results suggested that ECHS1 may promote cell proliferation in HCC in an EGFR-dependent manner.


Subject(s)
Carcinogenesis , Carcinoma, Hepatocellular/genetics , Enoyl-CoA Hydratase/genetics , ErbB Receptors/genetics , Liver Neoplasms/genetics , Animals , Carcinoma, Hepatocellular/pathology , Cell Proliferation/genetics , Enoyl-CoA Hydratase/biosynthesis , ErbB Receptors/biosynthesis , Gene Knockdown Techniques , Hep G2 Cells , Humans , Liver Neoplasms/pathology , Mice , Mitogen-Activated Protein Kinase 3/biosynthesis , Oncogene Protein v-akt/biosynthesis , Phosphorylation , Signal Transduction
14.
APMIS ; 123(4): 315-20, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25706354

ABSTRACT

It has been reported that NKD1 was an antagonist of the canonical Wnt/ß-catenin pathway. While there is little information regarding NKD1 expression pattern in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinicopathologic significance and expression pattern of NKD1 in HCC. NKD1 protein expressions in 69 paired HCC cancer/adjacent non-cancerous tissues were detected by Western blot. Immunohistochemical studies were performed on 58 cases of HCC with integrated clinical information. NKD1 protein expression was divided into normal and low expression group and correlations between NKD1 protein expression and clinicopathologic factors were then evaluated. Western blot results showed that NKD1 protein levels were significantly lower in cancerous tissues compared with corresponding normal tissue (p < 0.05). In addition, we found that the level of NKD1 protein expression in HCC was significantly associated with tumor size (p = 0.011), intra or extra-hepatic metastasis (p = 0.010) and differentiation (p = 0.003). This is to our knowledge the first report investigating NKD1 protein expression pattern in HCC. Our data show that decreased NKD1 protein expression is associated with clinicopathologic factors, and suggest that NKD1 may play an important role in the development of HCC and could serve as a novel biomarker for HCC after further investigation.


Subject(s)
Carcinoma, Hepatocellular/genetics , Carrier Proteins/biosynthesis , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Adaptor Proteins, Signal Transducing , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/biosynthesis , Calcium-Binding Proteins , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Child , Down-Regulation , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Middle Aged , Prognosis , Thrombosis/pathology , Wnt Proteins/metabolism , Wnt Signaling Pathway , Young Adult , beta Catenin/metabolism
15.
Int J Oncol ; 46(2): 782-90, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25420499

ABSTRACT

Dysregulation of growth factor signaling plays a pivotal role in controlling the malignancy phenotype and progression of hepatocellular carcinoma (HCC). However, the precise oncogenic mechanisms underlying transcription regulation of certain tumor suppressor genes (TSGs) by growth factors are poorly understood. In the present study, we report a novel insulin-like growth factor 1 (IGF1) pathway that mediates de novo DNA methylation and TSG (such as DLC1 and CHD5) silencing by upregulation of the DNA methyltransferase 1 (DNMT1) via an AKT/ß-transducin repeat-containing protein (ßTrCP)-mediated ubiquitin-proteasome pathway in HCC. Analysis of DNA methylation in CpG islands of target genes revealed high co-localization of DNMT1 and DNMT3B on the promoters of TSGs associated with enhanced CpG hypermethylation. Our results point to a novel epigenetic mechanism for growth factor-mediated repression of TSG transcription that involves DNA methylation.


Subject(s)
Carcinoma, Hepatocellular/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , Liver Neoplasms/genetics , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , CpG Islands , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/biosynthesis , DNA Methylation/drug effects , Epigenesis, Genetic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Gene Targeting , Hep G2 Cells , Humans , Intercellular Signaling Peptides and Proteins/administration & dosage , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Mice , Neoplasm Proteins/biosynthesis , Promoter Regions, Genetic , Xenograft Model Antitumor Assays , DNA Methyltransferase 3B
16.
J Cell Sci ; 126(Pt 13): 2877-89, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23613467

ABSTRACT

Wnt signalling through ß-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified let-7 miRNAs as downstream targets of the Wnt-ß-catenin pathway. Expression studies indicated that the Wnt-ß-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-ß-catenin pathway. Loss of function of Lin28 impairs Wnt-ß-catenin-pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt-ß-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that the Wnt-ß-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by the Wnt-ß-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-ß-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-ß-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.


Subject(s)
Gene Expression Regulation, Neoplastic , MicroRNAs/metabolism , Neoplastic Stem Cells/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction/genetics , Wnt1 Protein/metabolism , beta Catenin/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Female , Genes, Reporter , Humans , Luciferases/genetics , Luciferases/metabolism , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Mice , Mice, Knockout , MicroRNAs/genetics , Neoplastic Stem Cells/pathology , RNA-Binding Proteins/genetics , Transcriptional Activation , Wnt1 Protein/genetics , beta Catenin/genetics
17.
APMIS ; 121(11): 1047-53, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23593969

ABSTRACT

Chloride intracellular channel 1 (CLIC1) is expressed in many human tissues and has been reported to be involved in the regulation of cell cycle, cell proliferation, and differentiation. Its roles in human hepatic tumor, however, remain unclear. The aim of this study was to investigate the clinicopathological significance and expression pattern of CLIC1 in human primary hepatic tumors. We examined the expression pattern of CLIC1 mRNA and protein in hepatic tumors using real-time quantitative RT-PCR and Western blot, respectively. CLIC1 protein and mRNA levels were significantly higher in cancerous tissues compared with corresponding normal tissue. In 85 hepatic tumor tissues, CLIC1 was significantly higher in 69 cases (81.2%), as determined by immunohistochemical staining. Increased CLIC1 expression was correlated with tumor size (p = 0.021), distant metastasis (p = 0.025), pathological TNM (pTNM) stage (p = 0.023), and poor survival (25.11 ± 2.27 vs 45.29 ± 4.28 months, p = 0.001). Our data show that increased CLIC1 protein expression is associated with clinicopathological factors and a poor prognosis of hepatic tumors, and suggest that CLIC1 might represent a valuable prognostic marker for human hepatic tumors.


Subject(s)
Chloride Channels/physiology , Liver Neoplasms/mortality , Chloride Channels/analysis , Chloride Channels/genetics , Humans , Liver/chemistry , Liver Neoplasms/chemistry , Liver Neoplasms/pathology , Middle Aged , Prognosis , RNA, Messenger/analysis
18.
EMBO Mol Med ; 5(1): 137-48, 2013 01.
Article in English | MEDLINE | ID: mdl-23197407

ABSTRACT

Angiotensin II (AngII) induces cardiac hypertrophy and increases the expression of TR3. To determine whether TR3 is involved in the regulation of the pathological cardiac hypertrophy induced by AngII, we established mouse and rat hypertrophy models using chronic AngII administration. Our results reveal that a deficiency of TR3 in mice or the knockdown of TR3 in the left ventricle of rats attenuated AngII-induced cardiac hypertrophy compared with the respective controls. A mechanistic analysis demonstrates that the TR3-mediated activation of mTORC1 is associated with AngII-induced cardiac hypertrophy. TR3 was shown to form a trimer with the TSC1/TSC2 complex that specifically promoted TSC2 degradation via a proteasome/ubiquitination pathway. As a result, mTORC1, but not mTORC2, was activated; this was accompanied by increased protein synthesis, enhanced production of reactive oxygen species and enlarged cell size, thereby resulting in cardiac hypertrophy. This study demonstrates that TR3 positively regulates cardiac hypertrophy by influencing the effect of AngII on the mTOR pathway. The elimination or reduction of TR3 may reduce cardiac hypertrophy; therefore, TR3 is a potential target for clinical therapy.


Subject(s)
Cardiomegaly/etiology , Cardiomegaly/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , TOR Serine-Threonine Kinases/metabolism , Angiotensin II/administration & dosage , Animals , Cardiomegaly/pathology , Gene Knockdown Techniques , Humans , Male , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Inbred C57BL , Mice, Knockout , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors , Nuclear Receptor Subfamily 4, Group A, Member 1/chemistry , Nuclear Receptor Subfamily 4, Group A, Member 1/deficiency , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Proteins/chemistry , Proteins/metabolism , Rats , Signal Transduction , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/chemistry , Tumor Suppressor Proteins/metabolism , Ubiquitination
19.
Hepatogastroenterology ; 59(117): 1529-36, 2012.
Article in English | MEDLINE | ID: mdl-22683969

ABSTRACT

BACKGROUND/AIMS: In the injured liver, hepatic stellate cells (HSCs) induce immunosuppression activity and thus participate in the pathogenesis of liver disease, including HCC. Therefore, finding new drugs to inhibit their immunosuppression activity is necessary. This study tests whether bear bile can affect the immunosuppression activities of HSCs. METHODOLOGY: The mice were gavaged with bear bile for 4 weeks. The expression of HSCs was detected through desmin and ±-smooth muscle antibody immunohistochemistry. HSCs were isolated from these mice liver and then cultured with T cells in a mixed leukocyte reaction for 3 days. Stellate cell surface makers, T-cell apoptosis, regulatory T cells and the ability of T cells to kill hepatocellular carcinoma were determined via flow cytometry. Cytokines were determined by a mouse cytokine array panel and T-cell proliferation was determined through a BrdU kit. RESULTS: Bear bile decreased HSCs and their surface molecules, and affected cytokine secretion. Interestingly, HSCs from the mice gavaged with bear bile promoted T-cell proliferation, inhibited T-cell apoptosis, decreased CD4+CD25+Foxp3+ regulatory T cells and enhanced the activation of T cells killing hepatocellular carcinoma. CONCLUSIONS: Bear bile can inhibit the immunosuppression activity of HSCs and enhance immune response especial anti-tumor immune response.


Subject(s)
Bile/immunology , Hepatic Stellate Cells/immunology , Immune Tolerance/drug effects , T-Lymphocytes, Regulatory/drug effects , Actins/metabolism , Analysis of Variance , Animals , Apoptosis/drug effects , Carcinoma, Hepatocellular/immunology , Cell Proliferation/drug effects , Cells, Cultured , Cytokines/drug effects , Cytokines/metabolism , Desmin/metabolism , Hepatic Stellate Cells/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Ursidae
20.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 6): m784-5, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21754666

ABSTRACT

In the title compound, [Zn(2)(C(10)H(2)O(8))(C(16)H(20)N(4))(H(2)O)(2)](n), the Zn(II) atom is in a distorted tetra-hedral environment, being coordinated by one N atom from a 1,4-bis-(3-pyridyl-meth-yl)piperazine (3-bpmp) ligand, two O atoms from two carboxyl-ate groups of the pyromellitate anion and one water mol-ecule. The distortion of the tetrahedral coordination may be ascribed to the hydrogen bonds between the carboxyl-ate groups and the adjacent water mol-ecules. Each Zn(II) atom links to three organic ligands and each pyromellitate ligand coordinates to four Zn(II) atoms, forming a (3,4)-connected infinite three-dimensional framework. O-H⋯N inter-actions also occur.

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