Search

Hepatocellular carcinoma (HCC), the most common type of liver tumor, is a leading cause of cancer-related deaths, and the incidence of liver cancer is still increasing worldwide. Curative hepatectomy or liver transplantation is only indicated for a small population of patients with early-stage HCC. However, most patients with HCC are not candidates for radical resection due to disease progression, leading to the choice of the conventional tyrosine kinase inhibitor drug sorafenib as first-line treatment. In the past few years, immunotherapy, mainly immune checkpoint inhibitors (ICIs), has revolutionized the clinical strategy for HCC. Combination therapy with ICIs has proven more effective than sorafenib, and clinical trials have been conducted to apply these therapies to patients. Despite significant progress in immunotherapy, the molecular mechanisms behind it remain unclear, and immune resistance is often challenging to overcome. Several studies have pointed out that the complex intercellular communication network in the immune microenvironment of HCC regulates tumor escape and drug resistance to immune response. This underscores the urgent need to analyze the immune microenvironment of HCC. This review describes the immunosuppressive cell populations in the immune microenvironment of HCC, as well as the related clinical trials, aiming to provide insights for the next generation of precision immunotherapy., Competing Interests: YF, XG, LS, TC, CW, JW, YL, LL No competing interests declared, (© 2024, Fu, Guo et al.)

Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a highly immunosuppressive tumor microenvironment and a typical pattern of disturbances in hepatic lipid metabolism. Long non-coding RNAs are shown to play an important role in the regulation of gene expression, but much remains unknown between tumor microenvironment and lipid metabolism as a bridging molecule. Here, long intergenic nonprotein coding RNA 01116 (LINC01116) acts as this molecular which is frequently upregulated in HCC patients and associated with HCC progression in vitro and in vivo is identified. Mechanistically, LINC01116 stabilizes EWS RNA-binding protein 1 (EWSR1) by preventing RAD18 E3 Ubiquitin Protein Ligase (RAD18) -mediated ubiquitination. The enhanced EWSR1 protein upregulates peroxisome proliferator activated receptor alpha (PPARA) and fatty acid binding protein1 (FABP1) expression, a long-chain fatty acid (LCFA) transporter, and thus cancer cells outcompete T cells for LCFAs, especially linoleic acid, for seeding their own growth, leading to T cell malfunction and HCC malignant progression. In a preclinical animal model, the blockade of LINC01116 leads to enhanced efficacy of anti-PD1 treatment accompanied by increased cytotoxic T cell and decreased exhausted T cell infiltration. Collectively, LINC01116 is an immunometabolic lncRNA and the LINC01116-EWSR1-PPARA-FABP1 axis may be targetable for cancer immunotherapy., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Hepatocellular carcinoma (HCC) is one of the most prevalent and leading causes of cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. The lncRNA PWRN1 (PWRN1), acts as a tumor suppressor factor, which is low expressed in some cancers. However, the molecular mechanisms underlying the effects of PWRN1, especially the regulatory relationship with RNA binding protein in HCC remain largely unknown. In the present study, we demonstrated that PWRN1 was significantly down-regulated in HCC and correlated with better prognosis; furthermore, gain-of-function experiments showed that PWRN1 inhibited the proliferation of HCC cells. We further found that PWRN1 up-regulated pyruvate kinase activity and thus hinders the proliferation of HCC in vitro and in vivo. Mechanistically, pyruvate kinase M2 (PKM2) was bound to it and maintained the high activity state of PKM2, thereby hindering PKM2 from entering the nucleus in the form of low-activity dimers, reducing the expression of c-Myc downstream gene LDHA, leading to a decrease in lactate levels, and inhibiting the growth of tumor cells. In addition, PWRN1 was found to inhibit aerobic glycolysis. Finally, TEPP-46, a pyruvate kinase activator, appeared to inhibit HCC proliferation by maintaining tetramer stability and increasing pyruvate kinase activity. Taken together, our results provide new insights into the biology hindering HCC proliferation and indicate that PWRN1 in combination with PKM2 activators might represent a novel therapeutic target for HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

As a crucial protumorigenic long noncoding RNA, colorectal tumor differential expression (CRNDE) has been confirmed to facilitate the progression of various cancers. However, its role in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) is still unclear. Here we determined that CRNDE was upregulated in HCC samples and that CRNDE-positive cells were predominantly enriched in malignant tumor cells. In vivo functional assays revealed that CRNDE-induced tumor cells supported HCC progression, recruited abundant granulocyte myeloid-derived suppressor cells (G-MDSCs) and restricted the infiltration of T cells. In terms of mechanisms, CRNDE bound with Toll-like receptor 3 (TLR3) and activated NF-κB signaling to increase the secretion of c-x-c motif chemokine ligand 3 (CXCL3). CRNDE knockdown could significantly suppress the accumulation of G-MDSCs and enhance the infiltration of T cells in the TME of HCC in vivo. Taken together, our study reveals the CRNDE-NF-κB-CXCL3 axis plays a crucial role in driving the immunosuppressive niche to facilitate HCC progression by recruiting G-MDSCs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The development of novel biomarkers is crucial for the treatment of HCC. In this study, we investigated a new molecular therapeutic target for HCC. Fidgetin-like 1 (FIGNL1) has been reported to play a vital role in lung adenocarcinoma. However, the potential function of FIGNL1 in HCC is still unknown., Objective: This study aims to investigate the key regulatory mechanisms of FIGNL1 in the formation of HCC., Methods: The regulatory effect of FIGNL1 on HCC was studied by lentivirus infection. In vitro , the effects of FIGNL1 on the proliferation, migration and apoptosis of cells were investigated by CCK8, colony formation assay, transwell and flow cytometry. Meanwhile, the regulation of FIGNL1 on HCC formation in vivo was studied by subcutaneous transplanted tumors. In addition, using transcriptome sequencing technology, we further explored the specific molecular mechanism of FIGNL1 regulating the formation of HCC., Results: Functionally, we demonstrated that FIGNL1 knockdown significantly inhibited HCC cell proliferation, migration and promoted cell apoptosis in vitro . Similarly, the knockdown of FIGNL1 meaningfully weakened hepatocarcinogenesis in nude mice. Transcriptome sequencing revealed that FIGNL1 affected the expression of genes involved in extracellular matrix-receptor (ECM-receptor) interaction pathway, such as hyaluronan mediated motility receptor (HMMR). Further validation found that overexpression of HMMR based on knockdown FIGNL1 can rescue the expression abundance of related genes involved in the ECM-receptor interaction pathway., Conclusion: Our study revealed that FIGNL1 could modulate the ECM-receptor interaction pathway through the regulation of HMMR, thus regulating the formation of HCC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background & Aims: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown., Methods: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment., Results: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1 + macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand‒receptor networks among malignant cells, SPP1 + macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1 + macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration., Conclusions: We identified that the TIB structure formed by the interaction of SPP1 + macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC., Impact and Implications: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

SLP2, a protein located on mitochondrial, has been shown to be associated with mitochondrial biosynthesis. Here we explored the potential mechanisms by which SLP2 regulates the development of hepatocellular carcinoma. SLP2 could bind to the c-terminal of JNK2 to affect the ubiquitinated proteasomal degradation pathway of JNK2 and maintain the protein stability of JNK2. The increase of JNK2 markedly increases SREBP1 activity, promoting SREBP1 translocation into the nucleus to promote de novo lipogenesis. Alteration of the JNK2 C-terminal disables SLP2 from mediating SLP2-enhanced de novo lipogenesis. YTHDF1 interacts with SLP2 mRNA in a METTL3/m 6 A-dependent manner. In a spontaneous HCC animal model, SLP2/c-Myc/sgP53 increases the incidence rate of spontaneous HCC, tumor volume, and tumor number. Importantly, statistical analyses show that levels of SLP2 correlate with tumor sizes, tumor metastasis, overall survival, and disease-free survival of the patients. Targeting the SLP2/SREBP1 pathway effectively inhibits proliferation and metastasis of HCC tumors with high SLP2 expression in vivo combined with lenvatinib. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic SLP2, providing a mechanistic link between de novo lipogenesis and HCC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The incidence of hepatocellular carcinoma (HCC) is increasing in the world. However, its role and underlying molecular mechanism in HCC progression remain unclear. We found that CYB5A plays a key role in HCC metastasis by inhibiting the JAK1/STAT3 pathway through binding to STOML2. CYB5A combined with STOML2 can predict the outcome of patients. To demonstrate the effect of CYB5A on JAK1 inhibitor function, we applied Ruxolitinib in metastatic tumors with high CYB5A expression and found that it slowed disease progression and prolonged survival in mice. To the best of our knowledge, this study is the first to report the Ruxolitinib effect on the metastatic ability of HCC cells in vivo and in vitro., (© 2022. The Author(s).)

As a member of the phospholipase family, phospholipase C beta 1 ( PLCB1 ) is involved in phospholipid hydrolysis and is frequently upregulated in human cancer. However, little is known about the role of PLCB1 in cholangiocarcinoma (CCA). In this study, we uncover a role for PLCB1 in CCA progression and identify the underlying mechanisms. Both human CCA tissues and CCA cell lines expressed high levels of PLCB1. PLCB1 promoted tumor development and growth in various CCA mouse models, including transposon-based tumorigenesis models. PLCB1 activated PI3K/AKT signaling to induce CCA cells to undergo epithelial-to-mesenchymal transition (EMT). Mechanistically, PABPC1 interacted with PLCB1 and PI3K to amplify PLCB1-mediated EMT via PI3K/AKT/GSK3β/Snail signaling. Ectopic PLCB1 induced resistance to treatment with gemcitabine combined with cisplatin, which could be reversed by the AKT inhibitor MK2206. PLCB1 expression was regulated by miR-26b-5p through direct interaction with PLCB1 3'UTR. Collectively, these data identify a PLCB1-PI3K-AKT signaling axis vital for CCA development and EMT, suggesting that AKT can be used as a therapeutic target to overcome chemotherapy resistance in CCA patients with high PLCB1 expression. SIGNIFICANCE: PLCB1 functions as an oncogenic driver in cholangiocarcinoma development that confers an actionable therapeutic vulnerability to AKT inhibition., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Clinically, the total and residual liver volume must be accurately calculated before major hepatectomy. However, liver volume might be influenced by pneumoperitoneum during surgery. Changes in liver volume change also affect the accuracy of simulation and augmented reality navigation systems, which are commonly first validated in animal models. In this study, the morphologic changes in porcine livers in vivo under 13 mm Hg pneumoperitoneum pressure were investigated., Materials and Methods: Twenty male pigs were scanned with contrast-enhanced computed tomography without pneumoperitoneum and with 13 mm Hg pneumoperitoneum pressure., Results: The surface area and volume of the liver and the vascular diameter of the aortic lumen, inferior vena cava lumen, and portal vein lumen were measured. There were statistically significant differences in the surface area and volume of the liver (P=0.000), transverse diameter of the portal vein (P=0.038), longitudinal diameter of the inferior vena cava (P=0.033), longitudinal diameter of the portal vein (P=0.036), vascular cross-sectional area of the inferior vena cava (P=0.028), and portal vein (P=0.038) before and after 13 mm Hg pneumoperitoneum pressure., Conclusions: This study indicated that the creation of pneumoperitoneum at 13 mm Hg pressure in a porcine causes liver morphologic alterations affecting the area and volume, as well as the diameter of a blood vessel., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFβ1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFβ1 signaling. Approach: ALPPS was performed in rat models with N -diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFβ1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFβ1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFβ1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFβ1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFβ1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFβ1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFβ1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime reducing component 2 (MARC2) as a newly discovered molybdenum enzyme was downregulated in human HCC tissues and HCC cells. Downregulated MARC2 was significantly associated with clinicopathological characteristics of HCC, such as tumor size, AFP levels, and tumor grade and was an independent risk factor of poor prognosis. Both in vitro and in vivo studies suggested that MARC2 suppressed the progression of HCC by regulating the protein expression level of p27. The Hippo signaling pathway and RNF123 were required for this process. Moreover, MARC2 regulated expression of HNF4A via the Hippo signaling pathway. HNF4A was recruited to the promoter of MARC2 forming a feedback loop. MARC2 levels were downregulated by methylation. We demonstrated the prognostic value of MARC2 in HCC and determined the mechanism by which MARC2 suppressed the progression of HCC in this study. These findings may lead to new therapeutic targets for HCC.

Objective: Understanding the three-dimensional (3D) spatial position and orientation of vessels and tumor(s) is vital in laparoscopic liver resection procedures. Augmented reality (AR) techniques can help surgeons see the patient's internal anatomy in conjunction with laparoscopic video images., Method: In this paper, we present an AR-assisted navigation system for liver resection based on a rigid stereoscopic laparoscope. The stereo image pairs from the laparoscope are used by an unsupervised convolutional network (CNN) framework to estimate depth and generate an intraoperative 3D liver surface. Meanwhile, 3D models of the patient's surgical field are segmented from preoperative CT images using V-Net architecture for volumetric image data in an end-to-end predictive style. A globally optimal iterative closest point (Go-ICP) algorithm is adopted to register the pre- and intraoperative models into a unified coordinate space; then, the preoperative 3D models are superimposed on the live laparoscopic images to provide the surgeon with detailed information about the subsurface of the patient's anatomy, including tumors, their resection margins and vessels., Results: The proposed navigation system is tested on four laboratory ex vivo porcine livers and five operating theatre in vivo porcine experiments to validate its accuracy. The ex vivo and in vivo reprojection errors (RPE) are 6.04 ± 1.85 mm and 8.73 ± 2.43 mm, respectively., Conclusion and Significance: Both the qualitative and quantitative results indicate that our AR-assisted navigation system shows promise and has the potential to be highly useful in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)