DigitalUM :: Browsing by Subject "Hepatocellular carcinoma"

Browsing by Subject "Hepatocellular carcinoma"

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Open Access
Aberrant expression of a fetal glycoprotein 68 in hepatocellular carcinoma: a comparative study on the expression of alpha-fetoprotein and carcinoembryonic antigen
(Murcia : F. Hernández, 2004) Kato, Massuo J.; Shinozawa, T.; Kato, S.; Terada, T.
A rat IgG2a monoclonal antibody against a stage-specific fetal glycoprotein with a molecular mass of 68 kDa (FGP68) was produced and applied to paraffin sections. This monoclonal antibody was used to compare the expression of FGP68 with that of both alphafetoprotein (AFP) and carcinoembryonic antigen (CEA) in 75 hepatocellular carcinomas (HCCs). Seventy-five primary HCCs from patients aged 36 to 77 years were examined. Formalin-fixed, paraffin-embedded tissue sections were used for immunohistochemical analyses. Histologically, 6 cases of HCC were classified as type I according to the Edmondson and Steiner criteria, 57 cases as type II, and 12 cases as type III. The cancer tissues showed positive reactions with the antibody against FGP68. Approximately one-third of the HCCs (26/75) contained tumor cells that expressed FGP68 - (21/57 for Edmondson and Steiner type II; 4/12 for type III; and 1/6 for type I) - and positive immunoreactivity was observed in the cytoplasm of the cancer cells. Twenty-five of the 75 HCCs had tumor cells that expressed AFP and there was a significant correlation between FGP68 expression and AFP expression. Twenty-three of the 75 HCCs had tumor cells that expressed CEA and there was no significant correlation between FGP68 expression and CEA expression. No positive reactions for FGP68, AFP and CEA were observed in samples of non-neoplastic liver tissues. Based on the possibility that stage-specific FGP68 plays an important role in liver embryogenesis, FGP68- expressing tumor cells might ontogenetically revert to more primitive cells.
Open Access
Alteration of cell cycle-related genes in hepatocarcinogenesis
(Murcia : F. Hernández, 1997) Nishida, N.; Fukuda, Y.; Ishizaki, K.; Nakao, K.
The mammalian cell cycle is controlled by regulators of the G1 to S transition such as tumor suppressor proteins, p53 and retinoblastoma (RB); cyclin D1 and cyclin-dependent kinase 4; and inhibitor of cyclin dependent kinase, Recently, aberrations of these cell cycle-related genes have been reported to contribute to the formation and development of cancer. In human hepatocellular carcinoma (HCC), high frequencies of aberration have been detected in the p53 and RB genes. Loss of heterozygosity (LOH) of chromosome 13q was detected in 35% of HCC and LOH on chromosome 17p was detected in 49%. Mutation of the p53 gene was also detected in 32%. The aberrations of these genes were observed more frequently in poorly differentiated and in advanced HCCs. On the other hand, genetic alterations of the cyclin DI and p161NK4A genes were not so frequent, but appeared to be associated with the aggressive behavior of the tumor, which suggests that disruption of the cell cycle-related genes results in the progression of HCC. Further study with a substantial number of cases is required to determine the actual frequency of the aberrations of the G1 controlling genes in hepatocarcinogenesis.
Open Access
Analysis of NQO1 polymorphisms and p53 protein expression in patients with hepatocellular carcinoma
(Murcia : F. Hernández, 2009) Mei-Miao, Chiu; Ying-Ju, Ko; Ann-Ping, Tsou; Gar-Yang, Chau; Yat-Pang Chau
NAD(P)H: quinone oxidoreductase 1 (NQO1), a cytosolic enzyme which catalyzes the twoelectron reduction of quinone compounds, has been suggested to prevent the generation of semiquinone free radicals and reactive oxygen species, thus protecting cells from oxidative damage. However, the enzymatic activity of NQO1 strongly depends on the individual genetic polymorphism of the NQO1 gene. A common NQO1 polymorphism is a C to T transition at position 609, which results in an inactive enzyme. Recent studies showed that NQO1 is an important enzyme for stabilizing p53 protein, which is involved in antitumorigenesis. Thus, the lack of enzymatic activity in the homozygous C609T NQO1 polymorphism may play a pivotal role in tumor development. This study aimed to investigate the relationship between C609T NQO1 polymorphism and p53 expression in human hepatocellular carcinoma (HCC). Genotyping of NQO1 was performed on 100 HCC specimens by PCR-RFLP analysis. In addition, NQO1 and p53 protein expression in HCC samples at different TNM stages was determined by immunohistochemistry. Our data showed that (1) the frequency of C609T NQO1 was significantly increased in TNM stage III HCC patients; (2) no significant association was found between p53 expression and C609T polymorphism of NQO1 gene; and (3) a tumor/non-tumor (T/N) ratio > 1.27 of NQO1 expression revealed by real-time qPCR analyses was positively correlated with poorer survival in patients with tumors >5 cm, suggesting that an increase of NQO1 expression may be an indicator of advanced tumor progression. This study provides important information about NQO1 genotypes and its expression to HCC tumor development and progression.
Open Access
Analytical histopathological diagnosis of small hepatocellular nodules in chronic liver diseases
(Murcia : F. Hernández, 1998) Nakanuma, Y.; Hirata, K.; Terasaki, S.; Ueda, K.; Matsui, O.
Due to the recent progress in radiology and increased clinical and pathological interest, small hepatocellular nodules about 1 cm in size are frequently being detected in patients with chronic liver disease, particularly liver cirrhosis. Two new types of small hepatocellular nodules are now known: low-grade hepatocellular carcinomas (HCC) and dysplastic nodules, in addition to the previously known HCC (classical) and regenerative nodules. Ultrasound-guided needle biopsies from these nodules are routinely used for the differential diagnosis. For comparison, a simultaneous needle biopsy from the liver remote from the nodule is strongly recommended. Low-grade HCC, which are different from classical HCC in their morphological atypia and also biological behaviors, show local invasion into the portal tracts and surrounding hepatic parenchyma, but not intrahepatic or extrahepatic metastasis. Dysplastic nodules show mild cellular and structural atypia, a finding which is not sufficient for making a diagnosis of malignancy. An increased nuclear/cytoplasmic (N/C) ratio and nuclear crowding, small cell-dysplasia, increased cytoplasmic staining, clear cell change, pseudogland formation, and fatty change of hepatocytes are variably seen in these nodules. Nuclear changes, local invasion to the portal tract and surrounding liver, and loss of the reticulum fibers along the hepatocytes are useful markers favoring low-grade HCC rather than dysplastic nodules. These low-grade HCC and dysplastic nodules should also be distinguished from classical HCC as well as large-sized regenerative nodules. A comparative analysis of the histological findings observed in individual nodules is a reasonable approach to differential diagnosis at present. The recognition and analysis of these two new hepatocellular nodules may augur a new horizon in the study of hepatocellular neoplasm.
Open Access
Androgen receptor mRNA under-expression in poorly differentiated human hepatocellular carcinoma
(Murcia : F. Hernández, 2002) Tavian, D.; De Petro, G.; Pitozzi, A.; Portolani, N.; Giulini, S.M.; Barlati, S.
Many studies suggest that hepatocellular carcinoma (HCC) is an androgen-dependent tumor with an incidence five times higher in males, but few data are available on the androgen receptor (AR) mRNA levels in different physiological classes of human liver specimens. In this study 108 human hepatic samples have been analyzed for AR mRNA expression by a comparative RT-PCR assay. These consisted of 35 non-tumoral hepatic samples (3 normal parenchymas, 4 steatosis, 10 hepatitis, 18 cirrhosis), 38 tumoral specimens derived from uninodular and multinodular HCCs and 35 peritumoral hepatic tissues. Normalized AR mRNA levels in tumoral and peritumoral liver tissues spanned from 0 to 146% and from 7 to 125% respectively. Only in a relatively small percentage of HCCs, the levels of expression of AR mRNA were higher than in the corresponding peritumoral tissues (16% of total HCCs). Although extremely variable, the AR mRNA levels were related to histological tumoral differentiation and proved to be lower in the highly dedifferentiated HCCs as compared to the well differentiated ones. Therefore, the evaluation of AR expression in HCC patients might be relevant for the planning of clinical studies on anti-androgen therapies, which might be useful only in the cases in which a high level of AR mRNA is detected, considering the high heterogeneity of AR mRNA levels which characterizes HCC samples. It is likely that the HCCs, expressing low or undetectable levels of AR mRNA, would not benefit by the antiandrogen therapy.
Open Access
Apoptosis in hepatocellular carcinomas with neuroendocrine differentiation
(Murcia : F. Hernández, 1997) Zhao, M.; Zimmermann, Astrid
We have studied apoptosis in a subset of thirty hepatocellular carcinomas (HCCs) exhibiting neuroendocrine differentiation (ND). Apoptosis was assessed by use of in situ DNA end labelling, and was quantified employing a TdT labelling index. It turned out that apoptosis occurred in HCCs with ND, albeit at different rates. Apoptosis was visualized as a clearly detectable reaction product mostly localized in tumor cell nuclei and in apoptotic bodies. Almost no staining was observed in nuclei of multinuclear tumor giant cells. In HCCs with ND, apoptosis was not related to type or grade, but tumors mainly consisting of hepatocyte-like cells andlor clear cells showed a significantly higher apoptotic rate. This was also the cell type most frequently disclosing neuroendocrine features. The apoptotic rate was significantly higher in HCCs with ND han in a control group of HCCs not showing ND. The findings suggest that neuroendocrine differentiation in liver cell tumors is associated with an aitered pattem of programmed cell death, and that this phenomenon may therefore have an influence on clinical behavior.
Open Access
Biomarkers for novel targeted therapies of hepatocellular carcinoma
(Murcia : F. Hernández, 2009) Okamoto, Kinya; Neureiter, Daniel
Increasing insights into molecular alterations of signalling pathways have led to the development of specific targeted therapies for cancer. Due to the high specificity of monoclonal antibodies or small molecule inhibitors, identification of patients who will benefit from these therapeutics is crucial for treatment success. Furthermore, as classical endpoints of clinical trials are not fully applicable to targeted therapies, biomarkers for monitoring treatment response have to be identified. The recent introduction of a multi-kinase inhibitor for the treatment of liver cancer has accelerated efforts in the field of biomarker research. As further novel targeted therapies are on the horizon for liver cancer therapy, we will here review candidate markers for new hepatocellular carcinoma therapies, with a focus on EGF- and VEGF-receptor related pathways.
Open Access
Cancer-related microRNAs and their role as tumor suppressors and oncogenes in hepatocellular carcinoma
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Gailhouste, Luc; Ochiya, Takahiro
MicroRNAs (miRNAs) have emerged as key factors involved in several biological processes, including development, differentiation, cell proliferation, and tumorigenesis. In hepatocellular carcinoma (HCC), miRNAs frequently present aberrant expression profiles, which make them potentially attractive for diagnostic or prognostic applications. Currently, accumulating evidence is indicating the role of miRNAs as tumor suppressors or oncogenes in hepatic malignancies. In particular, comprehensive studies have made possible a better understanding of HCC behavior, such as tumor growth, response to therapies, metastatic potential, or recurrence, regarding the altered expression of cancerrelated miRNAs. Based on these findings, efforts are under way to define new markers for liver cancer in both invasive (hepatic biopsy or tumor resection) and noninvasive (circulating miRNAs in blood serum) ways. Due to their implication in the control of various cell processes altered in HCC, cancer-related miRNAs also offer encouraging perspectives for the development of innovative cancer therapies. In this article, we review the importance of miRNA deregulation in HCC progression and the role of these small non-coding RNAs as tumor suppressors and oncogenes. The significance of miRNAs in HCC diagnosis and miRNA-based therapeutic strategies is then discussed.
Open Access
Chromosomal instability and human hepatocarcinogenesis
(Murcia : F. Hernández, 2003) Nishida, N.; Nishimura, T.; Ito, T.; Komeda, T.; Fukuda, Y.; Nakao, K.
Recently, many studies have identified losses and gains of several chromosomal loci in human hepatocellular carcinoma (HCC) with fine microsatellite analysis and comparative genomic hybridization. Although distribution of aberrant chromosomal arms differs among HCCs, loss of 1p, 4q, 6q, 8p, 9p, 10q, 13q, 16q and 17p, and gain of 1q, 6p, 8q, 17q and 20q have been recurrently reported, and loss of 4q and 16q seems to occur preferentially in hepatitis B virus-related HCCs. Accumulation of these aberrant chromosomal regions is associated with tumor progression, and some chromosomal aberrations, such as loss of 1p, are frequently identified in well-differentiated HCCs and also detected even in dysplastic nodule and cirrhotic nodule. This evidence suggests that chromosomal instability (CIN) emerges at an early stage during hepatocarcinogenesis and is successively inherent to tumor cells, resulting in acquisition of malignant phenotype. The molecular basis of CIN is beginning to be explored; however, several mechanisms may be involved for CIN of HCC.
Open Access
Efficacy of expressions of Arg-1, Hep Par-1, and CK19 in the diagnosis of the primary hepatocellular carcinoma subtypes and exclusion of the metastases
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Atta, Ihab Shafek
Many conflicts arise using immunohistochemistry of Hepatocellular carcinoma (HCC), some of these conflicts arise from the biliary part within the tumor itself or from liver metastasis. The aim of this study is to investigate the extent of Arg-1, HepPar-1, and CK-19 expressions in the primary HCC subtypes as well as studying of some metastatic cases to find a distinctive immunohistochemical panel utilizing it to differentiate between these entities. Material and methods. A paraffin-embedded block including 62 cases of primary HCC, and 18 cases diagnosed as metastatic tumors, were subjected for this study using Anti-liver Arginase antibody (ab125134 Cambridge, USA, polyclonal antibody, 3.75 µg/ml), HepPar-1 (polyclonal mouse antibody OCH1E5; 1:600; DAKO, CA, USA), and CK 19 Anti-Cytokeratin 19 antibody (ab15463, rabbit polyclonal antibody; 1:100; Cambridge, USA). The intensity of immunostaining was scored (0 to 3+). Nuclear and cytoplasmic staining with Arg-1 and cytoplasmic for both HepPar-1 and CK 19 are reported. Results. The histopathological patterns were mainly trabecular no=(24, 38.7%), and pseudoglandular (no=14, 22.5%), mixed hepatocellular cholangio-carcinoma was observed in one case (1.6%). Arginase-1 positivity was in 55 cases (88.7%) opposite to 46 (74.19%) and 8 (12.9%) for HepPAr.1% -1 and CK 19, respectively. The intensity of expression was marked in well and moderate differentiation for Arg-1 and HepPar-1and in poorly differentiated for CK 19. Metastatic carcinoma cases revealed two cases positive for Arg-1 (11.1%), 4 cases (22.2%) positive for HepPar-1, and 13 cases (72.2%) positive for CK 19. Conclusion. Arg-1 and HepPar-1 are confirmative in the diagnosis of primary HCC in most cases, either separately or collectively but the priority of selection leans more towards Arg-1. Arg-1 and HepPar-1 positive with negative CK 19 expressions give more support to diagnosis of primary HCC while the reverse will support the diagnosis of tumour of biliary origin or liver metastasis.
Open Access
Emerging evidence of molecular biomarkers in hepatocellular carcinoma
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Umeda, Shinichi; Kanda, Mitsuro; Kodera, Yasuhiro
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Patients with HCC generally present at an advanced stage resulting in death within 6-20 months. Therefore, novel treatment modalities and sensitive prognostic markers that can decrease the mortality rate of HCC are required. HCC is a complex and heterogeneous tumor with multiple genetic aberrations. It has been well described that accumulation of genetic and epigenetic changes leads to the clonal selection of cancer cells harboring aggressive tumor behavior. Aberrant expression of cancer-related genes is one of the hallmarks of cancer cells and plays a role in hepatocarcinogenesis. Epigenetic alterations, such as the alteration of DNA methylation and histone modification in cancer cells, can also induce the activation and inactivation of cancer-related genes. Studies have shed light on the link between HCC-related genes and molecules, and a better understanding of the mechanisms of HCC pathogenesis could be translated into clinical biomarker tools. Moreover, analyses of genetic and epigenetic alterations have identified potential biomarkers that might be targeted therapeutically. In this review, we update the current knowledge of biomarkers in HCC, examine recently published literature, and introduce some representative molecules in each category.
Open Access
HBx-induced androgen receptor expression in HBV-associated hepatocarcinoma is independent of the methylation status of its promoter
(Murcia: F. Hernández, 2011) Zhu, Rong; Zhang, Jian-Sheng; Zhu, Ya-Zhen; Fan, Jia; Mao, Yi; Chen, Qi; Zhu, Zhu
A remarkable feature of HBV-associated HCC is male predominance. The cooperation of hepatitis B virus X protein (HBx) with androgen receptor (AR) signaling pathway has been documented to contribute to this dominance. HBx, a multifunctional viral regulator, has been documented to induce promoter hypermethylation and low expression of tumor suppressor genes via activation of DNA methyltransferase (DNMT) in hepatocarcinogenesis. In prostate cancer, hypermethylation of AR promoter is associated with loss of AR expression. However, the relationship among HBx, DNMTs, the methylation status of AR and AR expression in HBV-associated HCC is still unknown. In this report, we found that HBx correlated with high levels of AR in HCC cases and induced AR expression by stimulating its transcription in liver cell lines. HBx correlated with high expression of DNMTs in HCC cases too. Both in vivo and in vitro, however, the expression of AR was not associated with its promoter methylation status, and the methylation status of AR was not regulated by DNMTs. AR expression is higher in peritumoral tissues than in tumors, as well as being higher in HBV-associated HCC than in HBV-negative cases. Therefore, HBx-induced high expression of AR plays a role during hepatocarcinogenesis, but is not involved with its promoter methylation or DNMTs. HBx-mediated DNMT deregulation is gene-specific, and the expression and methylated regulation of AR is tissue-specific.
Open Access
Hepatocellular carcinoma in non-alcoholic fatty liver disease (NAFLD) - pathological evidence for a predominance of steatohepatitic inflammatory non-proliferative subtype
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Campos de, Priscila B.; Oliveira, Claudia P.; Stefano, José T.; Martins-Filho, Sebastião N.; Chagas, Aline L.; Herman, Paulo; Albuquerque de, Luiz C.; Alvares-da-Silva, Mário R.; Longatto-Filho, Adhemar; Carrilho, Flair J.; Alves, Venancio A.F.
Objectives. This study evaluated clinical and pathological aspects of patients with hepatocellular carcinoma (HCC) secondary to non-alcoholic fatty liver disease (NAFLD) and related these factors to immunohistochemical markers representative of the proliferative class. Methods. We evaluated 35 HCC nodules from 21 patients diagnosed with NAFLD undergoing liver resection (n=12) or liver transplantation (n=8) or both (n=1). Demographic, clinical and biochemical data were compared to histological features and to immunohisto- chemical reactivity for K19 and Ki-67. Results. Cirrhosis was present in 58% of patients. Ages ranged from 50 to 77 years. Sixteen patients (76%) were male and had type 2 diabetes mellitus, 81% had arterial hypertension, and 90% had BMI above 25 kg/m 2. Alpha-fetoprotein levels were normal in 62% of patients. Twenty-five (70%) nodules were diagnosed as “steatohepatitic HCC”. Only 32% of the nodules presented high levels of Ki-67 (>10%) and/or K19 (>5%), although 63% were poorly differentiated (G.3/G.4) according to Edmondson & Steiner grading system. K19 positivity (>5%) was associated with higher degree of intratumoral inflammation (G.2/G.3), and with fibrosis, both at the center of the tumor and at the tumor front, whereas Ki-67 positivity (>10%) was associated with ballooning of neoplastic cells and occurred in more than 70% in non-cirrhotic patients. Conclusion. NAFLD-related HCC was found in non- cirrhotic patients in 42% of cases, alpha-fetoprotein level was normal in 63% and "steatohepatitic HCC" was the predominant histological type. Immunoexpression of K19 and/or Ki-67 occurred in 32% of the nodules and were associated with intratumoral inflammation and ballooning, suggesting that HCC in MtS may be preferentially “an inflammatory, non-proliferative subtype of HCC”
Open Access
High expression of DEK is associated with poor prognosis in hepatocellular carcinoma.
(Celular e Histiologia Universidad de Murcia, Departamento de Biologia, 2019) Lee, Soo Yeon; Jung, Wonkyung; Lee, Jinhwan; Kim, Aeree; Kim, Han Kyeom; Kim, Baek-Hui
DEK is an oncogene that has been identified as part of the DEK-CAN fusion gene. DEK plays a role in carcinogenesis through WNT signaling and induces cell proliferation through cyclin-dependent kinase signaling. DEK overexpression has been reported in HCC, but the clinical significance is unclear. This study enrolled 221 cases of HCC. The expression of DEK protein was evaluated by immunohistochemical staining. Cdk4, cyclin D1, Wnt10b, E-cadherin, and β-catenin were also immunohistochemically stained and analyzed for correlation. The association of clinicopathologic factors with DEK expression was analyzed. DEK expression was observed in 44.8% (99/221) of cases. DEK expression showed a statistical association with clinicopathologic factors, including Edmondson-Steiner grade, presence of vascular emboli, and multiplicity (p<0.05). Among the other IHC markers, the expression of cdk4 was correlated with DEK expression (p<0.05). Patients with high DEK expression showed a significantly lower overall survival rate (p=0.006). However, the disease-free survival rate did not differ significantly. In addition, in a Cox regression model analysis, DEK expression was an independent prognostic factor. In summary, high expression of DEK was observed in HCC and was associated with poor prognostic marker expression and poor prognosis.
Open Access
High FITM2 expression promotes cell migration ability of hepatocellular carcinoma by regulating the formation of caveolae and indicates poor patient survival
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Chen, Yan; Ji, Li-juan; Wang, Yan; Guo, Xiang-Feng
Background. Hepatocellular carcinoma (HCC) is among the most malignant tumors with high recurrence and low 5-year survival rate. Lipid metabolism is essential in tumor metastasis, although how altered lipid metabolism promotes HCC progression has not been well elucidated. Fat Storage Inducing Transmembrane Protein 2 (FITM2) is a gene involved in lipid homeostasis and cytoskeletal organization; however, its role in regulating tumor biological behavior has not been evaluated. Methods. In this study, immunohistochemistry was performed to evaluate the expression of FITM2 in HCC. Univariate and multivariate analysis was performed to identify the prognostic factors. RNA interference wound healing and transwell experiments were performed to analyze the biological role of FITM2. Western blot analysis was performed to investigate the potential downstream signaling. Results. The results revealed that FITM2 was highly expressed in the intratumoral tissues of HCC. Expression of intratumoral FITM2 was associated with microvascular invasion. FITM2 is an independent risk factor of HCC disease-free survival and overall survival. In vitro studies revealed that knockdown of FITM2 significantly inhibited the migration ability of HCC cells. FITM2 promotes HCC cell migration by regulating the expression of caveolin-1 and promoting the formation of caveolae. These results indicate that high intratumoral expression of FITM2 is associated with poor HCC prognosis, which may be applied to develop a new adjuvant therapy
Open Access
Hsa_circ_0088036 promotes tumorigenesis and chemotherapy resistance in hepatocellular carcinoma via the miR-140-3p/KIF2A axis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Wang, Zhong; Wang, Lei; Yin, Guoqing; Li, Heng; Zhang, Rong; Feng, Yuan; Chang, Wen; Biología Celular e Histología
Background. Hepatocellular carcinoma (HCC) is a cancer with high morbidity and mortality. There are limited treatment options, particularly for chemotherapy-resistant HCC patients. Circular RNA hsa_circ_0088036 was associated with the development of bladder cancer and non-small cell lung cancer. However, whether it might be a potential therapeutic target for HCC remains elusive. Methods. Hsa_circ_0088036 expression was detected in HCC tumor tissues and cell lines using real-time PCR. The influences of hsa_circ_0088036 on proliferation and invasion as well as chemotherapy sensitivity in HCC cells were investigated by gain- and loss-of-function analyses. Associations among hsa_circ_0088036, miR-140-3p, and KIF2A were validated by real-time PCR, miRNA pull-down assay, dual-luciferase reporter assay, and western blot. Furthermore, a rescue experiment using KIF2A overexpression was performed to evaluate the regulatory mechanism of hsa_circ_0088036 in HCC cells. Additionally, the effect and mechanism of hsa_circ_0088036 were confirmed in a xenograft mouse model. Results. Hsa_circ_0088036 was highly expressed in HCC tissues and cells, with even higher expression in oxaliplatin-resistant cells. This expression was positively correlated with tumor size and TNM stage of the patients. Overexpression of hsa_circ_0088036 promoted the proliferation and invasion of HCC cells, while silencing mediated the opposite effects. Meanwhile, knockdown of hsa_circ_0088036 enhanced chemo-therapy sensitivity, including oxaliplatin, doxorubicin, and sorafenib, in HCC cells. Furthermore, hsa_circ_ 0088036 silencing inhibited tumor growth and increased oxaliplatin sensitivity in vivo. Mechanically, hsa_circ_0088036 functioned via the miR-140-3p/KIF2A axis with the activation of PI3K/Akt and Notch signaling pathways. Conclusions. Hsa_circ_0088036 promoted HCC tumorigenesis and chemotherapy resistance by activating the PI3K/Akt and Notch pathways through regulating miR-140-3p/KIF2A signaling. Thus, hsa_circ_0088036 may be a potential therapeutic target in chemotherapy-resistant HC
Open Access
Hyper-methylation of RIZ1 tumor suppressor gene is involved in the early tumorigenesis of hepatocellular carcinoma
(Murcia : F. Hernández, 2008) Piao, G-H.; Piao, W-H.; He, Y.; Zhang, H.; Wang, G-Q.; Piao, Z.
The retinoblastoma protein-interacting zinc finger gene RIZ1 is a putative tumor suppressor gene, and the inactivation of the RIZ1 is frequently found in tumors through a loss of mRNA expression. In order to understand the role of RIZ1 inactivation in the tumorigenesis of hepatocellular carcinoma (HCC), we detected the RIZ1 promoter methylation status in 39 HCCs using a methylation specific PCR (MSP) method, and carried out LOH study with marker P704. We also assessed the associations between the methylation status and clinicopathological parameters, tumor size, tumor differentiation, and fractional allelic loss (FAL). The results showed that the RIZ1 promoter methylated both in advanced tumors (>3 cm), (18/31, 58.0%) and in early tumors (<3 cm), (4/8, 50.0%). There were 54.6% (12/22) tumors with hyper-methylation in the low FAL group and 45.5% (10/22) in the high FAL group. Moreover, the DNA methylation of the RIZ1 promoter was found not only in the poorly differentiated tumors (12/22, 54.6%), but also in the well differentiated tumors (10/22, 45.5%). Among the 22 HCCs (22/39, 56.4%) that showed hypermethylation at the RIZ1 promoter region, 3 cases showed biallelic methylation. Interestingly, one case showed hyper-methylation on one allele and a loss of heterozygosity (LOH) on the other allele. In other words, 4 HCCs showed the biallelic inactivation of the RIZ1. These results suggest that the inactivation of the RIZ1 by DNA methylation at its promoter region is involved in the tumorigenesis of HCC, particularly in the early stage of disease.
Open Access
Impact of hepatitis virus and aging on DNA methylation in human hepatocarcinogenesis
(Murcia : F. Hernández, 2010) Nishida, Naoshi
Hepatocellular carcinoma (HCC) usually develops on the basis of chronic hepatitis and liver cirrhosis, where inactivation of several tumor suppressor genes (TSGs) takes place via methylation of the promoter. Interestingly, these methylation events are more prevalent in a background liver at high risk of HCC than one at low risk. Abnormal methylation is also observed in precancerous nodules such as dysplastic nodules and adenomas, suggesting that epigenetic alteration is an early event for HCC carcinogenesis. It is possible that infection with the hepatitis virus induces alteration of methylation at promoters of TSGs. Some studies suggested that viral proteins interfere with DNA methyltranferase in chronic hepatitis B. Induction of epigenetic alteration in chronic hepatitis C might, however, might be a consequence of oxidative stress. In addition, we proposed age should be taken into consideration for HCC development via epigenetic pathways. Further investigations are required to understand the mechanism of inducing epigenetic instability during hepatocarcinogenesis
Open Access
In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin
(Murcia : F. Hernández, 2007) Ribatti, Doménico; Nico, Beatrice; Mangieri, Doménica; Longo, V.; Sansonno, D.; Vacca, A.; Dammacco, F.
This paper illustrates the use of the chick embryo chorioallantoic membrane (CAM) assay to determine the single and combined antiangiogenic effects of very low doses of vinblastine (VBL) and rapamycin (RAP) in human hepatocellular carcinoma (HCC). The angiogenic response induced by human HCC biopsy specimens was inhibited by each drug and sinergistically by their combination. Morever, immunohistochemical detection of microvessels with anti-CD31 mAB showed that their area was significantly lower in specimens treated with VBL and RAP in combination. Sinergy on the part of these well-known drugs when used in combination as antiangiogenics at very low doses may be of significance in the designing of new ways of treating HCC.
Open Access
Inducible factors for cancer-associated fibroblasts in liver cancer versus myofibroblasts in inflammatory liver disease
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Okabe, Hirohisa; Hayashi, Hiromitsu; Nakagawa, Shigeki; Imai, Katsunori; Nitta, Hidetoshi; Arima, Kota; Hashimoto, Daisuke; Chikamoto, Akira; Ishiko, Takatoshi; Beppu, Toru; Baba, Hideo
The importance of cancer-associated fibroblasts (CAFs) in liver cancer, cholangiocarcinoma (CC) and hepatocellular carcinoma (HCC), has been appreciated in the past 5 years. We focused on how they get activated in the tumor microenvironment in this review. Not only hepatic stellate cells (HSCs) but also portal fibroblasts (PFs) have been appreciated to be key players in liver fibrogenesis, and their different roles have just started to be recognized. Since the role of cholangiocyte in biliary fibrogenic disease might have some similarities to that of CC, we focused on the role of cholangiocytes activating stromal fibroblasts, which would presumably be helpful for better understanding the mechanism of tumor-CAFs interaction. In addition, the activation of CAFs should be different from that of CAFs in HCC, which we consider to be potentially similar to MFs in hepatocyte injury-dependent liver fibrogesis. Herein, we describe the activation of CAFs in CC in comparison to MFs seen in other liver diseases such as 1) MFs in liver fibrosis caused by hepatocyte injury such as alcoholic hepatitis, viral hepatitis, and nonalcoholic steatosis, 2) MFs in liver fibrosis caused by cholestatic disease, and 3) CAFs in hepatocellular carcinoma (HCC). This review on the activation of fibroblasts either in liver cancer or in chronic liver disease would contribute to CAF-targeted therapy in liver cancer.