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BackgroudAt present, there is no definitive conclusion about the relative prognostic factors on intrahepatic cholangiocarcinoma perihilar large duct type (iCCAphl) and iCCA peripheral small duct type (iCCApps).Aim of the studyTo compare the prognoses of two different types of iCCA, and identify the independent risk factors affecting the long-term survival of patients undergoing radical resection for iCCA.MethodsThis study included 89 patients with iCCA who underwent radical resection at the Department of Hepatobiliary Surgery of the East Yard of the Shandong Provincial Hospital between January 2013 and March 2022. According to the tumor origin, these patients were divided into the iCCAphl group (n = 37) and iCCApps group (n = 52). The prognoses of the two groups were compared using Kaplan–Meier analysis, whereas the independent risk factors of their prognoses were identified using Cox univariate and multivariate regression analyses.ResultsIn the iCCApps group, the independent risk factors for overall survival included diabetes history (p = 0.006), lymph node metastasis (p = 0.040), and preoperative carbohydrate antigen 19-9 (p = 0.035). In the iCCAphl group, the independent risk factors for overall survival included multiple tumors (p = 0.010), tumor differentiation grade (p = 0.008), and preoperative jaundice (p = 0.009).ConclusionsAmong the iCCA patients who underwent radical resection, the long-term prognosis of iCCApps maybe better than that of iCCAphl. The prognoses of these two types of iCCA were affected by different independent risk factors.

Objective: The aim of this study was to investigate the role of matrix metallopeptidase 12 (MMP-12) in the development of hepatocellular carcinoma (HCC). Materials and Methods: A total of 343 HCC p...

Ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in several human cancer cells, but a role in cholangiocarcinoma (CAA) progression has not been investigated. We analyzed the expression of UBE2T in CAA tissues. Then, we generated UBE2T deregulation models in which it was overexpressed or silenced, and examined the effects on CAA malignant progression by flow cytometry, western blot, MTT assay, wound healing assay and transwell assay. We report the involvement of UBE2T in CAA malignant progression. UBE2T was found to be highly expressed in human CAA cells both in vitro and in vivo. Overexpression of UBE2T significantly enhanced epithelial-to-mesenchymal transition, proliferation, migration and invasion of CAA cells in vitro, while silencing UBE2T had opposing effects. Furthermore, UBE2T appears to exert its effects via the mammalian target of rapamycin (mTOR) pathway as the cellular effects caused by UBE2T overexpression are inhibited by the mTOR inhibitor rapamycin. Our findings suggest that UBE2T may have potential as a new therapeutic target for the prevention or treatment of CAA.

Determining an effective biomarker for predicting the prognosis of patients with hepatocellular carcinoma (HCC) may improve patient survival rates. The present study aimed to investigate the expression of glucose transporter 3 (GLUT-3) in HCC and to determine its predictive value for the survival of patients with HCC. Immunohistochemistry was used to detect GLUT-3 expression in HCC tissues of 275 and 140 patients with HCC from training and validation cohorts, respectively. The association between GLUT-3 expression and the clinicopathological characteristics of patients with HCC, and between GLUT-3 expression and patient survival rates were analyzed. The predictive value of GLUT-3 expression was confirmed using the validation cohort. The results demonstrated that the high GLUT-3 expression in HCC tissues was significantly associated with elevated α-fetoprotein level, large tumor size, poor histological differentiation and Tumor-Node-Metastasis stages III and IV (P

BACKGROUND We explored the relationship of interferon-γ (IFN-γ) and MHC class-I chain related gene A (MICA) genes polymorphisms with hepatocellular carcinoma (HCC) risk, and tried to determine whether the interaction existed between these two genes polymorphisms on the basis of HCC. MATERIAL AND METHODS Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the genotypes of the 3 single-nucleotide polymorphisms (SNPs) and to analyze the correlation of each SNP with HCC susceptibility in 120 HCC patients and 124 healthy people. The association strength between the 3 SNPs and HCC is represented with odds ratio (OR) and 95% confidence interval (95% CI). Hardy-Weinberg equilibrium (HWE) was tested by χ2 test in the control group. RESULTS GG genotype of IFN-γ rs2069727 polymorphism had apparently different distributions in case and control groups (P

Insulin-like growth factor-1 (IGF-1), a small polypeptide hormone similar to insulin in protein structures, has been identified as an activator of epithelial-mesenchymal transition (EMT) pathways in several types of cancers. As a member of the inhibitor of apoptosis protein (IAP) family, survivin is implicated in the EMT of some cancers. However, the role of survivin on IGF-1-mediated EMT of hepatocellular carcinoma (HCC) has not been clarified. In the present study, we demonstrated that survivin was involved in the EMT process induced by IGF-1 in HCC cell line SMMC7721. With administration of different concentrations of IGF-1, survivin mRNA and protein expression were significantly increased and stimulated EMT in the tested cell line, while the increased invasive and migratory abilities of HCC cells and activation of the EMT process induced by IGF-1 were reversed after silencing of survivin expression by transfecting small interfering RNA. This was further confirmed by the observation of morphological changes, the decrease of invasive and migratory abilities and the downregulation of EMT markers, N-cadherin, vimentin and Snail, and the upregulation of E-cadherin. In conclusion, survivin may play a vital role in the IGF-1 signaling pathway by mediating EMT in HCC through the upregulation of the expression of EMT markers, and the knockdown of survivin expression may suppress the metastasis of HCC, which may provide new insights for the molecular therapy of HCC patients in clinical treatment.

Background/Aims: miR-448 has been reported to exhibit abnormal expression in hepatocellular carcinoma (HCC), however, the essential role of miR-448 in HCC progression is still unclear. Methods: real-time PCR was used to detect the expression of miRNAs and candidate genes in HCC samples (n=117). miR-448 mimics and inhibitor were tansfected in human HCC cells. The transwell assay was used to examine the cell invasive ability. The regulation mechanism was confirmed by luciferase reporter assay. The markers of EMT were detected by using Western blot. Results: miR-448 was decreased in HCC samples and associated with HCC development. Inhibition of miR-448 significantly promoted cell invasion, while the effect of miR-448 up-regulation was reverse. miR-448 could regulate ROCK2 in hepatocellular carcinoma. Knockdown of ROCK2 expression partially reversed the effect of miR-448 inhibitor. Abnormal expression of miR-448 could regulate the markers of epithelial-mesenchymal transition (EMT). Conclusions: miR-448 may contribute to the progression of HCC via regulating ROCK2 expression.

Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways. Metformin upregulated the expression of p21Waf1 and p27kip1, and downregulated the expression of cyclin D1, a key protein required for cell cycle progression. The combination of gemcitabine and cisplatin inhibited the proliferation and induced the apoptosis of human cholangiocarcinoma cells by inducing the phosphorylation of AMPK, downregulating cyclin D1, and activating caspase-3. Administration of metformin enhanced the efficacy of gemcitabine and cisplatin to suppress the growth of cholangiocarcinoma tumors established in experimental models by inhibiting cell proliferation and inducing cell apoptosis through their effects on AMPK, cyclin D1 and caspase-3. Given that metformin has been used to treat type 2 diabetes patients for over half a century due to its superior safety profile, the results presented here indicate that metformin may be a potent agent for enhancing the efficacy of gemcitabine and cisplatin in the treatment of cholangiocarcinoma.

Background CCAT1 has been reported to be linked with pathogenesis of malignancies including colon cancer and gastric cancer. However, the regulatory effect of CCAT1 in hepatocellular carcinoma (HCC) remains unclear. The purpose of this research was to identify any role of CCAT1 in the progression of HCC. Materials and methods Real time-PCR was performed to test the relative expression of CCAT1 in HCC tissues. A computation screen of CCAT1 promoter was conducted to search for transcription-factor-binding sites. The association of c-Myc with CCAT1 promoter in vivo was tested by Pearson correlation analysis and chromatin immunoprecipitation assay. Additionally, Kaplan-Meier analysis and Cox proportional hazards analyses were performed. Results c-Myc directly binds to the E-box element in the promoter region of CCAT, and when ectopically expressed increases promoter activity and expression of CCAT1. Moreover, Kaplan-Meier analysis demonstrated that the patients with low expression of CCAT1 demonstrated better overall and relapse-free survival compared with the high expression group. Cox proportional hazards analyses showed that CCAT1 expression was an independent prognostic factor for HCC patients. Conclusions The findings demonstrated CCAT1, acting as a potential biomarker in predicting the prognosis of HCC, is regulated by c-Myc.

Hepatocellular carcinoma (HCC) is a prototype of liver cancer, which is closely related to manifested metabolism of lip and glucose. Upstream transcription factor 1 (USF1) is an important transcription factor in human genome, and it regulates the expression of multiple genes associated with lipid and glucose metabolism. This study aims at investigating the correlation between seven common USF1 polymorphisms (i.e., -1994 G>A, -202 G>A, 7998 A>G, -844 C>T, 9042 C>G, 9441 T>C, and -2083 G>A) and the risk of HCC. Elucidation of the interaction might be of vital importance to the diagnosis and prognosis of HCC. One hundred and fifty-five HCC patients and 160 healthy controls from a Chinese Han population were involved in this study. Tag single-nucleotide polymorphisms (SNPs) were identified with reference to CBI-dbSNP and HapMap databases. DNA was extracted from blood samples, and matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was conducted to determine the polymorphisms of USF1. Odds ratio (OR) and 95% confidence interval were applied to evaluate the difference of genotype distribution. Seven SNPs were selected to be representatives. No significant difference was observed concerning -1994 G>A, 7998 A>G, 9042 C>G, 9441 T>C, and -2083 G>A polymorphisms (all P > 0.05). A significantly elevated genotype frequency regarding -202 G>A polymorphism was observed in HCC patients [AA vs. GG: OR 2.13 (1.13-4.01), P = 0.019; AA vs. GG+GA: OR 2.22 (1.32-3.75), P = 0.003; A allele vs. G allele: OR 1.46 (1.07-2.01), P = 0.018]. Subjects carrying mutant -844 C>T genotypes also had a higher risk of HCC [CT vs. CC: OR 1.88 (1.17-3.04), P = 0.009; CT+TT vs. CC: OR 1.83 (1.17-2.86), P = 0.008; T allele vs. C allele: OR 1.49 (1.06-2.09), P = 0.020]. Further studies are recommended to validate our findings in different ethnicity and to clarify the functional relationship between USF1 polymorphisms and the susceptibility of HCC.

Hepatocellular carcinoma is a lethal malignancy with poor prognosis, partially due to tumor metastasis, recurrence and resistance to chemo- or radio-therapy. Cisplatin can inhibit cancer cell DNA replication, and is widely used in the clinical treatment of tumors. The present study aimed to generate eukaryotic expression vectors for Livin shRNA and to examine the effects of Livin shRNA on the chemosensitivity of HepG2 hepatocellular carcinoma cells. Eukaryotic expression vectors for Livin shRNA (pSD11-U6/Neo/GFP/Livin) were designed and constructed. The HepG2 hepatocellular carcinoma cell line was transfected with this vector using the liposome method. The expression levels of Livin mRNA and protein were measured by quantitative polymerase chain reaction and western blot analysis. The rate of cell growth inhibition was measured using MTT assay following treatment of the cells with cisplatin (2.0 mg/l). DNA sequencing confirmed that the construction of the eukaryotic expression vector for Livin shRNA had been successful. Transfection of these vectors into HepG2 cells led to a significant reduction in the expression levels of Livin mRNA and protein (P

Aims and Background Hepatocellular carcinoma (HCC) is a dismal malignancy associated with multiple molecular changes. The purpose of this study was to identify the differentially expressed genes and analyze the biological processes related to HCC. Methods and Study Design Datasets of HCC were obtained from the NCBI Gene Expression Omnibus. Integrated analysis of differentially expressed genes was performed using the INMEX program. Then Gene Ontology enrichment analyses and pathway analysis were performed based on the Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction network was constructed using the Cytoscape software; the netwerk served to find hub genes for HCC. Real-time RT-PCR was used to validate the microarray data for hub genes. Results We identified 273 genes that were differentially expressed in HCC. Gene Ontology enrichment analyses revealed response to cadmium ion, cellular response to cadmium ion, and cellular response to zinc ion for these genes. Pathway analysis showed that significant pathways included fatty acid metabolism, butanoate metabolism, and PPAR signaling pathway. The protein-protein interaction network indicated that CDH1, ECHS1, ACAA1, MT2A, and MYC were important genes which participated in many interactions. Experimental validation of the role of four upregulated genes ( ECHS1, ACAA1, MT2A and MYC) in the progression of HCC was carried out. Conclusions Our study displayed genes that were consistently differentially expressed in HCC. The biological pathways and protein-protein interaction networks associated with those genes were also identified. We predicted that CDH1, ECHS1, ACAA1, MT2A, and MYC might be target genes for diagnosing HCC.