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Introduction: Laparoscopic repeat hepatectomy (LRH) is considered to be a technically challenging procedure which has not been widely applied. This study aimed to assess the accessibility and security of LRH for patients with hepatic tumor recurrence., Methods: Between January 2010 and October 2020, we performed 48 LRHs and 31 open repeat hepatectomies (ORHs) for recurrent liver cancer. LRHs were matched to ORHs (1:1) using propensity score matching (PSM) created by comparing preoperative factors. The perioperative data of patients were retrospectively analyzed, including baseline data, operative time, intraoperative blood loss, pathology, days of postoperative stay, complication morbidity, and mortality within 30 days. Overall survival and recurrence-free survival rates with appropriate follow-up were obtained to evaluate the long-term outcomes., Results: Compared with the ORH, LRH was related with shorter operative duration (169.9 versus 232.9 ml, p < 0.01), less intraoperative bleeding (100.0 versus 500.0 ml, p < 0.01), lower rate of blood transfusion (8.3% versus 58.1%, p < 0.01), and shorter hospitalization (5.0 versus 11.0 days, p < 0.01). The median follow-up was 31 months. The LRH 1-, 3-, and 5-year overall survival were 77.1%, 61.6%, and 46.2% versus 82.3%, 66.5%, and 29.5% for ORH (p = 0.77). The 1-, 3-, and 5-year disease-free survival rates of the two groups were 73.4%, 62.0%, and 44.3% versus 66.1%, 44.1%, and 14.7%, respectively (p = 0.22)., Conclusions: Laparoscopic repeated hepatectomy is safe and practicable with great short-term results for selected patients., (© 2022. The Author(s).)

Rationale and Objectives To evaluate the effectiveness of radiomics analysis based on Gd-EOB-DTPA enhanced hepatic MRI for functional liver reserve assessment in HCC patients. Materials and Methods Radiomics features were extracted from Gd-EOB-DTPA enhanced MRI images in 60 HCC patients. Boruta algorithm was performed to select features associated with indocyanine green retention rate at 15 min (ICG R15). Prediction and classification model were built by performing Random Forest regression analysis. Pearson correlation analysis and AUC of ROC were used to assess performance of the two models. Results A total of 165 radiomics features were extracted. Six radiomics features were selected to build the prediction model. A Predicted value of ICG R15 for each patient was calculated by the prediction model. Pearson correlation analysis revealed that predicted values were significantly associated with actual values of ICG R15 (R value = 0.90, p < 0.001). Nine radiomics features were selected to build the classification model. AUC of ROC revealed favorable performance of the classification model for identifying patients with ICG R15 <10% (AUC: 0.906, 95%CI: 0.900-0.913), <15% (AUC: 0.954, 95%CI: 0.950-0.958), and <20% (AUC: 0.996, 95%CI: 0.995-0.996). Conclusion Radiomics analysis of Gd-EOB-DTPA enhanced hepatic MRI can be used for assessment of functional liver reserve in HCC patients., (Copyright © 2021 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: The presence of clinically significant portal hypertension (CSPH) remains a relative contraindication to liver resection for patients with resectable hepatocellular carcinoma (HCC). The goal of this study was to explore whether a laparoscopic approach could extend the indications for hepatectomy to patients with PH., Method: Patients who underwent laparoscopic liver resection (LLR) from February 2016 to September 2019 performed by a single medical team were included in this study. We analyzed the surgical and oncological outcomes between groups with and without CSPH before and after propensity score matching (PSM)., Result: We enrolled 156 patients divided into two groups according to the presence (CSPH, n = 26) or absence (non-CSPH, n = 130) of CSPH. CSPH group was associated with more clinical signs of liver dysfunction (p < 0.05). After PSM (n = 48 patients), the CSPH group tended to have a longer postoperative hospital stay (p = 0.054); however, there was no difference in operation time (p = 0.329), blood loss volume (p = 0.392), transfusion rates (p = 0.701), rate of conversion to open surgery (p = 0.666), surgical margin (p = 0.306), surgical mortality (n = 0), or comprehensive complication index (p = 0.844) between the two groups. The median follow-up time for the entire cohort was 19.6 months (range 0.2-40.6 months). The 3-year overall survival rate was 62.9% in the CSPH group and 84.3% in the non-CSPH group (p = 0.1090), and results were similar after PSM (p = 0.5734)., Conclusions: LLR is safe and feasible for HCC with PH. The introduction of minimally invasive surgery, represented by LLR, can appropriately expand the indications for hepatectomy.

Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (β 1 integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. Methods : A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo . Interactions among miR-378a-3p, LXRα, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXRα and its downstream miR-378a-3p. Results : miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXRα), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment in vitro and in vivo . Conclusions : Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXRα was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Repeat laparoscopic hepatectomy (LRH) offers an option for recurrent tumors in liver remnants following an initial liver resection of recurrent hepatocellular carcinoma (HCC), colorectal liver metastasis (CRLM) and cholangiocellular carcinoma (CCC), showing advantages in some outcomes. The objective of the study was to evaluate the feasibility, safety, and potential benefits of LRH in comparison with repeat open hepatectomy (ORH) for recurrent liver cancer., Methods: A systematic review was performed in compliance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) and AMSTAR (Assessing the methodological quality of systematic reviews) guidelines. We performed a systematic search of PubMed, Embase, Cochrane Library, and Web of Science to identify studies that compared LRH with ORH from inception to September 30, 2019. Outcomes of interest included operation time, intraoperative estimated blood loss, length of hospital stay, complication rate, transfusion and R0 resection rate. The protocol was registered with the PROSPERO register of systematic reviews., Results: 10 retrospective observational studies were suitable for this analysis, involving 767 patients with 334 undergoing LRH (43.5%) and 433 undergoing ORH (56.5%). Compared with ORH, LRH had less intraoperative blood loss (SMD = -1.03; 95% CI: 1.48~-0.59, P < 0.001), less overall postoperative complications (OR = 0.40; 95% CI: 0.16-0.99, P = 0.048), less major complications (OR = 0.31, 95% CI: 0.15-0.62, P = 0.001), shorter hospital stay (SMD = -0.98; 95% CI: 1.41~-0.54, P < 0.001) and higher R0 resection rate (OR = 2.30, 95% CI: 1.39-3.81, P = 0.001). It was comparable in operation time (WMD = -7.66; 95% CI: 52.50-37.19, P = 0.738), transfusion rate (OR = 0.33; 95% CI:0.11-1.05, P = 0.060), and mortality (OR = 0.76; 95% CI: 0.27-2.18, P = 0.615) between LRH and ORH., Conclusion: Our results indicate that LRH is a safe and effective technique. Benefits, especially less intra-operative blood loss, less complications rate, shorter hospital stay and higher R0 resection, might be offered in the laparoscopic approach., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Ltd.)

In most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and currently the third leading cause of cancer-related deaths, worldwide. Epithelial-mesenchymal transition (EMT) plays a major role in HCC progression. In this study, we first found that the expression of E74-like ETS transcription factor 3 (ELF3), a member of the E-twenty-six family of transcription factors, was increased in HCC tissues, and that ELF3 overexpression was associated with poor prognoses for HCC patients. Gain-of-function and loss-of-function studies revealed that increased ELF3 expression promoted HCC cell proliferation, migration, and invasion, while these processes were inhibited when ELF3 was silenced. Additionally, ELF3 was found to promote EMT, which we demonstrated through decreased E-cadherin expression and increased N-cadherin and fibronectin expression. ELF3 knockdown reversed EMT via repressing ZEB1 expression through miR-141-3p upregulation. Chromatin immunoprecipitation assays revealed that ELF3 bound to the miR-141-3p promoter, suppressing miR-141-3p expression. Taken together, our data show that ELF3 repressed E-cadherin and promoted EMT in HCC cells by suppressing miR-141-3p, thereby activating ZEB1. Thus, ELF3 may be a potential prognostic biomarker and/or therapeutic target for HCC.

Sorafenib, the only approved drug for hepatocellular carcinoma, acts as a remarkable inhibitor of Raf serine-threonine kinases. However, Sorafenib is expensive, and clinical experience shows that it is not an effective treatment for many patients. Previous study has demonstrated that phosphorylated ERK (pERK) is a key downstream component in the RAF/MEK/ERK signaling pathway. Here, we investigate whether pERK is a useful biomarker for treating HCC with Sorafenib. In vitro cell viability assays showed that the efficacy of Sorafenib was distinctly different according to the level of pERK. Furthermore, in established patient-derived xenografts from HCC specimens, we found that the growth rate of tumors with high levels of pERK was significantly decreased by Sorafenib treatment. Taken together, pERK is a potential biomarker for the sensitivity to Sorafenib in treating HCC., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy as a result of complex genetic and epigenetic alterations. HCC is characterized by a clear gender disparity for which there is lack of a clear mechanistic understanding. Androgen receptor (AR) is thought to be critical for such bias. Meanwhile, the potential function of circular RNA (circRNA), regulated by RNA editing enzyme, remained largely unknown in malignancy till now. By utilizing circRNA microarray survey coupled with in vitro analysis, we analyzed the influence of AR on circRNA expression in HCC. Our results indicated that AR could suppress circRNA expression by upregulating ADAR1 p110. Such effect is because AR served as a transcriptional activator of ADAR1 promoter. More significantly, data collected from our center strongly suggest that ADAR1 expression can effectively predict HCC patients' prognosis and an abnormal overexpression of ADAR1 is positively correlated with AR in HCC. In addition, we found CircARSP91 (hsa&#95;circ&#95;0085154), one of the circRNAs downregulated by AR in an ADAR1-dependent manner, could inhibit HCC tumor growth both in vitro and in vivo. These findings highlight the fact that AR as a contributing factor for gender disparity in HCC can cause complex consequences though regulation of circRNA expression. Better understanding of the roles of circRNA during HCC initiation and progression will provide a novel angle to develop potential HCC therapies.

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been reported to be a new treatment strategy for patients with predicted small volumes of future liver remnant (FLR). ALPPS is associated with rapid hypertrophy of FLR but it has a high postoperative mortality and morbidity. Up to now, it is controversial to apply ALPPS in hepatocellular carcinoma, especially for patients with liver cirrhosis., Methods: Between May 2014 and June 2015, consecutive patients who underwent ALPPS with hepatitis B-related hepatocellular carcinoma with cirrhosis carried out in our center were included into the study. Demographic characteristics, surgical outcomes, and pathological results were evaluated. Subsequently, follow-up was still in progress., Results: The median operating time of the first (n = 12) and the second procedures (n = 10) were 285.0 and 212.5 minutes, respectively. The median blood loss were 200 and 800 mL for 2 stages of operations. The severe complication (≥IIIB) rates for the first and the second operations were 25.0% versus 40.0%, respectively. Six patients with too small future live remnant died of postoperative hepatic failure. On a median follow-up of 16 months of the 6 patients discharged, 4 patients were still alive and of 2 were disease-free., Conclusion: In terms of the feasibility and safety, this study showed that ALPPS in the treatment of hepatocellular carcinoma with insufficient future liver remnant might be a double-edged sword, and careful patients selected was proposed. Too small of FLR/SLV, less than 30%, is not recommended for ALPPS in liver with cirrhosis.

Exosomes are small vesicles that were initially thought to be a mechanism for discarding unneeded membrane proteins from reticulocytes. Their mediation of intercellular communication appears to be associated with several biological functions. Current studies have shown that most mammalian cells undergo the process of exosome formation and utilize exosome-mediated cell communication. Exosomes contain various microRNAs, mRNAs and proteins. They have been reported to mediate multiple functions, such as antigen presentation, immune escape and tumour progression. This concise review highlights the findings regarding the roles of exosomes in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. However, further elucidation of the contributions of exosomes to intercellular information transmission is needed. The potential medical applications of exosomes in liver diseases seem practical and will depend on the ingenuity of future investigators and their insights into exosome-mediated biological processes., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Although the transcatheter arterial chemoembolization (TACE) was demonstrated to be an alternative treatment of hepatocellular carcinoma with favorable oncological effect, the benefit of postoperative adjuvant TACE was still controversial. The aim of this study was to evaluate the effect of postoperative TACE in hepatocellular carcinoma., Results: The 1, 3, and 5-year overall and disease-free survival rates were comparable between Surgery+TACE and Surgery groups. In subgroup analysis, tumor size (≥ 5 cm) was detrimental to disease-free survival (p = 0.028) and an inferior tendency of overall survival was presented. Besides, repeated TACE for patients contributed to a poor disease-free survival (p = 0.005). While, postoperative adjuvant TACE improved the overall survival in patients with high preoperative alpha-fetoprotein or positive pathologically (p = 0.039 and p = 0.045)., Materials and Methods: The data were collected from consecutive patients between January 2010 and September 2014. After propensity score matching, baseline characteristics, overall and disease-free survival were compared between two groups. Subsequently, univariate and subgroup analysis were carried on., Conclusions: Our study indicated that single postoperative adjuvant TACE was beneficial for selected patients of stage I with tumor less than 5 cm, or high preoperative alpha-fetoprotein in serum or positive of alpha-fetoprotein pathologically.

Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The β-catenin is an important effector in WNT/β-catenin signaling pathway, which exerts a crucial role in the development and progression of hepatocellular carcinoma (HCC). Some researchers have suggested that the overexpression of β-catenin in cytoplasm and/or nucleus was closely correlated to metastasis, poor differentiation and malignant phenotype of HCC while some other researchers hold opposite point. So far, no consensus was obtained on the prognostic and clinicopathological significance of cytoplasmic/nuclear β-catenin overexpression for HCCs., Methods: Systematic strategies were applied to search eligible studies in all available databases. Subgroup analyses, sensitivity analyses and multivariate analysis were performed. In this meta-analysis, we utilized either fixed- or random-effects model to calculate the pooled odds ratios (OR) and its 95% confidence intervals (CI)., Results: A total of 22 studies containing 2334 cases were enrolled in this meta-analysis. Pooled data suggested that accumulation of β-catenin in cytoplasm and/or nucleus significantly correlated with poor 1-, 3- and 5-year OS and RFS. Moreover, nuclear accumulation combined with cytoplasmic accumulation of β-catenin tended to be associated with dismal metastasis and vascular invasion while cytoplasmic or nuclear expression alone showed no significant effect. Besides, no significant association was observed between cytoplasmic and/or nuclear β-catenin expression and poor differentiation grade, advanced TNM stage, liver cirrhosis, tumor size, tumor encapsulation, AFP and etiologies. Additional subgroup analysis by origin suggested that the prognostic value and clinicopathological significance of cytoplasmic and/or nuclear β-catenin expression was more validated in Asian population. Multivariate analyses of factors showed that cytoplasmic and/or nuclear β-catenin expression, as well as TNM stage, metastasis and tumor size, was an independent risk factors for OS and RFS., Conclusions: Cytoplasmic and/or nuclear accumulation of β-catenin, as an independent prognostic factor, significantly associated with poor prognosis and deeper invasion of HCC, and could serve as a valuable prognostic predictor for HCC.