• Asian Pacific Journal of Cancer Prevention
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• v.15 no.12
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• pp.4969-4976
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• 2014

Background: miR-152 is involved in the genesis and development of several malignancies. However, its role in HCC has not been fully clarified. The aim of this study was to investigate the clinicopathological significance of miR-152 and its effect on the malignant phenotype of HCC cells. Methods: miR-152 expression was detected using real-time quantitative RT-PCR in 89 pairs of HCC formalin-fixed paraffin-embedded and their adjacent tissues. Functionally, in vitro effects and mechanisms of action of miR-152 on proliferation, viability, caspase activity, apoptosis and motility were explored in HepG2, HepB3 and SNU449 cells, as assessed by spectrophotometry, fluorimetry, fluorescence microscopy, wound-healing and Western blotting, respectively. Results: miR-152 expression in HCC was downregulated remarkably compared to that in adjacent hepatic tissues. miR-152 levels in groups of advanced clinical stage, larger tumor size and positive HBV infection, were significantly lower than in other groups. A miR-152 mimic could suppress cell growth, inhibit cell motility and increase caspase activity and apoptosis in HCC cell lines. Furthermore, Western blotting showed that the miR-152 mimic downregulated Wnt-1, DNMT1, ERK1/2, AKT and TNFRS6B signaling. Intriguingly, inverse correlation of TNFRF6B and miR-152 expression was found in HCC and bioinformatics confirmed that TNFRF6B might be a target of miR-152. Conclusions: Underexpression of miR-152 plays a vital role in hepatocarcinogenesis and lack of miR-152 is related to the progression of HCC through deregulation of cell proliferation, motility and apoptosis. miR-152 may act as a tumor suppressor miRNA by also targeting TNFRSF6B and is therefore a potential candidate biomarker for HCC diagnosis, prognosis and molecular therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.225-229
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• 2012

Background: Males have a higher prevalence of hepatocellular carcinoma (HCC) than females in general, but the reasons for the sex disparity are still obscure. DNA copy number alteration (CNA) is a major feature of solid tumors including HCC, but whether CNA plays a role in sex-related differences in HCC development has never been evaluated. Methods: High-resolution array comparative genomic hybridization (CGH) was used to examine 17 female and 46 male HCC patients with chronic hepatitis B virus (HBV) infection in Shanghai, China. Two-tailed Fisher's exact or ${\chi}^2$ tests was used to compare CNAs between females and males. Results: The overall frequencies and patterns of CNAs in female and male cases were similar. However, female HCC tumors presented more copy number gains compared to those in males on 1q21.3-q22 (76.5% vs. 37.0%, P = 0.009), 11q11 (35.3% vs. 0.0%, P = 0.0002) and 19q13.31-q13.32 (23.5% vs. 0.0%, P = 0.004), and loss on 16p11.2 (35.3% vs. 6.5%, P = 0.009). Relative to females, male cases had greater copy number loss on 11q11 (63.0% vs. 17.6%, P = 0.002). Further analyses showed that 11q11 gain correlated with 19q13.31-q13.32 gain (P = 0.042), 11q11 loss (P = 0.011) and 16p11.2 loss (P = 0.033), while 1q21.3-q22 gain correlated with 19q13.31-q13.32 gain (P = 0.046). Conclusions: These findings suggest that CNAs may play a role in sex-related differences in HBVassociated HCC development.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4443-4448
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• 2014

Background: A number of studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism with susceptibility to hepatocellular carcinoma (HCC). However, the results were inconsistent and inconclusive. The aim of this study was to comprehensively explore the association of XRCC1 Arg399Gln variant with HCC risk. Materials and Methods: Systematic searches of PubMed, Elsevier, Science Direct, CNKI and Chinese Biomedical Literature Database were performed. Pooled odds ratio (OR) with 95% confidence intervals (CI) was calculated to estimate the strength of association. Results: Overall, we observed an increased HCC risk among subjects carrying XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln genotypes (OR=1.20, 95%CI: 1.05-1.38, OR=1.16, 95%CI: 1.05-1.28, and OR=1.14, 95%CI: 1.04-1.24, respectively) based on 20 studies including 3374 cases and 4633 controls. In subgroup analysis, we observed an increased risk of XRCC1 codon 399 Gln/Gln, Arg/Gln and Gln/Gln+Arg/Gln polymorphisms for HCC in hospital-based study (OR=1.25, 95%CI: 1.03-1.51, OR=1.21, 95%CI: 1.07-1.36 and OR=1.18, 95%CI: 1.06-1.31, respectively) and in Asian population (OR=1.19, 95%CI: 1.03-1.38, OR=1.17, 95%CI: 1.04-1.30 and OR=1.14, 95%CI: 1.04-1.25, respectively). Limiting the analysis to the studies with controls in agreement with Hardy-Weinberg equilibrium (HWE), we observed an increased HCC risk among Gln/Gln, Arg/Gln and Gln/ Gln+Arg/Gln genotype carriers (OR=1.17, 95%CI: 1.05-1.29, OR=1.12, 95%CI: 1.00-1.25 and OR=1.11, 95%CI: 1.02-1.21, respectively). Conclusions: This updated meta-analysis results suggest that XRCC1 Arg399Gln variants may contribute to HCC risk. Well-designed studies with larger sample size were required to further verify our findings.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.4077-4082
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• 2016

Background: Hepatocellular carcinoma (HCC) is a dreadful complication of end stage liver disease with high morbidity and mortality. Aim: The aim was to assess the role of serum talin-1 and non-invasive fibrosis in patients with HCC. Materials and Methods: A total of eighty seven subjects were enrolled, with 22 two healthy individuals as a control group (n=22), 22 patients in the cirrhosis group and finally 43 in the group with HCC diagnosed with positive triphasic CT abdomen criteria. Serum talin-1 and noninvasive fibrosis parameters were assessed in all subjects. Results: Compared to the cirrhosis group, patients with HCC had higher serum talin-1 ($32.9{\pm}12.6$ vs. $11.1{\pm}2.79ng/ml$), FIB4 ($9.96{\pm}15.3$ vs. $2.90{\pm}1.87$) and $fibro-{\alpha}$ ($10.9{\pm}18.1$ vs. $1.55{\pm}0.28$) but not fibrosis index scores ($4.47{\pm}0.95$ vs. $4.98{\pm}0.96$; p=0.046). Patients with large focal lesions (${\geq}5cm$) had different ALBI scores ($-1.02{\pm}0.63$ vs. $-1.72{\pm}0.59$; p=0.001) serum talin-1 ($9.72{\pm}13.81$ vs. $28.6{\pm}38.89ng/ml$; p=0.007) and fibrosis index scores ($0.85{\pm}0.99$ vs. $4.20{\pm}4.85$; p=0.026). No statistical differences were noted between patients with and without portal vein thrombosis. For detection of HCC, serum talin-1 had 97.7% sensitivity and 100% specificity with a 17.2 ng/ml cutoff. AFP at a 13.7 ng/ml cutoff had 72.1% sensitivity and 6.3.6% specificity. The cutoff for the $fibro-{\alpha}$ score was 1.61 with 81.4% sensitivity and 77.3% specificity. Serum talin-1 (odds=1.08; C.I=1.016-1.150; p=0.014), fibrosis index score (odds=2.35; C.I=1.055-5.217; p=0.037) and the ALBI score (odds=6.9; C.I=1.924-24.708; p=0.003) were predictors of large focal lesions. Conclusions: Serum talin-1, AST/ALT ratio, $fibro-{\alpha}$ score are useful for the assessment of HCC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2383-2388
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• 2016

Background: The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) gene is a novel transformation suppressor gene linked to several malignancies. Objective: To analyze any association between RECK gene rs10814325 single-nucleotide polymorphism (SNP) and HCC susceptibility with various clinicopathological and laboratory data. Materials and Methods: RECK gene rs10814325 SNP was estimated, using real-time PCR, in 30 HCC patients on top of HCV infection, 30 HCV related cirrhotic patients and 30 healthy controls. Results: No special pattern of association could be detected on comparing the RECK gene rs10814325 genotypes(P=0.5), or alleles(P=0.49) among the studied groups. HCC patients with TT genotype had younger age (mean of $54.1{\pm}6.0$ years vs $60.6{\pm}10.2$ years for TC/CC genotypes, P=0.035). Abdominal distension was significantly greater in TT genotype patients (75% vs 30%for TC/CC genotypes, P=0.045). The TT genotype was present in 75% of patients with lymph node metastasis. Serum GGT levels were higher in TT genotype patients [80 (48.5-134.8) IU/L vs 40 (33-87.5) IU/L for TC/CCgenotypes], and lower limb edema was observed in 60% for TT vs 20% for TC/CCgenotypes, but both just failed to reach significance (p=0.05 and p=0.06 respectively). Conclusions: RECK gene rs10814325 T>C could not be considered a risk factor for HCC development on top of HCV, but may be related to the disease progression and metastasis.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.1649-1654
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• 2013

Objective: This work aimed to evaluate the safety and clinical efficacy of transcatheter arterial chemoembolization (TACE) combined with c-arm cone-beam CT guided synchronous radiofrequency ablation (RFA) in treatment of large hepatocellular carcinoma (HCC). Methods: 21 patients with large HCC were studied from January 2010 to March 2012. TACE combined with synchronous C-arm cone-beam CT guided RFA were performed on a total of 25 lesions. Conventional imaging examination (CEUS, enhanced CT or MRI) and AFP detection were regularly conducted to evaluate the technical success rate of combined treatment, complications, treatment response, time without disease recurrence and survival rate. Results: The technical success rate of combined treatment was 100%, without any significant complication. After 1 month, there were 19 cases with complete response and 2 cases with partial response, with an complete response rate of 90.4% (19/21) and a clinical effective rate of 100% (21/21). The complete response rates of single nodular lesions (100%, 17/17) was significantly higher than that of multiple nodular lesions (50%, 2/4) (P<0. 05). During 2 to 28 months of follow-up, in 19 cases with complete response, the average time without disease recurrence was $10.8{\pm}6$ months. The total survival rates of 6, 12 and 18 months in 21 patients were 100%, respectively. Conclusion: TACE combined with synchronous C-arm CT guided RFA is safe and effective for treatment of large HCC. The treatment efficacy for single nodular lesion is better than that for multiple nodular lesions.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2145-2150
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• 2016

Background: Infection with hepatitis B virus (HBV) is a major global public health problem, with a wide spectrum of clinical manifestations. Human cytosolic glutathione-S-transferases (GSTs) include several classes such as alpha (A), mu (M), pi (P), sigma (S), zeta (Z), omega (O) and theta (T). The present study aimed to investigate the role of GST omega genes (GSTO1 and GSTO2) in different groups of patients infected with HBV. Materials and Methods: HBV groups were classified according to clinical history, serological tests and histological analysis into normal carriers (N), acute (A), chronic (CH), cirrhosis (CI) and hepatocellular carcinoma (HCC) cases. The study focused on determination of the genotypes of GST omega genes (GSTO1 and GSTO2) and GST activity and liver function tests. Results: The results showed that GSTO1 (A/A) was decreased in N, A, CH, CI and HCC groups compared to the C-group, while, GSTO1 (C/A) and GSTO1(C/C) genotypes were increased significantly in N, A, CH, CI and HCC groups. GSTO2 (A/A) was decreased in all studied groups as compared to the C-group but GSTO2(A/G) and GSTO2(G/G) genotypes were increased significantly. In addition, GST activities, albumin and TP levels were decreased in all studied groups compared to the C-group, while the activities of transaminases were increased to differing degrees. Conclusions: The results indicate that GSTO genetic polymorphisms may be considered as biomarkers for determining and predicting the progression of HBV infection.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10917-10922
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• 2015

Background: This study was conducted to determine DEPDC1 expression in hepatocelluar carcinomas (HCCs) and to reveal its potential role in diagnosis and prognosis of affected patients. Materials and Methods: DEPDC1 expression at the mRNA level was detected by quantitative real-time PCR (qRT-PCR) in 205 cases of HCC and paired adjacent normal liver tissues, and by semi-quantitative RT-PCR in 20 cases. Survival curves were obtained by using Kaplan-Meier method and Log-rank test. Independent predictors associated with regard to disease free survival (DFS) and overall survival (OS) were identified using the Cox proportional hazard model. Results: High DEPDC1 mRNA levels were detected in 144 out of 205 cases (70.24%) of HCC, significantly associated with clinicopathological parameters, including tumor size (${\geq}4cm$), alpha-fetoprotein (${\geq}100ng/ml$), B-C of BCLC stage and recurrence. Kaplan-Meier survival analysis revealed that HCC patients with high DEPDC1 expression had poor OS and DFS. Multivariate analysis demonstrated that high DEPDC1 expression was an independent predictor for OS (HR=1.651; 95% 95%CI, 1.041-2.617; p=0.033) and DFS (HR=1.583; 95%CI, 1.01-2.483; p=0.045). Conclusions: Our results indicate DEPDC1 might be a novel diagnostic marker and an independent prognostic predictor for HCC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.747-752
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• 2013

Oncostatin M (OSM) is a multifunctional cellular regulator acting on a wide variety of cells, which has potential roles in the regulation of gene activation, cell survival, proliferation and differentiation. Previous studies have shown that OSM can induce morphological and/or functional differentiation and maturation of many tumor cells. However, the action of OSM on the induction of differentiation of human hepatocellular carcinoma (HCC) has not been reported. Here, we investigated the effects of different concentrations of OSM on human HCC cell line SMMC-7721 growth, proliferation, cell cycling, apoptosis and differentiation in vitro. Cell growth was determined via MTT assay, proliferation by cell cycle analysis, apoptosis by flow cytometry, morphology by transmission electronic microscopy, and cell function by detection of biochemical markers. Our results demonstrated that OSM strongly inhibited the growth of SMMC-7721 cells in a dose-dependent manner, associated with decreased clonogenicity. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. The apotosis rate was increased after OSM treatment compared to the control. These changes were associated with striking changes in cellular morphology, toward a more mature hepatic phenotype, accompanied by significant reduction of the expression of AFP and specific activity of ${\gamma}$-GT, with remarkable increase in secretion of albumin and ALP activity. Taken together, our findings indicate that OSM could induce the differentiation and reduce cell viability of SMMC-7721 cells, suggesting that differentiation therapy with OSM offers the opportunity for therapeutic intervention in HCC.

• BMB Reports
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• v.54 no.12
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• pp.614-619
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• 2021

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC), which is a highly aggressive cancer. HBV X protein (HBx), one of four HBV gene products, plays pivotal roles in the development and metastasis of HCC. It has been reported that HBx induces liver cancer cell migration and reorganizes actin cytoskeleton, however the molecular basis for actin cytoskeleton reorganization remains obscure. In this study, we for the first time report that HBx promotes actin polymerization and liver cancer cell migration by regulating calcium modulated protein, calmodulin (CaM). HBx physically interacts with CaM to control the level of phosphorylated cofilin, an actin depolymerizing factor. Mechanistically, HBx interacts with CaM, liberates Hsp90 from its inhibitory partner CaM, and increases the activity of Hsp90, thus activating LIMK1/cofilin pathway. Interestingly, the interaction between HBx and CaM is calcium-dependent and requires the CaM binding motif on HBx. These results indicate that HBx modulates CaM which plays a regulatory role in Hsp90/LIMK1/cofilin pathway of actin reorganization, suggesting a new mechanism of HBV-induced HCC metastasis specifically derived by HBx.