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Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c-Myc interacts with G9a in HCC and cooperates to regulate c-Myc-dependent gene repression. In addition, G9a stabilises c-Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic-lethal target of c-Myc, CDK9, demonstrates strong efficacy in patient-derived avatars of Myc-driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc-driven hepatic tumours., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Limited liver resections (LLRs) for tumours located in the posterosuperior segments of the liver are technically demanding procedures. This study compared outcomes of robotic (R) and laparoscopic (L) LLR for tumours located in the posterosuperior liver segments (IV, VII, and VIII)., Methods: This was an international multicentre retrospective analysis of patients who underwent R-LLR or L-LLR at 24 centres between 2010 and 2019. Patient demographics, perioperative parameters, and postoperative outcomes were analysed; 1 : 3 propensity score matching (PSM) and 1 : 1 coarsened exact matching (CEM) were performed., Results: Of 1566 patients undergoing R-LLR and L-LLR, 983 met the study inclusion criteria. Before matching, 159 R-LLRs and 824 L-LLRs were included. After 1 : 3 PSM of 127 R-LLRs and 381 L-LLRs, comparison of perioperative outcomes showed that median blood loss (100 (i.q.r. 40-200) versus 200 (100-500) ml; P = 0.003), blood loss of at least 500 ml (9 (7.4 per cent) versus 94 (27.6 per cent); P < 0.001), intraoperative blood transfusion rate (4 (3.1 per cent) versus 38 (10.0 per cent); P = 0.025), rate of conversion to open surgery (1 (0.8 per cent) versus 30 (7.9 per cent); P = 0.022), median duration of Pringle manoeuvre when applied (30 (20-46) versus 40 (25-58) min; P = 0.012), and median duration of operation (175 (130-255) versus 224 (155-300); P < 0.001) were lower in the R-LLR group compared with the L-LLR group. After 1 : 1 CEM of 104 R-LLRs with 104 L-LLRs, R-LLR was similarly associated with significantly reduced blood loss and a lower rate of conversion to open surgery., Conclusion: Based on a matched analysis of well selected patients, both robotic and laparoscopic access could be undertaken safely with good outcomes for tumours in the posterosuperior liver segments., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited treatment options. Through genome-wide growth depletion screens using clustered regularly interspaced short palindromic repeats and expression profiling of primary HCC tumors, we identified 13 clinically relevant target genes with therapeutic potential. Subsequent functional annotation analysis revealed significant enrichment of these 13 genes in the cell cycle, cell death, and survival pathways. Non-structural maintenance of chromosomes condensin I complex subunit G (NCAPG) was ranked the highest among the depletion screens and multiple HCC expression datasets. Transient inhibition of NCAPG using specific small interfering RNAs resulted in a significant reduction in cell growth, migration, and the down-regulation of mitochondrial gene expression in vitro . Small homologous RNA-mediated knockdown of NCAPG significantly impaired cell viability, caused aberrant mitotic division, fragmented the mitochondrial network, and increased cell death in vitro . HCC cells with a reduced expression of NCAPG formed significantly smaller xenograft tumors in vivo . Importantly, high NCAPG expression was significantly associated with poorer overall and disease-free survival in HCC patients. High NCAPG expression is a novel prognostic biomarker to predict HCC early recurrence after surgical resection. In conclusion, NCAPG is an essential gene for HCC tumor cell survival. It represents a promising novel target for treating HCC and a prognostic biomarker for clinical management of HCC.-Wang, Y., Gao, B., Tan, P. Y., Handoko, Y. A., Sekar, K., Deivasigamani, A., Seshachalam, V. P., OuYang, H.-Y., Shi, M., Xie, C., Goh, B. K. P., Ooi, L. L., Hui, K. M. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.

Early tumor recurrence after curative surgical resection poses a great challenge to the clinical management of hepatocellular carcinoma (HCC). We conducted whole genome expression microarrays on 64 primary HCC tumors with clinically defined recurrence status and cross-referenced with RNA-seq data from 18 HCC tumors in the Cancer Genome Atlas project. We identified a 77-gene signature, which is significantly associated with early recurrent (ER) HCC tumors. This ER-associated signature shows significant enrichment in genes involved in cell cycle pathway. We performed receiver operating characteristic (ROC) analysis to evaluate the prognostic biomarker potential of these 77 genes and Pearson correlation analysis to identify 11 close clusters. The one gene with the best area under the ROC curve in each of the 11 clusters was selected for validation using reverse-transcription quantitative PCR in an independent cohort of 24 HCC tumors. NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. In conclusion, NUF2 in combination with liver cirrhosis is a promising prognostic biomarker for early HCC recurrence., (© 2019 UICC.)

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival. Silencing MELK inhibited cell growth, invasion, stemness and tumorigenicity of HCC cells by inducing apoptosis and mitosis. We further showed that the overexpression of MELK in HCC samples strongly correlated with the cell cycle- and mitosis-related genes which are directly regulated as part of the forkhead transcription factor FoxM1-related cell division program. Together, our data establish MELK as an oncogenic kinase involved in the pathogenesis and recurrence of HCC and could provide a promising molecular target to develop therapeutic strategies for patients with advanced HCC., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients., Methods: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy., Discussion: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients., Trial Registration: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010.

Objectives: Hepatocellular 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 understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence., Design: PRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1., Results: PRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear β-catenin levels. Mechanistically, PRC1 interacts with the β-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes β-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear β-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling., Conclusions: We identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Hypertrophy of the contralateral liver lobe after treatment with yttrium-90 ((90)Y) microspheres has recently been reported. This study aimed to quantify left hepatic lobe hypertrophy after right-sided radioembolization for hepatocellular carcinoma (HCC) and to identify pretreatment predictive factors of hypertrophy in an Asian population., Methods: A retrospective review of patients with inoperable HCC undergoing selective internal radiation treatment (SIRT) with (90)Y microspheres at a single institution from January 2008 to January 2012 was performed. Only patients who had treatment delivered via the right hepatic artery alone were included., Results: In all, 17 patients fulfilling the study criteria were identified. The mean percentage of left-lobe hypertrophy was 34.2% ± 34.9% (range 19.0-106.5%) during a median of 5-month follow-up. Patients with hepatitis B were found to experience a significantly greater degree of hypertrophy than those with hepatitis C or alcoholic liver cirrhosis. There were no cases of acute liver failure after the administration of SIRT in this study and none of the patients developed disease in the contralateral lobe over the study period., Conclusions: Administration of unilobar SIRT to the right liver lobe in patients with HCC resulted in a significant degree of contralateral left lobe hypertrophy. Patients with hepatitis B experienced a greater degree of hypertrophy than those with hepatitis C or alcoholic liver cirrhosis., (© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)