Liang Qiao - Academia.edu (original) (raw)
Papers by Liang Qiao
Frontiers in physiology, 2018
The aim of this study was to observe the possible change of microRNAs (miRNAs) in serum extracell... more The aim of this study was to observe the possible change of microRNAs (miRNAs) in serum extracellular vesicles (EVs) from hepatocellular carcinoma (HCC) patients. The serum EVs were purified from 17 healthy donors, 16 chronic hepatitis B (CHB) patients and 24 HCC patients. The sequenced microRNAs in the purified EVs were analyzed to obtain highly differentially expressed genes (DEGs). Finally, the expression pattern of DEGs was validated using qRT-PCR. We found that the expression of hsa-miR-21-5p and hsa-miR-144-3p were significantly higher in EVs and liver cancer tissues compared with serum and the distal liver tissues in HCC patients. The ratio of hsa-miR-144-3p/hsa-miR-21-5p was significantly decreased in the patients with CHB but significantly increased in patients with HCC developed from CHB ( < 0.05). Hsa-144-3p/hsa-miR-21-5p exhibited greater performance than alpha-fetoprotein (AUC 0.780, 95% CI 0.601-0.960, versus AUC 0.626, 95% CI 0.410-0.843) in ROC curve analysis. Ext...
World Journal of Gastroenterology, 2004
AIM: To determine whether 2-(3-carboxy-1-oxopropy1) amino-2-deoxy-D-glucose (COPADG), a derivativ... more AIM: To determine whether 2-(3-carboxy-1-oxopropy1) amino-2-deoxy-D-glucose (COPADG), a derivative of Damino-glucose, inhibited the growth of human esophageal cancer cell line Eca-109. METHODS: Effects of COPADG on Eca-109 cells cultured in RPMI 1640 medium were examined by a tetrazoliumbased colorimetric assay (MTT assay). RESULTS: COPADG inhibited the growth of Eca-109 cells in a dose-and time-dependent manner; the maximum inhibition rate was 83.75%. CONCLUSION: COPADG can directly inhibit the proliferation of Eca-109 cells, which may serve as the experimental evidence for development of new drugs for esophageal cancer therapy.
Molecular Biology of the Cell, 2000
In primary hepatocytes and HepG2 hepatoma cells, prolonged activation of the p42/44 mitogen-activ... more In primary hepatocytes and HepG2 hepatoma cells, prolonged activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway is associated with a reduction in DNA synthesis, mediated by increased expression of the cyclin-dependent kinase inhibitor protein p21Cip-1/WAF1/mda6(p21). This study was performed to evaluate the contribution of transcriptional and post-transcriptional regulation in this response. Prolonged activation of the MAPK pathway in wild-type or p21 null hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Prolonged activation of the MAPK pathway in either wild-type or p21 antisense HepG2 cells also caused large decreases and increases, respectively, in DNA synthesis. MAPK signaling increased the phosphorylation of the transcription factors Ets2, C/EBPα, and C/EBPβ, and rapidly increased transcription from the p21 promoter via multiple Ets- and C/EBP-elements within the enhancer region. Eight hours after MAPK activation, loss of C/E...
International journal of oncology, Jan 28, 2015
The effects of hepatic stellate cells (HSCs) on tumorigenicity of HCC have been previously report... more The effects of hepatic stellate cells (HSCs) on tumorigenicity of HCC have been previously reported. However, the detailed mechanisms responsible for these effects remain unclear. In this study, we investigated the effects of HSCs on cisplatin-induced apoptosis in human hepatoma HepG2 cell lines. HepG2 cells were treated with cisplatin alone or co-cultured with LX-2 cells 3 days before incubation with cisplatin. Cisplatin causes apoptosis in HepG2 cells and LX-2 cells protect HepG2 cells from death. The protection of LX-2 cells against cisplatin-induced cytotoxicity in HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by cytotoxicity assay and nuclear staining analysis. p53 and Bax mRNA levels were elevated, and cell cycle arrest was produced after cisplatin treatment. LX-2 cells suppressed this elevation of p53 and Bax as well as the cell cycle arrest induced by cisplatin, when compared with those of the treated cells with cisplatin alone. The LX-2 ce...
International journal of molecular sciences, Jan 20, 2015
Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive... more Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.
The Korean Journal of Gastroenterology, 2014
Background/Aims: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of c... more Background/Aims: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether patients with cryptogenic HCC share clinical features similar to that of NAFLD. Methods: Cryptogenic HCC was defined as HCC that occurs in patients with the following conditions: HBsAg(−), anti-HCV(−), and alcohol ingestion of less than 20 g/day. All patients diagnosed with cryptogenic HCC from 2005 to 2012 (cryptogenic HCC group), and all patients diagnosed with HBV associated HCC between 2008 and 2012 (HBV-HCC group) were enrolled in the present study. Clinical features, BMI, lipid profiles, presence of diabetes mellitus, hypertension, and metabolic syndrome were compared between the two groups. Results: Cryptogenic HCC group was composed of 35 patients (19 males and 16 females) with a mean age of 70±11 years. HBV-HCC group was composed of 406 patients (318 males and 88 females) with a mean age of 56±7 years. Patients in the cryptogenic HCC group were older (p=0.001) and female dominant (p=0.042) than those in the HBV-HCC group. There were no differences in the laboratory test results including lipid profiles and Child-Turcotte-Pugh class between the two groups. Patients in the cryptogenic HCC group had higher prevalence of diabetes (37% vs. 17%, p=0.015), hypertension (49% vs. 27%, p=0.051), metabolic syndrome (37% vs. 16%, p=0.001), and higher BMI (25.3 kg/m 2 vs. 24.1 kg/m 2 , p=0.042) than those in the HBV-HCC group. The tumor stage was more advanced (stage III and IV) at diagnosis in the cryptogenic HCC group than in the HBV-HCC group (60% vs. 37%, p=0.007). Conclusions: Cryptogenic HCC has clinical features similar to that of NAFLD and is diagnosed at a more advanced tumor stage.
World journal of gastroenterology : WJG, Jan 7, 2013
To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric can... more To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric cancer cells. COX-2 expression in human gastric cancer cell lines SGC-7901, BGC-823, MGC-803 and AGS were measured at the mRNA and protein level. COX-2 rich cell line SGC-7901 was chosen for subsequent experiments. siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB), Snail, and E-cadherin in gastric cancer cells. Gene expression was determined by Western blot and real-time polymerase chain reaction. To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2 (PGE2) on E-cadherin, gastric cancer cells were treated with celecoxib or PGE2, in the presence of NF-κB specific siRNA. Highest expression level of COX-2 was found in SGC-7901 cells, both at mRNA and protein levels. siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail, but an increased expression of E-cadherin...
Molecular Biology of the Cell, 2001
Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR... more Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR) and the mitogen-activated protein kinase (MAPK) pathway can promote tumor cell survival in response to cytotoxic insults. In this study, we examined the impact of MAPK signaling on the survival of primary hepatocytes exposed to low concentrations of deoxycholic acid (DCA, 50 μM). Treatment of hepatocytes with DCA caused MAPK activation, which was dependent upon ligand independent activation of EGFR, and downstream signaling through Ras and PI3kinase. Neither inhibition of MAPK signaling alone by MEK1/2 inhibitors, nor exposure to DCA alone, enhanced basal hepatocyte apoptosis, whereas inhibition of DCA-induced MAPK activation caused ∼25% apoptosis within 6 h. Similar data were also obtained when either dominant negative EGFR-CD533 or dominant negative Ras N17 were used to block MAPK activation. DCA-induced apoptosis correlated with sequential cleavage of procaspase 8, BID, procaspase 9...
Molecular and Cellular Biology, 2003
Previously, we have demonstrated that deoxycholic acid (DCA)-induced signaling of extracellular s... more Previously, we have demonstrated that deoxycholic acid (DCA)-induced signaling of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in primary hepatocytes is a protective response. In the present study, we examined the roles of the ERK and c-Jun NH 2 -terminal kinase (JNK) pathways, and downstream transcription factors, in the survival response of hepatocytes. DCA caused activation of the ERK1/2 and JNK1/2 pathways. Inhibition of either DCA-induced ERK1/2 or DCA-induced JNK1/2 signaling enhanced the apoptotic response of hepatocytes. Further analyses demonstrated that DCA-induced JNK2 signaling was cytoprotective whereas DCA-induced JNK1 signaling was cytotoxic. DCA-induced ERK1/2 activation was responsible for increased DNA binding of C/EBPβ, CREB, and c-Jun/AP-1. Inhibition of C/EBPβ, CREB, and c-Jun function promoted apoptosis following DCA treatment, and the level of apoptosis was further increased in the case of CREB and c-Jun, but not C/EBPβ, by inhibition of MEK1/2. The...
Hepatology, 2004
Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in prima... more Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in primary hepatocytes is a protective response. In the present study, we examined the regulation of the phosphatidylinositol 3 (PI3) kinase/AKT/glycogen synthase (kinase) 3 (GSK3)/glycogen synthase (GS) pathway by bile acids. In primary hepatocytes, DCA activated ERBB1 (the epidermal growth factor receptor), ERBB2, and the insulin receptor, but not the insulin-like growth factor 1 (IGF-1) receptor. DCA-induced activation of the insulin receptor correlated with enhanced phosphorylation of insulin receptor substrate 1, effects that were both blocked by the insulin receptor inhibitor AG1024 and by expression of the dominant negative IGF-1 receptor (K1003R), which inhibited in trans. Expression of the dominant negative IGF-1 receptor (K1003R) also abolished DCA-induced AKT activation. Bile acid-induced activation of AKT and phosphorylation of GSK3 were blunted by the ERBB1 inhibitor AG1478 and abolished by AG1024. Bile acids caused activation of GS to a similar level induced by insulin (50 nM); both were blocked by inhibition of insulin receptor function and the PI3 kinase/AKT/GSK3 pathway. In conclusion, these findings suggest that bile acids and insulin may cooperate to regulate glucose storage in hepatocytes. (HEPATOLOGY 2004;39:456-463.
Frontiers in Bioscience, 2012
Introduction 3. Epidemiology of obesity 4. Epidemiology of GBC 5. Obesity and GBC: possible mecha... more Introduction 3. Epidemiology of obesity 4. Epidemiology of GBC 5. Obesity and GBC: possible mechanisms 5.1. Insulin resistance, hyperinsulinemia, and insulin-like growth factors (IGF) increase the cancer risk 5.2. Gallstone is an established risk factor for GBC 5.3. Adipokines 5.4. Sex hormones and GBC 5.5. Fatty infiltration in gallbladder may predispose to GBC 6. Lifestyle modification as a measure of preventing GBC in obese people 7. Conclusion 8. References
Frontiers in Bioscience, 2012
Introduction 3. Epidemiological evidence linking obesity and HCC 4. Underlying molecular mechanis... more Introduction 3. Epidemiological evidence linking obesity and HCC 4. Underlying molecular mechanisms linking obesity and HCC 4.1. Role of Insulin/IGF axis in obesity-related HCC 4.1.1. Insulin/IGF axis and obesity 4.1.2. Possible role of insulin/IGF axis in HCC 4.2. Role of adipose tissue-derived hormones (adipocytokines) in the development of HCC 4.2.1. Leptin 4.2.2. Adiponectin 5. Role of oxidative stress in obesity-associated HCC 6. Role of liver stem cells in obesity-related HCC 7. Effects of lifestyle modification on preventing obesity-related HCC 8. Conclusions 9. Acknowleddgement 11. References
Carcinogenesis, 2008
Pancreatic duodenal homeobox-1 (PDX1) is a transcription factor of homeobox genes family importan... more Pancreatic duodenal homeobox-1 (PDX1) is a transcription factor of homeobox genes family important in differentiation and development of the pancreas, duodenum and antrum. This study aims to clarify the putative role of PDX1 in gastric carcinogenesis. Methods: PDX1 expression was detected in gastric tissues with chronic gastritis and cancer as well as gastric cancer cell lines by immunohistochemistry, western blot, reverse transcriptionpolymerase chain reaction (RT-PCR) or quantitative real-time RT-PCR assays. The effects of PDX1 on cell proliferation, apoptosis, clone formation and migration were evaluated using cancer cell lines after transient or stable transfection with PDX1expressing vector. The ability of PDX1 stable transfectant in tumor formation in xenograft mice was assessed. Results: PDX1 was strongly expressed in normal gastric glands, but was absent in 29 of 39 of human gastric cancer and most gastric cancer cell lines. Negative correlation between PDX1 and Ki-67 expression was found in both gastric tissues and cell lines. Ectopic overexpression of PDX1 significantly inhibited cell proliferation and induced apoptosis, accompanied by the activation of caspases 3, 8, 9 and 10. Overexpression of PDX1 also impaired the ability of cancer cells in clonal formation and migration in vitro. Furthermore, stable transfection with PDX1 reduced the ability of cancer cells in tumor formation in nude mice. Conclusions: PDX1 expression is lost in gastric cancers. Its effect on cell proliferation/apoptosis, migration and tumor formation in vitro and in vivo suggested that this protein functions as a putative tumor suppressor in gastric cancer.
Cancer Letters, 2014
Primary liver cancer has several well-recognized risk factors, such as HBV and HCV infection, alc... more Primary liver cancer has several well-recognized risk factors, such as HBV and HCV infection, alcohol abuse and aflatoxin. Recent studies show that nonalcoholic fatty liver disease (NAFLD), especially its aggressive form nonalcoholic steatohepatitis (NASH) is associated with an increased risk of liver cancer, mainly hepatocellular carcinoma (HCC). On the other hand, clinical and epidemiological data have showed that HCC has rarely been found in a ''pure'' fatty liver in human. Thus, the question we need to ask is do we have sufficient evidence to support a causative role of NAFLD in liver cancer? Furthermore, if NAFLD is indeed a causative factor for liver cancer, what is the mechanism? Perhaps at this stage, fatty liver and NASH can be regarded as a definite risk factor for liver cancer, but to conclude that NAFLD induces HCC requires more robust in vitro and in vivo data.
Cancer Biology & Therapy, 2005
NF-κB nuclear transcription factor-kappa B H 2 O 2 hydrogen peroxide TUNEL TdT-mediated dUTP nick... more NF-κB nuclear transcription factor-kappa B H 2 O 2 hydrogen peroxide TUNEL TdT-mediated dUTP nick end labelling EMSA electrophoretic mobility shift assay
Acta virologica, 2013
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases and has the fourth hi... more Hepatocellular carcinoma (HCC) is one of the most common malignant diseases and has the fourth highest mortality rate worldwide. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in HCC. Currently available evidence support a critical role of hepatitis B virus x (HBx) gene and protein in the pathogenesis of HBV-induced HCC. HBx protein is a multifunctional regulator that modulates cellular signal transduction pathways, transcriptional regulations, cell cycle progress, DNA repair, apoptosis, and genetic stability by interacting with different host factors. This review describes the current state of knowledge about the biological roles of this protein in the development of HCC.
![Research paper thumbnail of Effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose} on human hepatocellular carcinoma cell line](https://attachments.academia-assets.com/107620852/thumbnails/1.jpg)
](Acta Pharmacologica Sinica, 2005
Aim: To study the effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose (COPADG) on cult... more Aim: To study the effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose (COPADG) on cultured human hepatocellular carcinoma cells (HepG2). Methods: HepG2 cells were cultured in RPMI-1640 medium. Cell proliferation was determined by MTT assay. Apoptosis was determined by fluorescence microscopy, transmission electron microscopy, agarose gel electrophoresis of DNA fragmentation, and flow cytometry. Results: At the concentration ranging between 1-30 µmol/L, COPADG potently inhibited the growth and induced apoptosis of HepG2 cells. Conclusion: COPADG could effectively induce apoptosis in human hepatocellular carcinoma cells. More investigations are warranted for the potential use of this compound as a new agent for the non-surgical management of human hepatocellular carcinoma.
International journal of molecular sciences, Jan 5, 2015
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the l... more Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epig...
Digestive Diseases and Sciences, 2009
An ideal animal model is necessary for a clear understanding of the etiology, pathogenesis, and m... more An ideal animal model is necessary for a clear understanding of the etiology, pathogenesis, and mechanisms of human non-alcoholic steatohepatitis (NASH) and for facilitating the design of effective therapy for this condition. We aimed to establish a rat model of NASH with fibrosis by using a high-fat diet (HFD). Male Sprague-Dawley (SD) rats were fed a HFD consisting of 88 g normal diet, 10 g lard oil, and 2 g cholesterol. Control rats were fed normal diet. Rats were killed at 4, 8, 12, 16, 24, 36, and 48 weeks after HFD exposure. Body weight, liver weight, and epididymal fat weight were measured. Serum levels of fasting glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), free fatty acids (FFA), insulin, and tumor necrosis factor-alpha (TNF-a) were determined. Hepatic histology was examined by H&E stain. Hepatic fibrosis was assessed by VG stain and immunohistochemical staining for transforming growth factor beta 1 (TGF-b1), and alpha-smooth-muscle actin (a-SMA). The liver weight and liver index increased from week 4, when hepatic steatosis was also observed. By week 8, the body weight and epididymal fat weight started increasing, which was associated with increased serum levels of FFA, cholesterol, and TNF-a, as well as development of simple fatty liver. The serum ALT level increased from week 12. Steatohepatitis occurred from weeks 12 through 48. Apparent hepatic perisinosodial fibrosis did not occur until week 24, and progressed from week 36 to 48 with insulin resistance. Therefore, this novel model may be potentially useful in NASH study.
QJM, 2011
We report a case of liver cancer with features consistent with fibrolamellar hepatocellular carci... more We report a case of liver cancer with features consistent with fibrolamellar hepatocellular carcinoma (FLHCC) detected by PET-CT scan. A 20-year-old female with a large liver tumor was diagnosed with 'malignant hepatic tumor' 2 years earlier and received five courses of transhepatic arterial chemoembolization (TACE) before she presented to our hospital with abdominal distension and mild pain at the right upper quadrant. Ultrasound and CT scan showed a large tumor in the right lobe of the liver. Contrast CT scan and 18 F-FDG PET-CT showed metastatic lesions in multiple organs. The imaging diagnosis was confirmed by an ultrasound-guided fine needle biopsy of the hepatic lesion which showed features of FLHCC. Immunohistochemical staining showed a marked increase in the expressions of Hepar, CD99, MIB1, proliferating cell nuclear antigen (PCNA), Fibronectin, E-cadherin and CK7. The recent knowledge on the FLHCC and the possible applications of PET-CT were discussed.
Frontiers in physiology, 2018
The aim of this study was to observe the possible change of microRNAs (miRNAs) in serum extracell... more The aim of this study was to observe the possible change of microRNAs (miRNAs) in serum extracellular vesicles (EVs) from hepatocellular carcinoma (HCC) patients. The serum EVs were purified from 17 healthy donors, 16 chronic hepatitis B (CHB) patients and 24 HCC patients. The sequenced microRNAs in the purified EVs were analyzed to obtain highly differentially expressed genes (DEGs). Finally, the expression pattern of DEGs was validated using qRT-PCR. We found that the expression of hsa-miR-21-5p and hsa-miR-144-3p were significantly higher in EVs and liver cancer tissues compared with serum and the distal liver tissues in HCC patients. The ratio of hsa-miR-144-3p/hsa-miR-21-5p was significantly decreased in the patients with CHB but significantly increased in patients with HCC developed from CHB ( < 0.05). Hsa-144-3p/hsa-miR-21-5p exhibited greater performance than alpha-fetoprotein (AUC 0.780, 95% CI 0.601-0.960, versus AUC 0.626, 95% CI 0.410-0.843) in ROC curve analysis. Ext...
World Journal of Gastroenterology, 2004
AIM: To determine whether 2-(3-carboxy-1-oxopropy1) amino-2-deoxy-D-glucose (COPADG), a derivativ... more AIM: To determine whether 2-(3-carboxy-1-oxopropy1) amino-2-deoxy-D-glucose (COPADG), a derivative of Damino-glucose, inhibited the growth of human esophageal cancer cell line Eca-109. METHODS: Effects of COPADG on Eca-109 cells cultured in RPMI 1640 medium were examined by a tetrazoliumbased colorimetric assay (MTT assay). RESULTS: COPADG inhibited the growth of Eca-109 cells in a dose-and time-dependent manner; the maximum inhibition rate was 83.75%. CONCLUSION: COPADG can directly inhibit the proliferation of Eca-109 cells, which may serve as the experimental evidence for development of new drugs for esophageal cancer therapy.
Molecular Biology of the Cell, 2000
In primary hepatocytes and HepG2 hepatoma cells, prolonged activation of the p42/44 mitogen-activ... more In primary hepatocytes and HepG2 hepatoma cells, prolonged activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway is associated with a reduction in DNA synthesis, mediated by increased expression of the cyclin-dependent kinase inhibitor protein p21Cip-1/WAF1/mda6(p21). This study was performed to evaluate the contribution of transcriptional and post-transcriptional regulation in this response. Prolonged activation of the MAPK pathway in wild-type or p21 null hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Prolonged activation of the MAPK pathway in either wild-type or p21 antisense HepG2 cells also caused large decreases and increases, respectively, in DNA synthesis. MAPK signaling increased the phosphorylation of the transcription factors Ets2, C/EBPα, and C/EBPβ, and rapidly increased transcription from the p21 promoter via multiple Ets- and C/EBP-elements within the enhancer region. Eight hours after MAPK activation, loss of C/E...
International journal of oncology, Jan 28, 2015
The effects of hepatic stellate cells (HSCs) on tumorigenicity of HCC have been previously report... more The effects of hepatic stellate cells (HSCs) on tumorigenicity of HCC have been previously reported. However, the detailed mechanisms responsible for these effects remain unclear. In this study, we investigated the effects of HSCs on cisplatin-induced apoptosis in human hepatoma HepG2 cell lines. HepG2 cells were treated with cisplatin alone or co-cultured with LX-2 cells 3 days before incubation with cisplatin. Cisplatin causes apoptosis in HepG2 cells and LX-2 cells protect HepG2 cells from death. The protection of LX-2 cells against cisplatin-induced cytotoxicity in HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by cytotoxicity assay and nuclear staining analysis. p53 and Bax mRNA levels were elevated, and cell cycle arrest was produced after cisplatin treatment. LX-2 cells suppressed this elevation of p53 and Bax as well as the cell cycle arrest induced by cisplatin, when compared with those of the treated cells with cisplatin alone. The LX-2 ce...
International journal of molecular sciences, Jan 20, 2015
Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive... more Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.
The Korean Journal of Gastroenterology, 2014
Background/Aims: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of c... more Background/Aims: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether patients with cryptogenic HCC share clinical features similar to that of NAFLD. Methods: Cryptogenic HCC was defined as HCC that occurs in patients with the following conditions: HBsAg(−), anti-HCV(−), and alcohol ingestion of less than 20 g/day. All patients diagnosed with cryptogenic HCC from 2005 to 2012 (cryptogenic HCC group), and all patients diagnosed with HBV associated HCC between 2008 and 2012 (HBV-HCC group) were enrolled in the present study. Clinical features, BMI, lipid profiles, presence of diabetes mellitus, hypertension, and metabolic syndrome were compared between the two groups. Results: Cryptogenic HCC group was composed of 35 patients (19 males and 16 females) with a mean age of 70±11 years. HBV-HCC group was composed of 406 patients (318 males and 88 females) with a mean age of 56±7 years. Patients in the cryptogenic HCC group were older (p=0.001) and female dominant (p=0.042) than those in the HBV-HCC group. There were no differences in the laboratory test results including lipid profiles and Child-Turcotte-Pugh class between the two groups. Patients in the cryptogenic HCC group had higher prevalence of diabetes (37% vs. 17%, p=0.015), hypertension (49% vs. 27%, p=0.051), metabolic syndrome (37% vs. 16%, p=0.001), and higher BMI (25.3 kg/m 2 vs. 24.1 kg/m 2 , p=0.042) than those in the HBV-HCC group. The tumor stage was more advanced (stage III and IV) at diagnosis in the cryptogenic HCC group than in the HBV-HCC group (60% vs. 37%, p=0.007). Conclusions: Cryptogenic HCC has clinical features similar to that of NAFLD and is diagnosed at a more advanced tumor stage.
World journal of gastroenterology : WJG, Jan 7, 2013
To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric can... more To investigate the mechanisms of how cyclooxygenase-2 (COX-2) regulates E-cadherin in gastric cancer cells. COX-2 expression in human gastric cancer cell lines SGC-7901, BGC-823, MGC-803 and AGS were measured at the mRNA and protein level. COX-2 rich cell line SGC-7901 was chosen for subsequent experiments. siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB), Snail, and E-cadherin in gastric cancer cells. Gene expression was determined by Western blot and real-time polymerase chain reaction. To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2 (PGE2) on E-cadherin, gastric cancer cells were treated with celecoxib or PGE2, in the presence of NF-κB specific siRNA. Highest expression level of COX-2 was found in SGC-7901 cells, both at mRNA and protein levels. siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail, but an increased expression of E-cadherin...
Molecular Biology of the Cell, 2001
Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR... more Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR) and the mitogen-activated protein kinase (MAPK) pathway can promote tumor cell survival in response to cytotoxic insults. In this study, we examined the impact of MAPK signaling on the survival of primary hepatocytes exposed to low concentrations of deoxycholic acid (DCA, 50 μM). Treatment of hepatocytes with DCA caused MAPK activation, which was dependent upon ligand independent activation of EGFR, and downstream signaling through Ras and PI3kinase. Neither inhibition of MAPK signaling alone by MEK1/2 inhibitors, nor exposure to DCA alone, enhanced basal hepatocyte apoptosis, whereas inhibition of DCA-induced MAPK activation caused ∼25% apoptosis within 6 h. Similar data were also obtained when either dominant negative EGFR-CD533 or dominant negative Ras N17 were used to block MAPK activation. DCA-induced apoptosis correlated with sequential cleavage of procaspase 8, BID, procaspase 9...
Molecular and Cellular Biology, 2003
Previously, we have demonstrated that deoxycholic acid (DCA)-induced signaling of extracellular s... more Previously, we have demonstrated that deoxycholic acid (DCA)-induced signaling of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in primary hepatocytes is a protective response. In the present study, we examined the roles of the ERK and c-Jun NH 2 -terminal kinase (JNK) pathways, and downstream transcription factors, in the survival response of hepatocytes. DCA caused activation of the ERK1/2 and JNK1/2 pathways. Inhibition of either DCA-induced ERK1/2 or DCA-induced JNK1/2 signaling enhanced the apoptotic response of hepatocytes. Further analyses demonstrated that DCA-induced JNK2 signaling was cytoprotective whereas DCA-induced JNK1 signaling was cytotoxic. DCA-induced ERK1/2 activation was responsible for increased DNA binding of C/EBPβ, CREB, and c-Jun/AP-1. Inhibition of C/EBPβ, CREB, and c-Jun function promoted apoptosis following DCA treatment, and the level of apoptosis was further increased in the case of CREB and c-Jun, but not C/EBPβ, by inhibition of MEK1/2. The...
Hepatology, 2004
Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in prima... more Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in primary hepatocytes is a protective response. In the present study, we examined the regulation of the phosphatidylinositol 3 (PI3) kinase/AKT/glycogen synthase (kinase) 3 (GSK3)/glycogen synthase (GS) pathway by bile acids. In primary hepatocytes, DCA activated ERBB1 (the epidermal growth factor receptor), ERBB2, and the insulin receptor, but not the insulin-like growth factor 1 (IGF-1) receptor. DCA-induced activation of the insulin receptor correlated with enhanced phosphorylation of insulin receptor substrate 1, effects that were both blocked by the insulin receptor inhibitor AG1024 and by expression of the dominant negative IGF-1 receptor (K1003R), which inhibited in trans. Expression of the dominant negative IGF-1 receptor (K1003R) also abolished DCA-induced AKT activation. Bile acid-induced activation of AKT and phosphorylation of GSK3 were blunted by the ERBB1 inhibitor AG1478 and abolished by AG1024. Bile acids caused activation of GS to a similar level induced by insulin (50 nM); both were blocked by inhibition of insulin receptor function and the PI3 kinase/AKT/GSK3 pathway. In conclusion, these findings suggest that bile acids and insulin may cooperate to regulate glucose storage in hepatocytes. (HEPATOLOGY 2004;39:456-463.
Frontiers in Bioscience, 2012
Introduction 3. Epidemiology of obesity 4. Epidemiology of GBC 5. Obesity and GBC: possible mecha... more Introduction 3. Epidemiology of obesity 4. Epidemiology of GBC 5. Obesity and GBC: possible mechanisms 5.1. Insulin resistance, hyperinsulinemia, and insulin-like growth factors (IGF) increase the cancer risk 5.2. Gallstone is an established risk factor for GBC 5.3. Adipokines 5.4. Sex hormones and GBC 5.5. Fatty infiltration in gallbladder may predispose to GBC 6. Lifestyle modification as a measure of preventing GBC in obese people 7. Conclusion 8. References
Frontiers in Bioscience, 2012
Introduction 3. Epidemiological evidence linking obesity and HCC 4. Underlying molecular mechanis... more Introduction 3. Epidemiological evidence linking obesity and HCC 4. Underlying molecular mechanisms linking obesity and HCC 4.1. Role of Insulin/IGF axis in obesity-related HCC 4.1.1. Insulin/IGF axis and obesity 4.1.2. Possible role of insulin/IGF axis in HCC 4.2. Role of adipose tissue-derived hormones (adipocytokines) in the development of HCC 4.2.1. Leptin 4.2.2. Adiponectin 5. Role of oxidative stress in obesity-associated HCC 6. Role of liver stem cells in obesity-related HCC 7. Effects of lifestyle modification on preventing obesity-related HCC 8. Conclusions 9. Acknowleddgement 11. References
Carcinogenesis, 2008
Pancreatic duodenal homeobox-1 (PDX1) is a transcription factor of homeobox genes family importan... more Pancreatic duodenal homeobox-1 (PDX1) is a transcription factor of homeobox genes family important in differentiation and development of the pancreas, duodenum and antrum. This study aims to clarify the putative role of PDX1 in gastric carcinogenesis. Methods: PDX1 expression was detected in gastric tissues with chronic gastritis and cancer as well as gastric cancer cell lines by immunohistochemistry, western blot, reverse transcriptionpolymerase chain reaction (RT-PCR) or quantitative real-time RT-PCR assays. The effects of PDX1 on cell proliferation, apoptosis, clone formation and migration were evaluated using cancer cell lines after transient or stable transfection with PDX1expressing vector. The ability of PDX1 stable transfectant in tumor formation in xenograft mice was assessed. Results: PDX1 was strongly expressed in normal gastric glands, but was absent in 29 of 39 of human gastric cancer and most gastric cancer cell lines. Negative correlation between PDX1 and Ki-67 expression was found in both gastric tissues and cell lines. Ectopic overexpression of PDX1 significantly inhibited cell proliferation and induced apoptosis, accompanied by the activation of caspases 3, 8, 9 and 10. Overexpression of PDX1 also impaired the ability of cancer cells in clonal formation and migration in vitro. Furthermore, stable transfection with PDX1 reduced the ability of cancer cells in tumor formation in nude mice. Conclusions: PDX1 expression is lost in gastric cancers. Its effect on cell proliferation/apoptosis, migration and tumor formation in vitro and in vivo suggested that this protein functions as a putative tumor suppressor in gastric cancer.
Cancer Letters, 2014
Primary liver cancer has several well-recognized risk factors, such as HBV and HCV infection, alc... more Primary liver cancer has several well-recognized risk factors, such as HBV and HCV infection, alcohol abuse and aflatoxin. Recent studies show that nonalcoholic fatty liver disease (NAFLD), especially its aggressive form nonalcoholic steatohepatitis (NASH) is associated with an increased risk of liver cancer, mainly hepatocellular carcinoma (HCC). On the other hand, clinical and epidemiological data have showed that HCC has rarely been found in a ''pure'' fatty liver in human. Thus, the question we need to ask is do we have sufficient evidence to support a causative role of NAFLD in liver cancer? Furthermore, if NAFLD is indeed a causative factor for liver cancer, what is the mechanism? Perhaps at this stage, fatty liver and NASH can be regarded as a definite risk factor for liver cancer, but to conclude that NAFLD induces HCC requires more robust in vitro and in vivo data.
Cancer Biology & Therapy, 2005
NF-κB nuclear transcription factor-kappa B H 2 O 2 hydrogen peroxide TUNEL TdT-mediated dUTP nick... more NF-κB nuclear transcription factor-kappa B H 2 O 2 hydrogen peroxide TUNEL TdT-mediated dUTP nick end labelling EMSA electrophoretic mobility shift assay
Acta virologica, 2013
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases and has the fourth hi... more Hepatocellular carcinoma (HCC) is one of the most common malignant diseases and has the fourth highest mortality rate worldwide. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in HCC. Currently available evidence support a critical role of hepatitis B virus x (HBx) gene and protein in the pathogenesis of HBV-induced HCC. HBx protein is a multifunctional regulator that modulates cellular signal transduction pathways, transcriptional regulations, cell cycle progress, DNA repair, apoptosis, and genetic stability by interacting with different host factors. This review describes the current state of knowledge about the biological roles of this protein in the development of HCC.
Acta Pharmacologica Sinica, 2005
Aim: To study the effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose (COPADG) on cult... more Aim: To study the effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose (COPADG) on cultured human hepatocellular carcinoma cells (HepG2). Methods: HepG2 cells were cultured in RPMI-1640 medium. Cell proliferation was determined by MTT assay. Apoptosis was determined by fluorescence microscopy, transmission electron microscopy, agarose gel electrophoresis of DNA fragmentation, and flow cytometry. Results: At the concentration ranging between 1-30 µmol/L, COPADG potently inhibited the growth and induced apoptosis of HepG2 cells. Conclusion: COPADG could effectively induce apoptosis in human hepatocellular carcinoma cells. More investigations are warranted for the potential use of this compound as a new agent for the non-surgical management of human hepatocellular carcinoma.
International journal of molecular sciences, Jan 5, 2015
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the l... more Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epig...
Digestive Diseases and Sciences, 2009
An ideal animal model is necessary for a clear understanding of the etiology, pathogenesis, and m... more An ideal animal model is necessary for a clear understanding of the etiology, pathogenesis, and mechanisms of human non-alcoholic steatohepatitis (NASH) and for facilitating the design of effective therapy for this condition. We aimed to establish a rat model of NASH with fibrosis by using a high-fat diet (HFD). Male Sprague-Dawley (SD) rats were fed a HFD consisting of 88 g normal diet, 10 g lard oil, and 2 g cholesterol. Control rats were fed normal diet. Rats were killed at 4, 8, 12, 16, 24, 36, and 48 weeks after HFD exposure. Body weight, liver weight, and epididymal fat weight were measured. Serum levels of fasting glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), free fatty acids (FFA), insulin, and tumor necrosis factor-alpha (TNF-a) were determined. Hepatic histology was examined by H&E stain. Hepatic fibrosis was assessed by VG stain and immunohistochemical staining for transforming growth factor beta 1 (TGF-b1), and alpha-smooth-muscle actin (a-SMA). The liver weight and liver index increased from week 4, when hepatic steatosis was also observed. By week 8, the body weight and epididymal fat weight started increasing, which was associated with increased serum levels of FFA, cholesterol, and TNF-a, as well as development of simple fatty liver. The serum ALT level increased from week 12. Steatohepatitis occurred from weeks 12 through 48. Apparent hepatic perisinosodial fibrosis did not occur until week 24, and progressed from week 36 to 48 with insulin resistance. Therefore, this novel model may be potentially useful in NASH study.
QJM, 2011
We report a case of liver cancer with features consistent with fibrolamellar hepatocellular carci... more We report a case of liver cancer with features consistent with fibrolamellar hepatocellular carcinoma (FLHCC) detected by PET-CT scan. A 20-year-old female with a large liver tumor was diagnosed with 'malignant hepatic tumor' 2 years earlier and received five courses of transhepatic arterial chemoembolization (TACE) before she presented to our hospital with abdominal distension and mild pain at the right upper quadrant. Ultrasound and CT scan showed a large tumor in the right lobe of the liver. Contrast CT scan and 18 F-FDG PET-CT showed metastatic lesions in multiple organs. The imaging diagnosis was confirmed by an ultrasound-guided fine needle biopsy of the hepatic lesion which showed features of FLHCC. Immunohistochemical staining showed a marked increase in the expressions of Hepar, CD99, MIB1, proliferating cell nuclear antigen (PCNA), Fibronectin, E-cadherin and CK7. The recent knowledge on the FLHCC and the possible applications of PET-CT were discussed.