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author:("Liu, zhimu")
1.  The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma 
In spite of progress in diagnostics and treatment of Hepatocellular Carcinoma (HCC), its prognosis remains poor, and improved treatment strategies for HCC require detailed understanding of the underlying mechanism. In this investigation we studied the role of Up-frameshift 1 (UPF1) in the tumorigenesis of HCC.
We determined the expression level of UPF1 in HCC tissues with quantitative real-time PCR and western blotting and then studied its clinical significance. Sodium bisulfite sequencing was used to investigate the regulation of UPF1. We explored the biological significance of UPF1 with gain-and-loss-of-function analyses both in vitro and in vivo. The relationship between UPF1 and SMAD7 was also investigated by western blotting and immunofluorescence.
A great downregulation of UPF1 due to promoter hypermethylation was observed in tumor tissues compared to their adjacent normal tissues. Meanwhile, patients with low UPF1 expression have significantly poorer prognosis than those with high expression. Functionally, UPF1 regulated HCC tumorigenesis both in vitro and in vivo. Moreover, the decreased UPF1 level in HCC reduces NMD efficiency and leads to up-regulation of Smad7, then affects the TGF-β pathway.
Our findings revealed that UPF1 is a potential tumor suppressive gene and may be a potential therapeutic target for HCC.
PMCID: PMC4711019  PMID: 26759305
Hepatocellular carcinoma; UPF1; Smad7; Hypermethylation
2.  Decreased expression of long non-coding RNA GAS5 indicates a poor prognosis and promotes cell proliferation and invasion in hepatocellular carcinoma by regulating vimentin 
Molecular Medicine Reports  2015;13(2):1541-1550.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are key in carcinogenesis. The aim of the present study was to investigate the role of lncRNA GAS5 in HCC tissues and to define the role of growth arrest-specific 5 (GAS5) in the regulation of hepatoma cell proliferation, invasion and apoptosis. Quantitative polymerase chain reaction and in situ hybridization were performed to investigate the expression of GAS5 in tumor tissues and corresponding adjacent tissues from 50 patients with HCC. Low expression of GAS5 was significantly correlated with differentiation (P<0.010) and portal vein tumor thrombosis (P=0.001). Multivariate analysis indicated that GAS5 expression was an independent predictor for overall survival (P=0.017). Further experiments demonstrated that overexpression of GAS5 significantly suppressed the proliferation and invasion of hepatoma cells in vitro. Overexpression of GAS5 significantly promoted the apoptosis of hepatoma cells. In addition, it was demonstrated that GAS5 negatively regulates vimentin expression in vitro and in vivo. Notably, vimentin knockdown promoted GAS5-pcDNA3.1-inhibition of hepatoma cell proliferation. In conclusion, the present study suggests an important role of GAS5 in the molecular etiology of HCC and suggests the potential application of GAS5 in HCC therapy.
PMCID: PMC4732840  PMID: 26707238
long noncoding RNA; growth arrest-specific 5; proliferation; hepatocellular carcinoma
3.  The association between three IL-6 polymorphisms and HBV-related liver diseases: a meta-analysis 
Background: A quantity of case-control studies have been performed to address the association between the three interleukin-6 (IL-6) polymorphisms (-572G/C, -597G/A and -174G/C) and the risk of HBV related liver diseases. However, previous research results are inconsistent. We conducted this meta-analysis to clarify the correlation between these IL-6 polymorphisms and HBV related liver diseases. Methods: We searched in PubMed, EMBASE, Cochrane Library as well as Chinese databases including China National Knowledge Infrastructure (CNKI) and WanFang database for all the relevant studies up to April 15, 2015. The data were extracted by two independent authors. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated. Results: A total of 10 studies consisting of 3879 cases and 2812 controls were included in this metaanalysis. For IL-6 polymorphism -572G/C, an association with increased chronic hepatitis B (CHB) risk was observed under in allelic, homozygous, heterozygous, dominant and recessive model. However, IL-6 polymorphisms (-572G/C) were not related to Inactive Carrier (IC), Liver Cirrhosis (LC) and Hepatocellular Carcinoma (HCC) risk in this study. We also found that IL-6 polymorphisms (-597G/A) were related to CHB in allelic, heterozygous, recessive model. For IL-6 polymorphism -174G/C, we did not find any association with CHB risk. Conclusion: The present meta-analysis indicated that IL-6 polymorphisms -572G/C and -597G/A significantly associate with CHB risk, but might not be significantly related to the progressive HBV such as LC and HCC. IL-6 polymorphisms -174G/C might not significantly associate with HBV related liver diseases.
PMCID: PMC4694194  PMID: 26770294
Interleukin-6; polymorphisms; hepatitis B virus; liver diseases; meta-analysis
4.  The Plasma S-adenosylmethionine Level is Associated With the Severity of Hepatitis B-Related Liver Disease 
Medicine  2015;94(4):e489.
Alterations in methionine metabolism that involve changes in the plasma S-adenosylmethionine (SAMe) level occur in chronic liver diseases. However, no evidence is available on whether circulating SAMe is involved in the development of liver cirrhosis and liver cancer.
Cross-sectional data on clinical characteristics and plasma SAMe were collected for 130 cases of chronic hepatitis B (CHB) and HCC as well as for normal volunteers. Univariate and multivariate linear regression and receiver operating characteristic curves were introduced to determine their correlations.
Serum ALB and PT levels were independent clinical factors that were correlated with the plasma SAMe levels in CHB and HCC patients. A higher SAMe concentration was observed in the HCC than in the normal and CHB. By exploring the association of the Child–Pugh score with the plasma SAMe level, we found a higher SAMe level at advanced Stage C than at stage A in CHB and HCC patients. We further assessed the diagnostic performance of SAMe with respect to the stages of liver fibrosis and Child–Pugh stage. The AUROC of SAMe for the prediction of cirrhosis was 0.721, and the sensitivity and specificity was 0.707 and 0.769, respectively. The AUROC of plasma SAMe to predict Child–Pugh stage C was 0.706 in patients with CHB and 0.825 in HCC patients. The sensitivity was 0.467 and 0.800, respectively; the specificity was 0.904 and 0.781, respectively.
The plasma SAMe level was positively correlated with the severity of liver disease and might be a potential noninvasive biomarker.
PMCID: PMC4602946  PMID: 25634198
5.  hSulf-1 inhibits cell proliferation and migration and promotes apoptosis by suppressing stat3 signaling in hepatocellular carcinoma 
Oncology Letters  2014;7(4):963-969.
Human sulfatase-1 (hSulf-1) has been shown to desulfate cellular heparin sulfate proteoglycans and modulate several growth factors and cytokines. However, hSulf-1 has not been previously shown to mediate the signal transducer and activator of transcription 3 (stat3) signaling pathway, which is known to regulate cell proliferation, motility and apoptosis. The present study investigated the role of hSulf-1 in stat3 signaling in hepatocellular cancer. hSulf-1 expression vector and stat3 small interfering RNA (siRNA) were constructed to control the expression of hSulf-1 and stat3 in HepG2 cells. hSulf-1 was found to inhibit the phosphorylation of stat3 and downregulate its targeted protein. MTT and Transwell chamber assays, as well as Annexin V/propidium iodide double-staining methods, were used to examine the effects of hSulf-1 on stat3-mediated motility, proliferation and apoptosis in HepG2 cells. Transfection with hSulf-1 cDNA and/or stat3 siRNA inhibited cell proliferation and motility, concurrent with G0/G1 and G2/M phase cell cycle arrest and apoptosis. Overall, the results of the current study suggested that hSulf-1 functions as a negative regulator of proliferation and migration and as a positive regulator of apoptosis in hepatocellular carcinoma, at least partly via the downregulation of stat3 signaling.
PMCID: PMC3961425  PMID: 24944651
human sulfatase-1; hepatocellular carcinoma; stat3 signaling
6.  Rather than Rs1800796 Polymorphism, Expression of Interleukin-6 is Associated with Disease Progression of Chronic HBV Infection in a Chinese Han Population 
Disease Markers  2013;35(6):799-805.
Interleukin-6 plays an important role in chronic inflammation as well as tumor growth and progression. Here, a case-control study was undertaken to investigate the association of rs1800796 polymorphism of IL-6 gene and serum levels with disease progression of chronic HBV infection. Rs1800796 polymorphism was genotyped in 641 Chinese Han patients with chronic HBV infection, including 23 IT, 25 IC, 292 CHB, 153 LC, and 148 HCC patients and 265 healthy controls. Serum IL-6 levels were measured in 23 IT, 25 IC, 47 CHB, 41 LC, and 49 HCC patients and 45 healthy controls, and the classifications of HCC were accorded to BCLC staging system. We found no significant association between rs1800796 polymorphism and disease progression of chronic HBV infection; however, serum IL-6 levels showed significant statistical differences between patients with CHB, LC, and HCC. Moreover, statistical differences can be observed in patients with terminal stage HCC compared with those of early to intermediate or advanced stage HCC. Our findings suggest that rs1800796 polymorphism unlikely contribute significantly to affect the progression of chronic HBV infection, and serum IL-6 levels can act as a useful indicator for disease progression and severity of chronic HBV infection.
PMCID: PMC3858883  PMID: 24371367
7.  Posterior mediastinal tuberculous lymphadenitis with dysphagia as the main symptom: a case report and literature review 
Journal of Thoracic Disease  2013;5(5):E189-E194.
Mediastinal tuberculous lymphadenitis (MTL) is mostly seen in primary tuberculosis in children, uncommon observed in adults. It usually presents the toxic symptoms of tuberculosis but rarely with symptoms characteristic of esophageal compression, such as dysphagia. Such patients can easily be misdiagnosed as esophageal neoplasm and get delayed or faulty treatment.
Case report
A 32-year-old man presented with dull chest pain of one month and dysphagia of five days. CRP was elevated, and a skin test was strongly positive. At upper endoscopy, a protruding lesion covered by normal mucosa was seen at 26 cm from the upper incisor. Barium swallow showed visible external compressive stricture on the middle-lower esophagus with normal mucosal pattern. Chest computed tomography (CT) scan showed a subcarinal mass adjacent to the esophageal wall in posterior mediastinum. An endoscopic ultrasonography (EUS) revealed a hypoechoic lesion suspected of esophageal stromal tumor in the fourth layer. A tissue was obtained by ultrasound-guided fine-needle aspiration (EUS-FNA), but cytopathology, bacilliculture and PCR test had no special findings. The patient required experimental antitubercular treatment and the protruding lesion shrank gradually during therapy period.
MTL could not be ignored in the differential diagnosis of posterior mediastinal mass with dysphagia. Analyzing and evaluating test results comprehensively is the key to make correct diagnosis and timely treatment. The experimental antituberculous treatment should be used if MTL is highly suspected.
PMCID: PMC3815737  PMID: 24255790
Mediastinal; tuberculous lymphadenitis; dysphagia
8.  Skull base metastases from a malignant solitary fibrous tumor of the liver. A case report and literature review 
Diagnostic Pathology  2011;6:127.
Solitary fibrous tumors (SFTs) of the liver are rarely described; only 38 cases have been reported in literature, most of which have shown benign clinical characteristics, and only 3 of these cases exhibited malignant variants. In this study, we present a 24-year-old woman with a 1-month history of a rapidly enlarging abdominal mass and a CT showing an exophytic heterogeneous liver mass with a firm parietal bone mass. The patient underwent a transcatheter arterial chemoembolization (TACE) before operation, and an extended right hepatectomy and craniectomy with a negative margin was performed under general anesthesia. The masses showed histological features of oval spindle cells haphazardly arranged in the classic short-storiform or so-called patternless pattern of solitary fibrous tumors. The tumor cells showed positive immunohistochemical reactions to CD34 and bcl-2. The tumor recurred in the residual liver 2 months after operation, metastatic osteoblastic lesions in the thoracic and lumbar vertebrae were identified 3 months after the operation, and lumbar vertebrae metastasis 7 months after operation paralyzed the patient. The patient underwent percutaneous ethanol injection therapy (PEI) and chemotherapy, but the patient died because of the uncontrolled tumor 16 months after the initial operation. To our knowledge, this is the first case of malignant solitary fibrous liver tumors with skeletal metastasis.
PMCID: PMC3260251  PMID: 22192457
Solitary fibrous tumor; Liver
9.  The X Protein of Hepatitis B Virus Inhibits Apoptosis in Hepatoma Cells through Enhancing the Methionine Adenosyltransferase 2A Gene Expression and Reducing S-Adenosylmethionine Production* 
The Journal of Biological Chemistry  2011;286(19):17168-17180.
The X protein (HBx) of hepatitis B virus (HBV) is involved in the development of hepatocellular carcinoma (HCC), and methionine adenosyltransferase 2A (MAT2A) promotes the growth of liver cancer cells through altering S-adenosylmethionine homeostasis. Thus, we speculated that a link between HBx and MAT2A may contribute to HCC development. In this study, the effects of HBx on MAT2A expression and cell apoptosis were investigated, and the molecular mechanism by which HBx and MAT2A regulate tumorigenesis was evaluated. Results from immunohistochemistry analyses of 37 pairs of HBV-associated liver cancer tissues/corresponding peritumor tissues showed that HBx and MAT2A are highly expressed in most liver tumor tissues. Our in vitro results revealed that HBx activates MAT2A expression in a dose-dependent manner in hepatoma cells, and such regulation requires the cis-regulatory elements NF-κB and CREB on the MAT2A gene promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) further demonstrated that HBx facilitates the binding of NF-κB and CREB to MAT2A gene promoter. In addition, overexpression of HBx or MAT2A inhibits cell apoptosis, whereas knockdown of MAT2A expression stimulates apoptosis in hepatoma cells. Furthermore, we demonstrated that HBx reduces MAT1A expression and AdoMet production but enhances MAT2β expression. Thus, we proposed that HBx activates MAT2A expression through NF-κB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. These findings should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC.
PMCID: PMC3089560  PMID: 21247894
Apoptosis; Cancer Tumor Promoter; Chromatin Immunoprecipitation (ChiP); CREB; DNA-Protein Interaction; DNA Viruses; Gene Regulation; Hepatitis Virus; Oncogene; S-Adenosylmethionine (AdoMet)

Results 1-9 (9)