• Hepatocellular carcinoma
• Potential mechanisms
• RNA-seq
• Sorafenib resistance
• WGCNA

• NO.RC20200102 Nanning Excellent Young Scientist Program

• Ethnicity
• Hepatic malignancy
• Independent prognostic factor
• Neuroendocrine tumors
• Prognosis

• Age
• Hepatocellular Carcinoma
• Sex Disparity
• Sex Steroids

• Male
• Humans
• Female
• Middle Aged
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Retrospective Studies
• Hepatectomy
• Estrogens
• Propensity Score
• Neoplasm Recurrence, Local/pathology

• androgen receptor
• estrogen receptor α
• hepatocellular carcinoma
• hormone therapy
• sex hormones

• Male
• Humans
• Carcinoma, Hepatocellular
• Hepatitis B virus
• Liver Neoplasms/epidemiology
• Hepatitis B/complications
• Hepatitis B/epidemiology
• Gonadal Steroid Hormones
• Hepatitis B, Chronic/complications

• BJ-2022-182 Beijing Hospital Clinical Research Project

Saliva is rich in proteins, DNA, RNA and microorganisms, and can be regarded as a biomarker library. In order to explore a noninvasive and simple means of early screening for liver cancer, proteomics was used to screen salivary markers of hepatitis B associated liver cancer. We used mass spectrometry coupled isobaric tags for relative and absolute quantitation (iTRAQ)-technology to identify differentially expressed proteins (DEPs). Western blot, immunohistochemistry and enzyme linked immunosorbent assay were used to detect marker expression of in tissues and saliva. Statistical analysis was used to analyze the diagnostic efficacy of the markers was analyzed through statistical analyses. By comparing the hepatocellular carcinoma (HCC) group with non-HCC groups, we screened out 152 salivary DEPs. We found orosomucoid 1(ORM1) had significantly higher expression in saliva of HCC patients compared with non-HCC groups (p < 0.001) and the expression of ORM1 in liver cancer tissues was significantly higher than that in adjacent normal tissues (p < 0.001). The combination of salivary ORM1 and alpha-fetoprotein (AFP) showed reasonable specificities and sensitivities for detecting HCC. In a word, salivary ORM1 as a new biomarker of hepatitis B associated hepatocellular carcinoma, combination of salivary ORM1 and AFP as an improved diagnostic tool for hepatocellular carcinoma.

• FOSL2
• Hepatocellular carcinoma (HCC)
• circ_0091581
• miR-591

• dextran sulfate sodium
• double transgenic zebrafish
• lipopolysaccharides
• liver tumor metastasis
• twist1a
• xmrk

To investigate the diagnostic efficacy of choline (Cho) value of magnetic resonance spectroscopy (MRS) in rabbit with VX2 liver tumor via comparative and quantitative analysis with the choline compounds concentration measured by enzyme linked immunosorbent assay (ELISA).

MRS was performed on normal liver and VX2 tumor. The Cho value of VX2 tumor was compared with that of normal liver. Tissues were harvested for ELISA to detect the concentrations of acetylcholine (ACh), glycophorophosphygholine (GPC) and phosphochorine (PC). The diagnostic performance of Cho value and concentrations of choline compounds were assessed by receiver operating characteristic (ROC) curve and area under ROC curve (AUC). The specificity and sensitivity were discussed by the maximum Youden’s index.

The concentration of ACh was obviously higher than that of GPC and PC both in VX2 tumor and normal liver (P < 0.01). Furthermore, the concentration differences among ACh, GPC and PG were the third power of 10. Both the ACh concentration and Cho value of MRS in VX2 tumor were significantly higher than those in normal liver (P < 0.01). The AUC of ACh in VX2 tumor was 0.883, when the cutoff value was 7259000, the sensitivity and specificity of the diagnosis of liver cancer were 94.4% and 77.8%, respectively. The AUC of Cho in VX2 tumor was 0.807, when the cutoff value was 28.35, the sensitivity and specificity of the diagnosis of liver cancer were 83.3% and 77.8%, respectively.

The change of Cho value in MRS between liver cancer and normal liver was consistent with the changes of concentrations of choline compounds measured by ELISA, especially the change of ACh concentration. The diagnostic efficiency of Cho value and that of choline compounds concentration in liver cancer were extremely similar, with the AUC more than 0.8. We conclude that MRS may be applied as an important, non-invasive biomarker for the diagnosis of liver cancer.

• 3.0 tesla
• choline
• liver cancer
• proton magnetic resonance spectroscopy

The histone acetyltransferase MOF (KAT8) is mainly involved in the acetylation of histone H4 at lysine 16 (H4K16) and some non‐histone proteins. The MOF expression level is significantly reduced in many cancers, however the biological function of MOF and its underlying mechanism are still elusive in hepatocellular carcinoma (HCC). Estrogen receptor α (ERα) has been considered as a tumor suppressor in HCC. Here, we demonstrated that MOF expression is significantly reduced in HCC samples, and is positively correlated with that of ERα. MOF interacts with ERα, and participates in acetylation of ERα at K266, K268, K299, thereby inhibiting ERα ubiquitination to maintain the stability of ERα. In addition, MOF participates in the upregulation of ERα‐mediated transactivation. Depletion of MOF significantly promotes cell growth, migration, and invasion in HCC cell lines. Taken together, our results provide new insights to understand the mechanism underlying the modulation function of MOF on ERα action in HCC, suggesting that MOF might be a potential therapeutic target for HCC.

• MOF
• acetylation
• estrogen receptor α
• hepatocellular carcinoma
• tumor suppression

Our previous study reported a method of using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to analyze the association between abnormal fucosylation of serum glycoproteins and the progression of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). In the present study, the aforementioned method was improved by focusing on fucosylated glycoproteins <10 kD, classification models were established and blind tests were performed on an enlarged sample size (n=299). According to the present results, the classification models had a sensitivity and specificity of 74.31 and 76.32%, respectively, to identify HCC among all serum samples, 81.65 and 83.08%, respectively, to distinguish HCC from HBV-associated cirrhosis and chronic hepatitis Band 88.99 and 84.62%, respectively, to distinguish HCC from HBV-associated cirrhosis. When combined with α-fetoprotein (AFP) measurements (AFP >20 ng/ml), the sensitivity and specificity of the models were significantly elevated to 80.73 and 87.37%, 87.16 and 90.00%, and 92.66 and 93.84%, respectively. In addition, the HBV-HCC vs. HBV-cirrhosis classification model was used to analyze serum samples collected from 9 patients with cirrhosis 1 year before they were diagnosed with HCC, and from 6 patients who had cirrhosis but developed no signs of HCC for the following 3 years. The model identified 7 patients (77.78%) with no significant clinical symptoms of HCC, and gave no false positive results, demonstrating that the classification models established in the present study may be useful for the early diagnosis of HCC. After isolation and purification, two proteins with differential expression were identified as isoform 1 of inter-α-trypsin inhibitor heavy chain 4 precursor, and thymosin β-4-like protein 3. These may be used as candidate markers for HCC diagnosis. Additionally, the present study indicates that defucosylation of serum glycoproteins may occur during the development and progression of HCC.

• MALDI-TOF MS profiling
• defucosylation
• early diagnosis
• fucosylation
• hepatitis B virus
• hepatocellular carcinoma

• CXCL6
• circ-HOMER1
• circular RNA
• hepatocellular carcinoma
• miR-1322

There is currently no evidence that hepatitis C virus (HCV) genotype affects survival in patients with hepatocellular carcinoma (HCC). This study aimed to investigate whether the HCV genotype affected the survival rate of patients with HCV-related HCC.

We performed a retrospective cohort study using the data of patients with HCV-related HCC evaluated at two centers in Korea between January 2005 and December 2016. Propensity score matching between genotype 2 patients and non-genotype 2 patients was performed to reduce bias.

A total of 180 patients were enrolled. Of these, 86, 78, and 16 had genotype 1, genotype 2, and genotype 3 HCV-related HCC, respectively. The median age was 66.0 years, and the median overall survival was 28.6 months. In the entire cohort, patients with genotype 2 had a longer median overall survival (31.7 months) than patients with genotype 1 (28.7 months; P = 0.004) or genotype 3 (15.0 months; P = 0.003). In the propensity score–matched cohort, genotype 2 patients also showed a better survival rate than non-genotype 2 patients (P = 0.007). Genotype 2 patients also had a longer median decompensation-free survival than non-genotype 2 patients (P = 0.001). However, there was no significant difference in recurrence-free survival between genotype 2 and non-genotype 2 patients who underwent curative treatment (P = 0.077). In multivariate Cox regression analysis, non-genotype 2 (hazard ratio, 2.19; 95% confidence interval, 1.29–3.71) remained an independent risk factor for death.

Among patients with HCV-related HCC, those with genotype 2 have better survival.

The online version of this article (10.1186/s12885-019-6040-3) contains supplementary material, which is available to authorized users.

• Genotype
• Hepatitis C virus
• Hepatocellular carcinoma
• Survival

Objective: This study aimed to develop and validate a simple-to-use nomogram for early hepatocellular carcinoma (HCC) patients undergoing a preoperative consultation and doctors conducting a postoperative evaluation.

Methods: A total of 2,225 HCC patients confirmed with stage I or II were selected from the Surveillance, Epidemiology, and End Results database between January 2010 and December 2015. The patients were randomly divided into two groups: a training group (n = 1,557) and a validation group (n = 668). Univariate and multivariate hazards regression analyses were used to identify independent prognostic factors. The Akaike information criterion (AIC) was used to select variables for the nomogram. The performance of the nomogram was validated concerning its ability of discrimination and calibration and its clinical utility.

Results: Age, alpha-fetoprotein (AFP), race, the degree of differentiation, and therapy method were significantly associated with the prognosis of early HCC patients. Based on the AIC results, five variables (age, race, AFP, degree of differentiation, and therapy method) were incorporated into the nomogram. The concordance indexes of the simple nomogram in the training and validation groups were 0.707 (95% CI: 0.683–0.731) and 0.733 (95% CI: 0.699–0.767), respectively. The areas under the receiver operating characteristic (ROC) curve of the nomogram in the training and validation groups were 0.744 and 0.764, respectively, for predicting 3-year survival, and 0.786 and 0.794, respectively, for predicting 5-year survival. Calibration plots showed good consistency between the predictions of the nomogram and the actual observations in both the training and validation groups. Decision curve analysis (DCA) showed that the simple nomogram was clinically useful, and the overall survival significantly differed between low- and high-risk groups divided by the median score of the nomogram in the training group (P < 0.001).

Conclusion: A simple-to-use nomogram based on a large population-based study is developed and validated, which is a conventional tool for doctors to facilitate the individual consultation of preoperative patients and the postoperative personalized evaluation.

• clinic utility
• early hepatocellular carcinoma
• nomogram
• prediction
• survival analysis

• Yttrium
• bioactive glass
• electron microscopy
• spray pyrolysis

• MOST 105-2221-E-011-034 Ministry of Science and Technology, Taiwan
• MOST 106-2221-E-011-049 Ministry of Science and Technology, Taiwan
• MOST 107-2218-E-009-003 Ministry of Science and Technology, Taiwan

• Egypt
• Hepatitis C virus
• Hepatocellular carcinoma
• Survival

• cancer - see oncology
• emergency medicine

• diabetes mellitus
• liver cancer
• meta-analysis
• metformin
• survival

MicroRNAs (miRNAs) exhibit essential regulatory functions related to cell growth, apoptosis, development and differentiation. Dysregulated expression of miRNAs is associated with a wide variety of human diseases. As such miRNA signatures are valuable as biomarkers for disease and for making treatment decisions. Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Here we screened for miRNAs in chronic HBV associated HCC.

To determine the miRNAs in HCC occurrence associated with HBV infection, we analyzed global miRNA expression profiles in 12 pairs of HCC and adjacent matched non-HCC tissues from HBV-positive and HBV-negative patients using microarray analyses. The microarray result was validated by real-time PCR in 32 HBV-positive and 24 HBV-negative patient HCC samples. The potential candidate target genes of the miRNAs were predicted by miRWalk software. Genes simultaneously predicted as targets by two or more miRNAs were subjected to GO and KEGG pathway analysis. The miRNA regulatory network analysis was performed using the Ingenuity Pathway Analysis (IPA) software.

Eight miRNAs (miR-223, miR-98, miR-15b, miR-199a-5p, miR-19b, miR-22, miR-451, and miR-101) were involved in HBV-unrelated HCC, 5 miRNAs (miR-98, miR-375, miR-335, miR-199a-5p, and miR-22) were involved in HBV infection, and 7 miRNAs (miR-150, miR-342-3p, miR-663, miR-20b, miR-92a-3p, miR-376c-3p and miR-92b) were specifically altered in HBV-related HCC. Gene Ontology and KEGG analyses predict that these HBV-related HCC miRNAs are involved in the regulation of: transcription, RNA polymerase II promoter, phosphorylation of proteins through MAPK signaling pathway, focal adhesion, and actin cytoskeleton. IPA analysis also suggest that these miRNAs act on AGO2, TP53, CCND1, and 11 other genes that significantly influence HCC occurrence and HBV infection.

Our data indicates that the unique 7 miRNAs expression signature could be involved in the development HBV- related HCC.

The online version of this article (10.1186/s12885-017-3816-1) contains supplementary material, which is available to authorized users.

• Hepatitis B virus
• Hepatocellular carcinoma
• Regulatory network
• microRNA

• Hepatocellular carcinoma
• Insulin
• Liver cancer
• Metformin
• NAFLD
• NASH
• SIRT-3
• Sorafenib
• Type II diabetes mellitus

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Databases, Factual
• Diabetes Mellitus, Type 2/diagnosis
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/mortality
• Disease-Free Survival
• Drug Interactions
• Drug Resistance, Neoplasm
• Female
• Humans
• Hypoglycemic Agents/adverse effects
• Hypoglycemic Agents/therapeutic use
• Immunohistochemistry
• Insulin/adverse effects
• Insulin/therapeutic use
• Italy
• Kaplan-Meier Estimate
• Liver Neoplasms/drug therapy
• Liver Neoplasms/enzymology
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Male
• Metformin/adverse effects
• Metformin/therapeutic use
• Middle Aged
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/adverse effects
• Phenylurea Compounds/therapeutic use
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/therapeutic use
• Retrospective Studies
• Sirtuin 3/analysis
• Sorafenib
• Time Factors
• Treatment Outcome

• liver tumor
• mortality
• reduction
• risk factor

• Adult
• Aged
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/mortality
• Case-Control Studies
• Estrogen Replacement Therapy/methods
• Female
• Humans
• Incidence
• Liver Neoplasms/drug therapy
• Liver Neoplasms/epidemiology
• Liver Neoplasms/mortality
• Middle Aged
• Risk Assessment
• Survival Analysis
• Treatment Outcome

• K07 CA106458 NCI NIH HHS
• P30 CA023108 NCI NIH HHS
• R01 CA186566 NCI NIH HHS

• cancer
• celecoxib
• chalcone epoxide
• cyclooxygenase 2
• prostaglandin E2

• Biomarker Data Analysis
• Classification Model
• Joint Distribution
• Liver Cancer
• Sensitivity
• Specificity

• ERα signaling
• Hepatocellular carcinoma
• Mouse model
• Tamoxifen therapy
• Tumorigenesis

Hepatocellular carcinoma (HCC) is a disease usually diagnosed in its advanced-stage, and is frequently not amenable to curative surgical treatment. Also, HCC is resistant to chemotherapy and less vulnerable to radiation therapy compared to normal hepatic parenchyma. Both of these facts render the efficacy of adjuvant and palliative treatments problematic. Selective internal radiation therapy (SIRT) with ⁹⁰Y-bearing microspheres is characterized by preferentially delivering substantially high doses of radiation to a liver tumor dose simultaneously limiting the damage to its non-tumorous cells, providing an opportunity for effective local tumor control and even tumor regression therapy. The current article reviews the specific characters, dosimetry, possible applications, and special considerations toward the pre-existing radiation therapy of ⁹⁰Y microsphere SIRT in treating HCC.

• 90Y microspheres
• 99mTc macroaggregated albumin
• External beam radiation therapy
• Hepatocellular carcinoma
• Radiation lobectomy
• Selective internal radiation therapy
• Transarterial chemoembolization

• Antibody-based proteomics
• Apoptosis
• Biomarker
• Early recurrence
• Hepatocellular carcinoma

• Hepatocellular carcinoma
• Racial disparity
• Survival

Transforming growth factor-β1 (TGF-β1) reportedly acts as a tumor suppressor in tumorigenesis. However, little is known as to how TGF-β1 concentrations change prior to the development of hepatocellular carcinoma (HCC) in humans. We examined the association between the serum TGF-β1 concentrations and death from HCC to determine whether the serum TGF-β1 can be a predictor of incident HCC.

We conducted a nested case-controlled study of participants in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. We used a conditional logistic regression analysis to estimate the adjusted relative risks (aRRs) of death from HCC according to the serum TGF-β1 concentrations among 1940 participants including 83 patients with HCC and 1857 controls matched for age, sex, and hepatitis C virus (HCV)-antibody seropositivity.

When serum TGF-β1 was modelled as a continuous variable, the aRR of death from HCC associated with a decrement of 7.9 ng/mL (one standard deviation) in the serum TGF-β1 concentrations was 2.3 (95% CI 1.7–3.0, P < 0.001) for all the subjects. The area under the receiver operating characteristic curve for the serum TGF-β1 concentrations was 0.78 (P < 0.05).

Our finding suggests that TGF-β1 serves as a predictor for HCC.

•

We studied whether TGF-β1 concentration predicts incident HCC.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and has a poor prognosis. HCC is difficult to diagnose early enough to perform a radical treatment. Nowadays there are several biomarkers, such as alpha-fetoprotein (AFP), but it is difficult to detect HCC in the early stage with those markers. To address this knowledge gap, we conducted a nested case-controlled study to find the predictor for HCC. We found that TGF-β1 concentrations were inversely associated with HCC occurrence. Our data demonstrates that low levels of TGF-β1 can identify patients who are at higher risk of developing HCC. TGF-β1 may be a predictor that becomes altered well before the development of clinically detectable malignancy.

• Hepatocellular carcinoma
• Nested case-controlled study
• Predictor
• TGF-β1

• Diabetes mellitus
• Hepatocellular carcinoma
• Metformin
• Risk

• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/prevention & control
• Comorbidity
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/epidemiology
• Humans
• Hypoglycemic Agents/therapeutic use
• Liver Neoplasms/epidemiology
• Liver Neoplasms/prevention & control
• Metformin/therapeutic use
• Risk Factors

Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) mRNA. A genetic HCC mouse model was employed to assess the ability of metformin to reduce tumor formation, induce apoptosis, and control 4E-BP1 activation and Mcl-1 protein expression. In parallel, the HCC cell line Huh7 was transduced with scrambled shRNA (control) or shRNAs targeting 4E-BP1 and 4E-BP2 (4E-BP knock-down (KD)) to measure differences in mRNA translation, apoptosis, and Mcl-1 protein expression after metformin treatment. In addition, immunohistochemical staining of eIF4E and 4E-BP1 protein levels was addressed in a HCC patient tissue microarray. We found that metformin decreased HCC tumor burden, and tumor tissues showed elevated apoptosis with reduced Mcl-1 and phosphorylated 4E-BP1 protein levels. In control but not 4E-BP KD Huh7 cells, metformin induced apoptosis and repressed Mcl-1 mRNA translation and protein levels. Immunostaining of HCC patient tumor tissues revealed a varying ratio of eIF4E/4E-BP1 expression. Our results propose that metformin induces apoptosis in mouse and cellular models of HCC through activation of 4E-BPs, thus tumors with elevated expression of 4E-BPs may display improved clinical chemopreventive benefit of metformin.

• 4E-BPs
• hepatocellular carcinoma
• mRNA translation
• mTORC1
• metformin

• 1-Deoxynojirimycin/analogs & derivatives
• 1-Deoxynojirimycin/pharmacology
• Antiviral Agents/pharmacology
• Cell Line, Tumor
• Cell Survival/drug effects
• DNA, Viral/drug effects
• Dose-Response Relationship, Drug
• Enzyme Inhibitors/pharmacology
• Glycoproteins/antagonists & inhibitors
• Glycoside Hydrolase Inhibitors
• Hepatitis B virus/drug effects
• Humans
• Lamivudine/pharmacology
• Microbial Sensitivity Tests
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Viral Envelope Proteins/antagonists & inhibitors

• AI054763 NIAID NIH HHS
• AI53884 NIAID NIH HHS

• adenocarcinoma
• carcinoma
• esophagus
• squamous

• Agglutinin
• Biomarker
• Glycoproteomics
• Hepatitis
• Hepatocellular Carcinoma
• Liver cirrhosis

Background: Intraductal papillary mucinous neoplasms (IPMNs) are precancerous lesions with a well-described adenoma-carcinoma sequence. Although the risk of malignant transformation has been well studied, data on trends in long-term survival and important prognostic factors associated with survival in malignant IPMN are lacking.

Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with confirmed malignant IPMN based upon pathologic diagnosis or radiographic evidence concerning for malignant potential. Median survival and age-adjusted incidence were calculated. Cox proportional hazard regression was used to determine independent mortality factors.

Results: Based upon the SEER database query, 2651 patients were diagnosed with malignant IPMN between 1990 and 2010. The age-adjusted incidence of IPMN in 1990 was 0.361 per 100 000 persons (95% confidence interval [CI]: 0.285–0.451) with a steady decline observed through 2010 (0.135 per 100 000 persons, 95% CI: 0.098–0.186). A total of 564 patients (21.3%) underwent a surgical procedure, though the number of patients who underwent surgery from 1990 to 2010 also decreased (1990–1995, n = 132 to 2006–2010, n = 96, respectively). The overall median survival was 4 months and remained relatively stable from 1990 to 2010. Performance of surgery (HR: 0.45, 95% CI: 0.40–0.53, P < 0.001) was associated with a decreased risk of death.

Conclusion: A significant decrease in the incidence of malignant IPMN was seen from 1990 to 2010. There was also no improvement observed in long-term survival. The small percentage of eligible cases receiving surgical treatment suggests that there is room for further improvement in survival, with increased utilization of surgery.

• incidence
• intraductal papillary mucinous neoplasm (IPMN)
• long-term survival
• malignant transformation

• Estrogen metabolism
• Estrogens
• Inflammation
• Liver disease
• Steroid sulfatase

After transcatheter delivery through hepatic artery, a hydrogel can be formed within tumor vasculature by the decrease of environmental pH, block the blood vessel and control the release of loaded anticancer drugs.

• diabetes
• hepatocellular carcinoma
• insulin
• metformin
• sorafenib