OBJECTIVE:Evaluating portal hypertension is crucial for patients with hepatocellular carcinoma (HCC) who are candidates for liver resection. Total bile acid (TBA) is an easily accessible marker, but its potential as a non-invasive indicator of portal hypertension in patients with HCC is yet to be fully established. METHODS:This study included patients with HCC classified as Child-Pugh stage A who underwent liver resection at a referral hospital. Elevated TBA levels were defined as serum TBA >10 μmol/L, while normal levels were ≤10 μmol/L. RESULTS:A total of 167 patients with HCC with Child-Pugh Class A who underwent liver resection were analyzed. The cohort was divided into normal (n = 125) and elevated TBA groups (n = 42). Compared to patients with normal TBA levels, those with elevated TBA had significantly higher 15-min indocyanine green retention rates (ICG R15) (p <0.001), higher Child-Pugh scores (p <0.001), more advanced Laennec fibrosis stages (p = 0.039), and a higher incidence of esophageal gastric varices (p = 0.001) and post-hepatectomy liver failure (p = 0.001). Multivariate analysis showed that elevated TBA was independently associated with ICG R15 (odds ratio [OR] = 1.150, 95% confidence interval [CI] = 1.055-1.254, p = 0.002), fibrosis stages (OR = 1.973, 95% CI = 1.026-3.796, p = 0.042), and Child-Pugh score (OR = 4.121, 95% CI = 1.367-12.424, p = 0.012). CONCLUSION:Elevated TBA levels in patients with HCC with Child-Pugh class A are significantly associated with portal hypertension and a higher incidence of post-hepatectomy liver failure.

As a kind of prevalent malignancy globally, hepatocellular carcinoma (HCC) is characterized by significant morbidity and mortality due to the difficulties in early diagnosis and limited treatment options. Circular RNAs (circRNAs) are a type of circular single-stranded RNA molecule formed by the back-splicing of the 5’ end and the 3’ end of linear RNA, possessing multiple biological functions. In recent years, numerous reports have demonstrated that circRNAs are potential biomarkers and therapeutic targets for HCC. In this study, we found that circITGA7 is significantly downregulated in HCC tissue compared to adjacent non-tumor tissue. Functional experiments such as CCK8, EdU, colony formation and wound healing assays proved that overexpression of circITGA7 can effectively inhibit the proliferation, migration and invasion of HCC cells. Further research found that circITGA7 can inhibit miR-330 to release BCL11B expression, thereby promoting P53 expression, blocking the cell cycle and promoting apoptosis in HCC cells. In addition, circITGA7 can impede the proliferation of HCC cells in vivo. Therefore, circITGA7 is a potential biomarker for the diagnosis of HCC development and a potential target for the treatment of HCC.

Background and aims Total bile acid (TBA) is associated with portal hypertension, a risk factor for post-hepatectomy liver failure (PHLF). We conducted this study to clarify whether TBA is also associated with PHLF in patients with hepatocellular carcinoma (HCC). Methods We recruited patients with HCC and Child-Pugh class A, who underwent liver resection, and applied multivariate analyses to identify risk factors for PHLF. Results We analyzed data from 154 patients. The prevalence of PHLF was 14.3%. The median maximum tumor diameter was 5.1 cm (2.9–6.9 cm). The proportions of patients with elevated TBA levels (P = 0.001), severe albumin-bilirubin (AIBL) grades (P = 0.033), and low platelet counts (P = 0.031) were significantly higher within the subgroup of patients with PHLF than in the subgroup without PHLF. The multivariate analysis results suggest that TBA level (OR, 1.08; 951.03–1.14; P = 0.003) and MRI tumor diameter (OR, 1.17; 95% CI, 1.01–1.35; P = 0.038) are independent preoperative risk factors for PHLF. The TBA levels correlated with the indocyanine green retention rate at 15 minutes (P = 0.001) and the effective hepatic blood flow (P < 0.001), two markers of portal hypertension. However, TBA levels did not correlate with tumor diameter (P = 0.536). Conclusions Compared to ICG R15 and AIBL score, preoperative TBA was risk factor for PHLF in Chinese patients with HCC, and it may impact PHLF through its potential role as a marker of portal hypertension.

BackgroundOrthotopic liver transplantation (OLT) is a life-saving option for patients with hepatocellular carcinoma (HCC), but the expanded OLT criteria remain controversial.ObjectiveThe study aimed to explore whether expanded OLT criteria can be applied to Chinese cirrhotic patients with HCC.MethodsThis retrospective study analyzed risk factors for HCC recurrence and death and compared patients’ tumor characteristics and outcomes in groups of Milan, “Up-to-seven,” and Hangzhou criteria, and groups between met and unmet the combinative criteria of “Up-to-seven” and AFP of < 1000 ng/mL.ResultsAmong 153 patients who underwent OLT for HCC from January 2015 to February 2019 in 4 years of follow-up, 20 (13.1%) patients had HCC recurrence, and 11 (7.2%) had HCC-related death. Multivariate Cox regression analysis showed that preoperative alpha-fetoprotein (AFP) of > 1000 ng/mL (hazard ratio [HR]: 10.05, 95% confidence interval [CI]: 2.45–41.13, P = 0.001) was an independent risk factor for HCC recurrence and HCC-related death (HR: 6.63, 95%CI: 1.31–33.52, P = 0.022). Patients who did not meet Milan criteria but satisfied the “Up-to-seven” criteria had no differences in overall survival (OS) (P = 0.69) and disease-free survival (DFS) (P = 0.35) than patients who met the Milan criteria. The combination of “Up-to-seven” criteria and AFP of < 1000 ng/mL differed significantly (HR: 18.9; 95% CI: 4.0–89.2; P < 0.001). Patients with HCC who met the “Up-to-seven” criteria and AFP of < 1000 ng/mL (n = 121) had excellent survival with 4-year OS of 91.6% (P < 0.001) and DFS of 90.8% (P < 0.001), which is significantly better compared to the other group (n = 32) (OS of 67.5% and DFS of 46.5%) and patients who met the Milan criteria (n = 108, OS of 89.8%, DFS of 89.6%), allowing 28.9% (13/45) of patients who did not meet the Milan criteria to benefit from OLT.ConclusionChinese cirrhotic patients with HCC who met the combinative criteria of “Up-to-seven” and AFP of < 1000 ng/mL had better survival than those who met the Milan criteria, and these combinative criteria benefited more patients and may become a better option for OLT.

Context Kuhuang (KH) injection is a widely used anticholestatic drug in the clinic and the mechanisms are still unclear. Objective This study uses a new 3D tissue-engineered (TE) liver platform to study the ability of kuhuang to ameliorate liver injury induced by chlorpromazine (CPZ) and the possible mechanisms involved. Materials and methods The TE livers (n = 25) were divided into 5 groups (n = 5 livers/group) as 3D, 3D + CPZ, 3D + CPZ + KH, 3D + CPZ + GW9662 (a PPAR gamma inhibitor) and 3D + CPZ + KH + GW9662. The treatments with kuhuang (1 mg/mL) and GW9662 (10 mu mol/L) were given to the desired groups on the 7th day of the experimental process. 20 mu mol/L CPZ was added on the 8th day. Results According to the 2D experimental results, the minimum effective concentration of kuhuang is 10 mu g/mL and the optimal effective concentration is 1 mg/mL. Kuhuang ameliorated tissue damage in the TE livers both in terms of tissue structure and culture supernatant. Kuhuang significantly reduced TBA accumulation (38%) and downregulated CYP7A1 (38%) and CYP8B1 (79%). It reduced hepatic levels of ROS (14%), MDA (27%) but increased the levels of GSH (41%), SOD (12%), BSEP (4.4-fold), and MRP2 (74%). Moreover, kuhuang downregulated DR5 (99%) but increased the mRNA expression of PPAR gamma (4-fold). Molecular docking analyses determined the bioactivity of the active compounds of kuhuang through their specific bindings to PPAR gamma. Conclusions Kuhuang could alleviate CPZ-induced cholestatic liver injury by activating PPAR gamma to reduce oxidative stress. Applying kuhuang for the treatment of CPZ-induced liver injury could be suggested.

Increasing evidence indicates that the oncoprotein murine double minute (MDM2) binding protein (MTBP) can be considered a pro-oncogene of human malignancies; however, its function and mechanisms in hepatocellular carcinoma (HCC) are still not clear. In the present work, our results demonstrate that MTBP could function as a co-activator of transcription factor E26 transformation-specific sequence (ETS-1), which plays an important role in HCC cell proliferation and/or metastasis and promotes proliferation of HCC cells. Using luciferase and real-time polymerase chain reaction (qPCR) assays, MTBP was found to enhance the transcription factor activation of ETS-1. The results from chromatin co-immunoprecipitation showed that MTBP enhanced the recruitment of ETS-1 to its downstream gene's (mmp1's) promoter region with ETS-1 binding sites. In cellular and nude mice models, overexpression of MTBP was shown to promote the proliferation of MHCC97-L cells with low endogenous MTBP levels, whereas the knockdown of MTBP led to inhibition of the proliferation of MHCC97-H cells that possessed high endogenous levels of MTBP. The effect of MTBP on ETS-1 was confirmed in the clinical specimens; the expression of MTBP was positively correlated with the downstream genes of ETS-1, mmp3, mmp9, and uPA. Therefore, by establishing the role of MTBP as a novel co-activator of ETS-1, this work expands our knowledge of MTBP or ETS-1 and helps to provide new ideas concerning HCC-related research.

Background: Organ donation from a deceased donor, which is donation after brain death followed by circulatory death, is a unique transplantation practice in China. Pathological features of grafts help guide the utilization of grafts. Material/Methods: We retrospectively reviewed our experiences in 188 DBCD allografts from May 2014 to April 2017. We divided 183 transplanted allografts into 3 groups according to pretransplant histology: the good quality graft group (n=62), the preservation injury group (n=27), and the steatotic graft group (n=94). Univariate and multivariate analyses were performed to identify factors in the steatotic graft group predicting the prognoses. Results: The prevalence rates of allografts in the good quality, steatotic liver, and preservation injury groups were 33.0% (62/188), 50.0% (94/188), and 14.4%(27/188), respectively, and the discarded rate was 2.7% (5/188). The 1- and 3-year overall survival rates were 92.1% and 88.1%, respectively. There were no differences in 1- and 3-year patient survival among the 3 groups (p=0.615). Some complications occurred: acute rejection in 7 cases, lung infection in 11 recipients, biliary stricture and bile leak in 9 patients, and portal thrombosis in 1 recipient; 17 recipients died of various causes. Cox multivariate analysis revealed that longer cold storage time was associated with worse outcome in the steatotic graft group. Conclusions: Clinical outcomes of adult liver transplantation from deceased donation in China are acceptable.

The expression of androgen receptor (AR) has been detected in hepatocellular cancer (HCC). However, there is no universal model detailing AR's function and mechanism in HCC. This study's results show that treatment with dihydrotestosterone (DHT), an endogenous androgen, promoted HCC cells' proliferation and up-regulated the transcription factor activity of ETS-1 (E26 transformation specific sequence 1), which mediates the migration and invasion of cancer cells via protein-protein interaction between AR and ETS-1. Results from luciferase assays showed that ETS-1's activity was significantly up-regulated following androgen treatment. AR mediated ETS-1's DHT-induced transcription factor activity. A potential protein-protein interaction between ETS-1 and AR was identified via glutathione S-transferase (GST) pull-down and co-immunoprecipitation assays. The mechanisms' data indicated that enhancing AR activity increases ETS-1's activity by modulating its cytoplasmic/nuclear translocation and recruiting ETS-1 to its target genes' promoter. Moreover, while overexpression of AR significantly increased the proliferation or in vitro migration or invasion of HepG2 cells in the presence of androgen, inhibiting AR's activity reduced these abilities. Thus, AR's function as a novel ETS-1 co-activator or potentially therapeutic target of HCC has been demonstrated.

The pregnane X receptor (PXR) is an important regulator of hepatocellular carcinoma cellular resistance to antitumor drugs. Activation of PXR was modulated by the co-regulators. The target protein for the Xenopus plus end-directed kinesin-like protein (Xklp2) known as TPX2 that was previously considered as a tubulin regulator, also functions as the regulator of some transcription factors and pro-oncogenes in human malignances. However, the actions of TPX2 on PXR and HCC cells are still unclear. In the present study, our results demonstrate that the high expression of endogenous mRNA level of TPX2 not only correlated with the poor prognosis of advanced HCC patients who received sorafenib treatment but also with expression of PXR's downstream genes, cyp3a4 and/or mdr-1. Results from luciferase and real-time polymerase chain reaction (qPCR) showed that TPX2 leads to enhancement of the transcription factor activation of PXR. Protein-protein interactions between PXR and TPX2 were identified using co-immunoprecipitation. Mechanically, overexpression of TPX2 led to enhancement of PXR recruitment to its downstream gene cyp3a4's promoter region (the PXRE region) or enhancer region (the XREM region). Treatment of HCC cells with paclitaxel, a microtubule promoter, led to enhancement of the effects of TPX2, whereas vincristine, a microtubule depolymerizing agent caused a decrease in TPX2-associated effects. TPX2 was found to cause acceleration of the metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI) in HCC cells and in turn led to the resistance to sorafenib by HCC cells. By establishing novel actions of TXP2 on PXR in HCC cells, the results indicate that TPX2 could be considered a promising therapeutic target to enhance HCC cells sensitivity to antitumor drugs.