Association Of Hepatocellular Carcinoma Research Articles

Exploring Selenoprotein P in Liver Cancer: Advanced Statistical Analysis and Machine Learning Approaches.

Selenoprotein P (SELENOP) acts as a crucial mediator, distributing selenium from the liver to other tissues within the body. Despite its established role in selenium metabolism, the specific functions of SELENOP in the development of liver cancer remain enigmatic. This study aims to unravel SELENOP's associations in hepatocellular carcinoma (HCC) by scrutinizing its expression in correlation with disease characteristics and investigating links to hormonal and lipid/triglyceride metabolism biomarkers as well as its potential as a prognosticator for overall survival and predictor of hypoxia. SELENOP mRNA expression was analyzed in 372 HCC patients sourced from The Cancer Genome Atlas (TCGA), utilizing statistical methodologies in R programming and machine learning techniques in Python. SELENOP expression significantly varied across HCC grades (p < 0.000001) and among racial groups (p = 0.0246), with lower levels in higher grades and Asian individuals, respectively. Gender significantly influenced SELENOP expression (p < 0.000001), with females showing lower altered expression compared to males. Notably, the Spearman correlation revealed strong positive connections of SELENOP with hormonal markers (AR, ESR1, THRB) and key lipid/triglyceride metabolism markers (PPARA, APOC3, APOA5). Regarding prognosis, SELENOP showed a significant association with overall survival (p = 0.0142) but explained only a limited proportion of variability (~10%). Machine learning suggested its potential as a predictive biomarker for hypoxia, explaining approximately 18.89% of the variance in hypoxia scores. Future directions include validating SELENOP's prognostic and diagnostic value in serum for personalized HCC treatment. Large-scale prospective studies correlating serum SELENOP levels with patient outcomes are essential, along with integrating them with clinical parameters for enhanced prognostic accuracy and tailored therapeutic strategies.

Recreational Drugs and the Risk of Hepatocellular Carcinoma.

Recreational or aesthetic drug use is a distinctive behavior of humans, principally attested in the last century. It is known that recreational and illegal drugs are major contributors to the universal morbidity rate worldwide. Many of these substances have a well-established hepatotoxic potential, causing acute or chronic liver injury, liver fibrosis and cirrhosis, but their implications for hepatocellular carcinoma or other varieties of liver tumors are little known. In this article, we perform an extensive literature review, aiming to provide updated information about recreational drug use and the risk of developing liver tumors. Khat use and pyrrolizidine alkaloid consumption (present in some natural plants) have been linked to liver cirrhosis. Kava intake is associated with different liver tumors in animal models but not in humans. Cannabis' potential to accelerate liver fibrosis in chronic hepatitis is controversial according to the existing data. Cigarette smoking is an important contributor to hepatocellular carcinoma, and anabolic androgen steroids are well-defined causes of a variety of liver cancers and other hepatic tumors. Long-term follow-up studies of subjects who have developed injuries in association with the use of recreational drugs are warranted so as to better define the risk of developing hepatocellular carcinoma in association with these substances and, thus, to implement health care policies to combat this preventable cause of cancer.

Pan-cancer analysis of the expression pattern of long non-coding RNA MIR22HG

To conduct a pan-cancer analysis of the expression of long non-coding RNA (lncRNA) MIR22HG and explore its association with clinical characteristics. We analyzed the expression of MIR22HG in different tumors and its association with clinical staging, lymph node metastasis, tumor mutation burden (TMB) and microsatellite instability (MSI) using R package based on the Cancer Genome Atlas (TCGA) datasets. The relationship between MIR22HG expression and infiltrating immune cells was analyzed using TIMER algorithm. The association of MIR22HG gene alteration frequency with the clinical outcomes was examined using cBioPortal online software. Data form Genomics of Drug Sensitivity in Cancer (GDSC) were used to analyze the relationship between MIR22HG and the sensitivity of chemotherapy drugs. We specifically analyzed MIR22HG expression in hepatocellular carcinoma (HCC) and its correlation with sorafenib treatment using GEO database and verified the results in 12 pairs of HCC specimens. Kaplan-Meier analysis was performed to analyze the correlation of MIR22HG with the outcomes of sorafenib treatment. We also tested the effects of MIR22HG overexpression and knockdown on IC50 of sorafenib in HCC cells. MIR22HG was downregulated in most tumors (P < 0.05), where its deletion mutations were frequent, and associated with a poor prognosis (P < 0.05). In many tumors, MIR22HG expression level was correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, immune checkpoint-related genes, and sensitivity to common chemotherapeutic drugs (P < 0.05). Among the 6 common infiltrating immune cells in cancers, neutrophil infiltration had the strongest correlation with MIR22HG expression level, especially in breast cancer, rectal cancer and kidney renal papillary cell carcinoma (P < 0.05). MIR22HG was downregulated in HCC in association with HCC progression (P < 0.05). In HCC patients, a low MIR22HG expression was associated with a favorable outcome after sorafenib treatment (HR=2.94, P=0.075) and was capable of predicting the response to sorafenib treatment (AUC=0.8095). Compared with the negative control, MIR22HG overexpression obviously reduced sorafenib sensitivity (with IC50 of 7.731 vs 15.61) while MIR22HG knockdown increased sorafenib sensitivity of HCC cells (with IC50 of 7.986 vs 5.085). MIR22HG expression level is correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, and chemosensitivity in most cancer, suggesting its potential as an immunotherapeutic target and also a prognostic biomarker for tumors.

Identification of miRNA-mRNA associations in hepatocellular carcinoma using hierarchical integrative model

BackgroundThe established role miRNA-mRNA regulation of gene expression has in oncogenesis highlights the importance of integrating miRNA with downstream mRNA targets. These findings call for investigations aimed at identifying disease-associated miRNA-mRNA pairs. Hierarchical integrative models (HIM) offer the opportunity to uncover the relationships between disease and the levels of different molecules measured in multiple omic studies.MethodsThe HIM model we formulated for analysis of mRNA-seq and miRNA-seq data can be specified with two levels: (1) a mechanistic submodel relating mRNAs to miRNAs, and (2) a clinical submodel relating disease status to mRNA and miRNA, while accounting for the mechanistic relationships in the first level.ResultsmRNA-seq and miRNA-seq data were acquired by analysis of tumor and normal liver tissues from 30 patients with hepatocellular carcinoma (HCC). We analyzed the data using HIM and identified 157 significant miRNA-mRNA pairs in HCC. The majority of these molecules have already been independently identified as being either diagnostic, prognostic, or therapeutic biomarker candidates for HCC. These pairs appear to be involved in processes contributing to the pathogenesis of HCC involving inflammation, regulation of cell cycle, apoptosis, and metabolism. For further evaluation of our method, we analyzed miRNA-seq and mRNA-seq data from TCGA network. While some of the miRNA-mRNA pairs we identified by analyzing both our and TCGA data are previously reported in the literature and overlap in regulation and function, new pairs have been identified that may contribute to the discovery of novel targets.ConclusionThe results strongly support the hypothesis that miRNAs are important regulators of mRNAs in HCC. Furthermore, these results emphasize the biological relevance of studying miRNA-mRNA pairs.

A Case of Moderately Differentiated Hepatocellular Carcinoma in Association with Extrahepatic Growth Type Monostotic Liver Abscess

肝細胞癌治療に関連して肝膿瘍を発症することは知られているが，治療開始前に肝細胞癌と肝膿瘍が併発する症例は本邦での報告が13例と稀であり，肝細胞癌の診断に難渋することも多い．今回われわれは，肝外発育型の単発性肝膿瘍と肝細胞癌が併発した症例を経験した．C型慢性肝炎の治療目的に紹介された77歳の女性で，初診時の腹部CTにて肝外側区域から尾側に突出する内部低吸収領域を伴う腫瘤を認めた．数日後に心窩部痛と発熱を認め入院し，抗菌薬治療で症状は軽快した．画像上も腫瘤が縮小したため肝膿瘍を疑ったが，一部に造影される充実部分が残存していたため肝悪性腫瘍の併存も疑った．肝左葉切除後の病理組織診断で肝膿瘍を併発した肝細胞癌と診断された．文献的考察を加えて報告する．

Unresectable hepatocellular carcinoma: new opportunities and prospects for therapy

Hepatocellular carcinoma (HCC) is the most common liver malignancy and ranks sixth for cancer prevalence and fourth place among the causes of cancer mortality. Despite the improvement of diagnostic techniques, the diagnosis of HCC is still determined in the late stages. The absence of screening programs in groups of risk of HCC (cirrhosis) and the late diagnosis of HCC show the mortality rate exceeds incidence rate in the Russian Federation. It is important to improve the diagnostic methods for early detection of HCC and to use the multidisciplinary approach in diagnosis and treatment of HCC in association with different specialists (hepatologist, oncologist, chemotherapist, surgeon, transplantologist, interventional radiologist). Systemic therapy should be used in all patients with unresectable HCC and compensated liver function. Since 2007 sorafenib has represented the only approved drug for treatment of unresectable HCC. In 2017, according to the results of REFLECT trial lenvatinib was registered for the treatment of unresectable HCC in the first line therapy. For the first time in the last 10 years the efficiency of lenvatinib application in comparison with sorafenib was practically the same, concerning the overall survival rate. Lenvatinib also demonstrated the statistically significant and clinically meaningful benefit in terms of improvement of survival without progression, the time to progression and frequency of objective response rate compared with sorafenib.

Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma.

Epigenetic modifications such as DNA and histone methylation functionally cooperate in fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1, along with that of their molecular adaptor ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was measured in human HCCs (n = 268), peritumoral tissues (n = 154), and HCC cell lines (n = 32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cell growth by pharmacological and genetic approaches. The activity of our lead compound, CM-272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a, DNMT1, and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM-272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM-272 inhibited the metabolic adaptation of HCC cells to hypoxia and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose-1,6-bisphosphatase (FBP1), epigenetically repressed in HCC, was restored by CM-272. Conclusion: Combined targeting of G9a/DNMT1 with compounds such as CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.

Immunohistochemical and electron microscopic morphometric image analysis of hepatocellular carcinoma in association of HCV infection

ABSTRACTEarly detection of hepatocellular carcinoma (HCC) is crucial for successful therapy. The present work examined the value of ultrastructural morphometric image analysis of hepatocyte nuclei in patients with chronic hepatitis C virus (HCV) versus HCC cases with chronic HCV and the corresponding surgical tumor-free safe margins (TFMs), to highlight any early predictive signs of neoplastic cellular transformation. This work also performed an immunohistochemical assessment of cytokeratin 19 (CK19) and Ki-67-positive cells to visualize any associated proliferative activity in the examined groups.The results showed significant decrease in the hepatocyte nuclear surface areas in the HCC and TFMs versus those in the HCV cases. The hepatocyte nucleolar surface area was significantly increased in the HCC cases versus that in the HCV cases. This increase was associated with a significant increase in Ki-67-positive cells in the HCC cases compared to those in the other groups. Conversely, the mean number of CK 19-positive cells was significantly reduced in the HCC cases compared to the cell numbers in TFMs and HCV cases with severe hepatic fibrosis. Liver progenitor cells (LPCs) were discerned in the reactive ductules and canaliculo-ductular junctions that characterized TFMs. LPCs were sporadically distributed in the liver lobules and reactive bile ductules in the HCC samples.In conclusion, CK 19 represents an important marker for distinguishing between dysplastic and malignant liver nodules. Electron microscopic morphometric image analysis may be considered as adjunct factor for assessing hepatocyte malignant transformation. Wider scale studies are needed to authenticate these results.

Downregulation of secreted clusterin potentiates the lethality of sorafenib in hepatocellular carcinoma in association with the inhibition of ERK1/2 signals.

Secretory clusterin (sCLU) is overexpressed in cancer and is associated with resistance to chemotherapy in several types of cancer, including hepatocellular carcinoma (HCC). Sorafenib (SOR), a multikinase inhibitor of Raf/mitogen‑activated protein kinase kinase/extracellular signal‑regulated kinase (ERK) signaling and the receptor tyrosine kinase, is recognized as the standard therapeutic strategy for patients with advanced HCC. However, the role of sCLU in the resistance of HCC to SOR remains to be fully elucidated. In the present study, sCLU was silenced by CLU short hairpin (sh)RNA in Bel‑7402 and SMMC‑7721 cell lines, following which the cells were treated with SOR. Cell proliferation was determined using a CCK‑8 assay. Apoptosis was quantified using flow cytometry. The production of sCLU, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated Xsprotein and phosphorylated (p)ERK1/2 was analyzed using western blot analysis. The results showed that sCLU was overexpressed in three HCC cell lines. The downregulation of sCLU by CLU shRNA synergistically increased SOR sensitivity in the Bel‑7402 and SMMC‑7721 cells, and potentiated SOR‑induced cell apoptosis. In addition, silencing sCLU or combination with PD98059 decreased the SOR‑induced activation of pERK1/2. These findings indicate a novel treatment strategy for HCC.

Abstract 4726: TonEBP promotes hepatocellular carcinoma and is associated with poor prognosis

Abstract Carcinogenesis is initiated by genetic changes due to aberrant processing of genetic information. Tumor microenvironment, however, should not be overlooked as cancer risk because they influence the development and progression. Indeed, the role of inflammation has received a lot of attention lately. Specifically, hepatocellular carcinoma (HCC) has been considered as an inflammation-associated tumor like colorectal cancer and lung cancer. In addition, high rate of recurrence is the major feature of HCC, and there is a need to identify novel biomarkers for post-operative prognosis of HCC patients Tonicity-responsive enhancer binding protein (TonEBP), also known as nuclear factor of activated T cell 5 (NFAT5), is a key transcriptional cofactor for the expression of pro-inflammatory genes such as TNF-α, IL-1β, and cyclooxygenase 2 (COX-2). Since chronic hepatic inflammation is essential for hepatocellular carcinogenesis, we asked whether TonEBP plays a role in HCC. To investigate the relevance of TonEBP in HCC development, TonEBP expression in hepatic tumors and their adjacent normal tissues were analyzed from of HCC patients. TonEBP expression was higher in tumors than adjacent normal hepatic tissues in 94% of HCC patients (n = 104). In a mouse model of diethylnitrosamine (DEN)-induced HCC, TonEBP expression was also higher in 100% of the tumors. Downregulation of miR-223 was responsible for the elevated TonEBP expression. miR-223 targeted the 3’-UTR of TonEBP gene and suppressed TonEBP translation. Interestingly, univariate analyses revealed that TonEBP expression in normal tissues adjacent to HCC was significantly associated with tumor size, tumor grade, vascular invasion, viral DNA replication, α-fetoprotein, PIVKA-II, recurrence, metastasis, and death. In addition, Kaplan-Meier estimation and multivariate analyses showed that the TonEBP expression was an independent prognostic marker for recurrence and death in HCC patients. In mice, TonEBP haplo-deficiency reduced both DEN- and DEN/high-fat diet (HFD)-induced HCC in association with lower COX-2 transcription and milder hepatic inflammation. Acute hepatic inflammation induced by DEN or lipopolysaccharide was also reduced in hepatocyte- or myeloid-specific TonEBP knockout mice. TonEBP-mediated activation of hepatic COX-2 promoter was dependent on the transcription factor Yin Yang 1 (YY1). TonEBP interacted with YY1 through the Rel-homology domain of TonEBP and spacer domain of YY1. In aggregate, our data demonstrate that TonEBP-mediated hepatic inflammation is a critical regulator of hepatocarcinogenesis. The miR-223-YY1/TonEBP-COX-2 pathway drives hepatic inflammation and commits the stressed hepatocytes to malignant fate. Thus, TonEBP promotes HCC via COX-2 expression and is a strong post-operative prognosticator of poor outcome in HCC patients. Citation Format: Jun Ho Lee, Jae hee Suh, Soo Youn Choi, Hyun Je Kang, Gap Ryol Lee, Whaseon Lee-Kwon, Neung Hwa Park, Hyug Moo Kwon. TonEBP promotes hepatocellular carcinoma and is associated with poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4726. doi:10.1158/1538-7445.AM2017-4726

Targeting β-catenin in hepatocellular cancers induced by coexpression of mutant β-catenin and K-Ras in mice.

Ras activation downstream of c-Met is sufficient to induce clinically relevant HCC in cooperation with mutant β-catenin. β-catenin suppression by a clinically relevant modality is effective in treatment of β-catenin-positive, GS-positive HCCs. (Hepatology 2017;65:1581-1599).

Hepatitis C virus and schistosomiasis as a causative factor for hTERT amplification in hepatocellular carcinoma

Telomere abnormalities appear to play a role in carcinogenesis. hTERT is the catalytic component of the telomerase complex. It is regulates telomerase activity in cancers such as hepatocellular carcinoma (HCC). Amplification of the hTERT gene have been detected in about 21% of HCC. HCC occurs frequently in patients with chronic viral hepatitis or liver cirrhosis. Hepatitis B virus (HBV) or hepatitis C virus (HCV) induce HCC. The schistosomal parasite plays a role in the development of HCC through modify the course of hepatitis C accelerating progression to hepatitis C-associated fibrosis and thus quicker progression to HCC. The present study was conducted to evaluate hTERT amplification in HCC in association with HCV and schistosomiasis. Fifteen surgically resected HCC (Grade two) and fourteen cirrhotic resected liver were examined using FISH technique. Amplification of hTERT gene were found in 80% (12/15) of HCC which is much higher than the previously reported data. Eight samples were HCV and schistosomiasis positive, 4 were HCV positive, 2 were schistosomiasis positive and one was HCV and schistosomiasis negative. Amplification of the hTERT gene was not observed in cirrhotic tissues except two cases which is probably due to extension of adjacent HCC. From our results, the coexistence of HCV and/or schistosomiasis with hTERT amplification, we can conclude that the HCV and schistosomiasis may play an important role in upregulation of this gene. Consequently, this may lead to the development of HCC rather than just a marker for cancer development. However this conclusion might need further investigation.

The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway

ObjectivesHepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly...

Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence.

Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment.

Tu2027 Endoscopic Versus Percutaneous Drainage for Management of Hilar Cholangiocarcinoma

Background: The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggest that HCC could arise in steatotic livers without the presence of cirrhosis. The aim of the current study was to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to those with HCC in association with liver cirrhosis (LC). Methods: A retrospective analysis was performed on all patients with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012. We characterized the patients with respect to demographic, clinical, histological and tumor features. Comparisons between the NCL and LC groups were done using t-test, Mann Whitney U test, and Chi square test as appropriate. P value 5 cm) (77.8% vs. 23 %), and receive hepatic resection as the modality for HCC treatment (66.7% vs. 17%); and were less likely to receive loco-regional therapy (16.7% vs. 51.1%) or liver transplant (0% vs. 72.3%), p value < 0.001 for all. Furthermore, 62% of patients without cirrhosis had HCC recurrence compared to only 12.5% in patients with cirrhosis (p < 0.001) and had worse survival with mortality rate of 41.7% at last follow up for the HCC-NCL group compared to 27.7% in the cirrhotic group (p = 0.008). Conclusion: Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.

Tu2026 Characterization of Hepatocellular Carcinoma (HCC) in NAFLD Patients Without Cirrhosis

Background: The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggest that HCC could arise in steatotic livers without the presence of cirrhosis. The aim of the current study was to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to those with HCC in association with liver cirrhosis (LC). Methods: A retrospective analysis was performed on all patients with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012. We characterized the patients with respect to demographic, clinical, histological and tumor features. Comparisons between the NCL and LC groups were done using t-test, Mann Whitney U test, and Chi square test as appropriate. P value 5 cm) (77.8% vs. 23 %), and receive hepatic resection as the modality for HCC treatment (66.7% vs. 17%); and were less likely to receive loco-regional therapy (16.7% vs. 51.1%) or liver transplant (0% vs. 72.3%), p value < 0.001 for all. Furthermore, 62% of patients without cirrhosis had HCC recurrence compared to only 12.5% in patients with cirrhosis (p < 0.001) and had worse survival with mortality rate of 41.7% at last follow up for the HCC-NCL group compared to 27.7% in the cirrhotic group (p = 0.008). Conclusion: Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.

CD95 rs1800682A/G variant and tumor risk in Asians: evidence from a meta-analysis of 36 case-control studies containing 22,438 samples.

BackgroundThe CD95 gene plays a key role in regulating cell growth and tumor genesis. To date, several publications have focused on the CD95 rs1800682A/G site polymorphism and various types of tumors in Asians; however, this association is still controversial and obscure. Therefore, a meta-analysis combined with all publications to clarify this association is necessary.Material/MethodsA search in the PubMed and SinoMed databases was performed to detect all relevant included publications. Odds ratio (OR) and 95% confidence intervals (CI) revealed association strengths.ResultsOverall, 36 case-control studies were chosen based on the search criteria. There was no association of the CD95 rs1800682A/G site polymorphism with tumor risk in total and ethnicity subgroup analysis. However, further stratified analysis in the cancer subgroup revealed weakly significant associations in hepatocellular carcinoma (AA+AG vs. GG: OR=0.93, 95% CI=0.87–0.99, P=0.035; AG vs. GG: OR=0.89, 95% CI=0.80–0.99, P=0.036).ConclusionsThe CD95 rs1800682A/G site polymorphism may be associated with hepatocellular carcinoma susceptibility. Further large-scale and well-designed studies regarding tumor types and ethnicities are still required to confirm our results.

MicroRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression.

Hepatocellular carcinoma (HCC) is classified as a poor prognostic tumor, and becomes frequently aggressive. MicroRNAs emerge as key contributors to tumor progression. This study investigated whether miR-148a dysregulation differentiates poor prognosis of HCC, exploring new targets of miR-148a. miR-148a dysregulation discriminated not only the overall survival and recurrence free survival rates of HCC, but the microvascular invasion. In the human HCC samples, ubiquitin specific protease 4 (USP4) and sphingosine 1-phosphate receptor 1 (S1P1) were up-regulated as the new targets of miR-148a. USP4 and S1P1 were up-regulated in mesenchymal-type liver-tumor cells with miR-148a dysregulation, facilitating migration and proliferation of tumor cells. The inverse relationship between miR-148a and the identified targets was verified in a tumor xenograft model. In the analysis of human samples, the expression of USP4, but not S1P1, correlated with the decrease of miR-148a. In a heterotropic patient-derived HCC xenograft model, USP4 was also overexpressed in G1 and G2 tumors when miR-148a was dysregulated, reflecting the closer link between miR-148a and USP4 for a shift in the expansion phase of tumorgraft. In conclusion, miR-148a dysregulation affects the poor prognosis of HCC. Of the identified targets of miR-148a, USP4 overexpression may contribute to HCC progression towards more aggressive feature.

Hepatitis B vs. hepatitis C infection on viral hepatitis-associated hepatocellular carcinoma

BackgroundTo determine clinical-pathologic variables in patients with a new diagnosis of hepatocellular carcinoma (HCC) and underlying hepatitis B vs. C infection.MethodsPatients presenting to a single urban hospital with a new diagnosis of HCC were entered into a clinical database. Variables including number and size of tumors, presence of metastases, serum alpha-Fetoprotein, hepatitis serologies, severity of hepatic dysfunction, and presence of cirrhosis were evaluated in 127 patients.ResultsPatients with hepatitis B (HBV) were more likely to develop HCC at a younger age than patients with hepatitis C (HCV) (HBV-26% under age 40, HCV-0% under age 40; p < 0.001), with greater serum alpha-Fetoprotein production (median level: HBV-1000 ng/ml vs. HCV-37 ng/ml; p = 0.002), with larger tumors (HBV-78% >5 cm, HCV-28% >5 cm; p < 0.001), in the absence of cirrhosis (HBV-40%, HCV-0%; p < 0.001), and a decreased eligibility for curative treatment (HBV-14%, HCV-34%; p < 0.05). Conversely, patients with HCV were more likely to develop HCC in association with multiple co-morbidities, cirrhosis, and older age.ConclusionsSignificant clinical-pathologic differences exist among HCC patients with underlying HBV vs. HCV. These differences impact eligibility for potentially-curative therapy and prognosis.

Characterization of hepatocellular adenoma based on the phenotypic classification: The Kanazawa experience

Hepatocellular adenoma (HCA) represents a heterogeneous entity, and recently four major subgroups were identified based on genotype and phenotype classification from Europe. HCA is rare in Asian countries including Japan and there has been no study regarding the subgroups of HCA in Japan. We took advantage of the reported genotype/phenotype classification to analyze 14 HCA (seven women) in Japan. We identified one hepatocyte nuclear factor (HNF)1α-inactivated HCA (one woman), two β-catenin-activated HCA (one woman), seven inflammatory HCA (IHCA, two women); four additional cases (three women) had no known phenotypic marker (unclassified HCA). The use of oral contraceptives was found only in two unclassified HCA (29%) cases. Fatty change of the background liver was seen in one β-catenin-activated HCA cases, four IHCA (57%) and two unclassified HCA (50%). Hepatic fibrosis was seen in five IHCA (71%) and two unclassified HCA (50%) cases. Four IHCA patients (one woman) were alcohol drinkers and one had alcoholic steatofibrosis and three had alcoholic cirrhosis. Eight HCA (57%) were multiple; one HNF1α-inactivated HCA (100%), four IHCA (57%) and three unclassified HCA (75%). The tumor was significantly larger in β-catenin-activated HCA than in other subgroups. The association of hepatocellular carcinoma was seen only in one case of unclassified HCA. This study suggests that IHCA arising in men with alcoholic liver disease may be a major subtype of HCA in Japan.