• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2019-2025
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• 2016

Hepatocellular carcinoma (HCC) is major health problem with high mortality rates, especially in patients with hepatitis B virus (HBV) infection. Telomerase function is one of common mechanisms affecting genome stability and cancer development. Recent studies demonstrated that genetic polymorphisms of telomerase associated genes such as telomerase associated protein 1 (TEP1) rs1713449 and PIN2/TERF1-interacting telomerase inhibitor 1 (PINX1) rs1469557 may be associated with risk of HCC and other cancers. In this study, 325 patients with HCC and 539 non-HCC groups [193 healthy controls, 80 patients with HBV-related liver cirrhosis (LC) and 266 patients with HBV-related chronic hepatitis (CH)] were enrolled to explore genetic polymorphisms of both SNPs using the allelic discrimination method based on MGB probe TaqMan real time PCR. We demonstrated that all genotypes of both genes were in Hardy-Wienberg equilibrium (P>0.05). Moreover, there was no significant association between rs1713449 genotypes and HCC risk, HCC progression and overall survival (P>0.05). Interestingly, we observed positive association of rs1469557 with risk of HCC when compared with the LC group under dominant (CC versus CT+TT, OR=1.89, 95% CI= 1.06-3.40, P=0.031) and allelic (C versus T alleles, OR=1.75, 95% CI=1.04-2.94, P=0.033) models, respectively. Moreover, overall survival of HCC patients with CC genotype of rs1469557 was significantly higher than non-CC genotype (Log-rank P=0.015). These findings suggest that PINX1 rs1469557 but not TEP1 rs1469557 might play a role in HCC progression in Thai patients with LC and be used as the prognosis marker to predict overall survival in HCC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4423-4426
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• 2012

Aim: XRCC1 and XPD are two major repair genes involved in nucleotide excision repair (NER), which is reported to be associated with risk of several cancers. We explored the association of XRCC1 and XPD polymorphisms with the risk of HCC. Methods: A total of 410 cases with HCC and 410 health controls were collected. XRCC1 Arg194Trp, XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Asn genotyping was performed by duplex polymerase-chain-reaction with the confronting-two-pair primer (PCR-CTPP) method. Results: XRCC1 194Trp/Trp was strongly significantly associated with an increased risk of HCC cancer when compared with the wide-type genotype (OR=2.26, 95% CI=(1.23-5.38). Individuals carrying the XRCC1 399Gln/Gln showed increased risk of HCC (OR=1.74, 95%CI=1.06-2.74). The XPD 751Gln/Gln and Gln allele genotype were associated with strong elevated susceptibility to HCC (OR=3.51 and 1.42, respectively). Conclusion: These results suggest that polymorphisms in XRCC1 and XPD may have functional significance in risk of HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.4103-4107
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• 2015

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Transarterial chemoembolisation (TACE) is the standardized therapy for intermediate stage HCC. However, the prognosis for HCC patients treated by TACE greatly varies. Thus, there is a critical need for finding biomarkers to predict the prognosis of HCC patients. The amino acid transporter-2 (ASCT2) is involved in tumorigenesis and progression of many malignancies. This study aimed to evaluate the predictive role of two single nuclear polymorphisms (SNPs, rs3826793 and rs2070246) in the ASCT2 gene in HCC patients treated by TACE. Materials and Methods: Two functional SNPs (rs3826793 and rs2070246) in the ASCT2 gene were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 448 unresectable Chinese HCC patients treated by TACE. Univariate and multivariate Cox proportional hazards models and Kaplan-Meier curves were used for the prognosis analyses. Results: There was no significant association between two SNPs (rs3826793 and rs2070246) in the ASCT2 gene and overall survival of TACE treated HCC patients. However, we demonstrated that patients with early stage HCC carrying T genotype in rs2070246 showed better OS than those carrying CC genotype (P=0.023). Conclusions: We demonstrated that patients with early stage HCC carrying T genotype in rs2070246 showed better OS than those carrying CC genotype.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6961-6967
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• 2014

Cytokine gene single nucleotide polymorphisms (SNPs) are involved in the genesis and progression of hepatocellular carcinoma (HCC). We hypothesized that combined effects of cytokine gene SNPs and SNP-SNP interactions are associated with HCC risk. Six SNPs in cytokine genes (IL-2, IFN-${\gamma}$, IL-$1{\beta}$, IL-6, and IL-10) were genotyped in a study of 720 Chinese HCC cases and 784 cancer-free controls. Although none of these SNPs individually had a significant effect on the risk of HCC, we found that the combined effects of these six SNPs may contribute to HCC risk (OR=1.821, 95% CI=1.078-3.075). This risk was pronounced among smokers, drinkers, and hepatitis B virus carriers. A SNP-SNP interaction between IL-2-330 and IFN-${\gamma}$-1615 was associated with an increased HCC risk (OR=1.078, 95% CI=1.022-1.136). In conclusion, combined effects of SNPs and SNP-SNP interactions in cytokine genes may contribute to HCC risk.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3663-3667
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• 2012

The hepatitis B virus (HBV) and the hepatitis C virus (HCV) are still public health problems in Yemen, with older individuals having much higher prevalence than younger generations. However, research on the prevalence of viral hepatitis in association with hepatocellular cancer (HCC) has not yet been undertaken in Yemen. The aim of this study was to determine the prevalence of HBV and HCV infection among HCC patients and to estimate the risk of these infections being associated with the development of HCC. A cross-sectional study was conducted on patients attending oncology outpatient in Sana'a, Yemen, through the period 2008-mid 2010 with confirmed diagnosis of HCC. A total of 88 cases were studied thoroughly with different investigations such as CT-scan, ultrasound, tumour marker, alpha-feto-protein and histopathological biopsy. A structured questionnaire was also applied and physical examination done to assess the general condition of the patients. Statistical package (SPSS version 16) was used for analysis of the data. The mean age of the cases was 61.2 years (${\pm}12.6$) with half over 60 years. There were fewer male patients (36%) compared to females and most (97%) only had basic /no formal education. Seventy nine (89%) were diagnosed as HCC cases with histopathological biopsy while the rest were diagnosed by ultrasound, CT scan, tumour marker, and alpha-feto-protein. Around one-third of the subjects were positive for HBsAg and HCV antibodies. Multivariate analysis showed infection with HCV and use of smoking was associated with HCC diagnosis. Although an association was observed between the occurrence of HCC and viral hepatitis (either HBV or HCV) and cigarette smoking, but the rate of viral infection was lower than what has been reported elsewhere.

• BMB Reports
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• v.51 no.2
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• pp.57-58
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• 2018

An accurate diagnostic marker for detecting early-stage hepatocellular carcinoma (eHCC) is clinically important, since early detection of HCC remarkably improves patient survival. From the integrative analysis of the transcriptome and clinicopathologic data of human multi-stage HCC tissues, we were able to identify barrier-to-autointegration factor 1 (BANF1), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) and splicing factor 3b subunit 4 (SF3B4) as early HCC biomarkers which could be detected in precancerous lesions of HCC, with superior capabilities to diagnose eHCC compared to the currently popular HCC diagnostic biomarkers: GPC3, GS, and HSP70. We then showed that SF3B4 knockdown caused G1/S cell cycle arrest by recovering $p27^{kip1}$ and simultaneously suppressing cyclins, and CDKs in liver cancer cells. Notably, we demonstrated that aberrant SF3B4 overexpression altered the progress of splicing progress of the tumor suppressor gene, kruppel like factor 4 (KLF4), and resulted in non-functional skipped exon transcripts. This contributes to liver tumorigenesis via transcriptional inactivation of $p27^{kip1}$ and simultaneous activation of Slug genes. Our results suggest that SF3B4 indicates early-stage HCC in precancerous lesions, and also functions as an early-stage driver in the development of liver cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5645-5650
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• 2013

Src homology 2 domain containing (SHC) is a proto-oncogene which mediates cell proliferation and carcinogenesis in human carcinomas. Here, the SHC SH2-domain binding protein 1 (SHCBP1) was first established to be up-regulated in human hepatocellular carcinoma (HCC) tissues by array-base comparative genome hybridization (aCGH). Meanwhile, we examine and verify it by quantitative real-time PCR and western blot. Our current data show that SHCBP1 was up-regulated in HCC tissues. Overexpression of SHCBP1 could significantly promote HCC cell proliferation, survival and colony formation in HCC cell lines. Furthermore, knockdown of SHCBP1 induced cell cycle delay and suppressed cell proliferation. Furthermore, SHCBP1 could regulate the expression of activate extracellular signal-regulated kinase 1/2 (ERK1/2) and cyclin D1. Together, our findings indicate that SHCBP1 may contribute to human hepatocellular carcinoma by promoting cell proliferation and may serve as a molecular target of cancer therapy.

• Korean Journal of Radiology
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• v.25 no.6
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• pp.550-558
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• 2024

Hepatocellular carcinoma (HCC) is a biologically heterogeneous tumor characterized by varying degrees of aggressiveness. The current treatment strategy for HCC is predominantly determined by the overall tumor burden, and does not address the diverse prognoses of patients with HCC owing to its heterogeneity. Therefore, the prognostication of HCC using imaging data is crucial for optimizing patient management. Although some radiologic features have been demonstrated to be indicative of the biologic behavior of HCC, traditional radiologic methods for HCC prognostication are based on visually-assessed prognostic findings, and are limited by subjectivity and inter-observer variability. Consequently, artificial intelligence has emerged as a promising method for image-based prognostication of HCC. Unlike traditional radiologic image analysis, artificial intelligence based on radiomics or deep learning utilizes numerous image-derived quantitative features, potentially offering an objective, detailed, and comprehensive analysis of the tumor phenotypes. Artificial intelligence, particularly radiomics has displayed potential in a variety of applications, including the prediction of microvascular invasion, recurrence risk after locoregional treatment, and response to systemic therapy. This review highlights the potential value of artificial intelligence in the prognostication of HCC as well as its limitations and future prospects.

• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.7.1-7.12
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• 2018

Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.

• BMB Reports
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• v.56 no.4
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• pp.225-233
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• 2023

Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal. Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo. However, the information provided by an multicelluar tumor spheroid (MCTS) model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases.