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Advanced Science (Weinheim,... Apr 2024Recent studies suggest that circular RNA (circRNA)-mediated post-translational modification of RNA-binding proteins (RBP) plays a pivotal role in metastasis of...
Recent studies suggest that circular RNA (circRNA)-mediated post-translational modification of RNA-binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi-omics approach. Has_circ_0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif-containing 21 to reduce the proteasome-mediated degradation of NCL via K48-linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient-derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi-omics landscape of circRNA-mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Humans; RNA, Circular; Ubiquitination; Mice; Animals; RNA-Binding Proteins; Cell Line, Tumor; Nucleolin; Neoplasm Metastasis; Tripartite Motif Proteins; Disease Models, Animal; Multiomics
PubMed: 38357830
DOI: 10.1002/advs.202306915 -
International Journal of Biological... 2023Although apatinib is a promising drug for the treatment of liver cancer, the underlying drug resistance mechanism is still unclear. Here, we constructed...
Although apatinib is a promising drug for the treatment of liver cancer, the underlying drug resistance mechanism is still unclear. Here, we constructed apatinib-resistant HepG2 cells. We then characterized the epigenomic, transcriptomic, and proteomic landscapes both in apatinib-resistant and non-resistant HepG2 cells. Differential expression, ATAC-seq, and proteomic data analyses were performed. We found that the cell cycle related protein RB1 may play an essential role in the process of apatinib resistant to hepatocarcinoma. Moreover, there were extensive variations at the transcriptome, epigenetic, and proteomic level. Finally, quantitative PCR (qPCR) and western blot analysis showed that expression level of RB1 in apatinib-resistant cell as well as the samples of patients in progressive disease were significantly lower than that in controls. Those results also showed that the RB1 pathway inhibitors CDK2-IN-73 and Palbociclib could relieve the resistance of apatinib resistant cells. Our results further enhance our understanding of the anti-tumorigenic and anti-angiogenic efficacy of apatinib in liver cancer and provide a novel perspective regarding apatinib resistance. Furthermore, we proved that CDKN2B inhibition of RB1 signaling promoted apatinib resistance in hepatocellular carcinoma. Those findings have greatly important biological significance for the resistance of apatinib and the treatment of liver cancer.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Liver Neoplasms; Multiomics; Proteomics; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases; Drug Resistance, Neoplasm
PubMed: 37781033
DOI: 10.7150/ijbs.83862 -
Transplant International : Official... 2023Liver transplantation offers the best chance of cure for most patients with non-metastatic hepatocellular carcinoma (HCC). Although not all patients with HCC are...
Liver transplantation offers the best chance of cure for most patients with non-metastatic hepatocellular carcinoma (HCC). Although not all patients with HCC are eligible for liver transplantation at diagnosis, some can be downstaged using locoregional treatments such as ablation and transarterial chemoembolization. These aforementioned treatments are being applied as bridging therapies to keep patients within transplant criteria and to avoid them from dropping out of the waiting list while awaiting a liver transplant. Moreover, immunotherapy might have great potential to support downstaging and bridging therapies. To address the contemporary status of downstaging, bridging, and immunotherapy in liver transplantation for HCC, European Society of Organ Transplantation (ESOT) convened a dedicated working group comprised of experts in the treatment of HCC to review literature and to develop guidelines pertaining to this cause that were subsequently discussed and voted during the Transplant Learning Journey (TLJ) 3.0 Consensus Conference that took place in person in Prague. The findings and recommendations of the working group on Downstaging, Bridging and Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma are presented in this article.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Transplantation; Treatment Outcome; Chemoembolization, Therapeutic; Neoadjuvant Therapy; Neoplasm Staging; Immunotherapy
PubMed: 37779513
DOI: 10.3389/ti.2023.11648 -
Annals of Hepatology 2023In hepatocellular carcinoma (HCC), the prognosis of patients with microvascular invasion (MVI) is poor. Therefore, in this study, we established and evaluated the...
INTRODUCTION AND OBJECTIVES
In hepatocellular carcinoma (HCC), the prognosis of patients with microvascular invasion (MVI) is poor. Therefore, in this study, we established and evaluated the performance of a novel nomogram to predict MVI in patients with HCC.
MATERIALS AND METHODS
We retrospectively obtained clinical data of 497 patients with HCC who underwent hepatectomy at Liaoning Cancer Hospital from November 1, 2018, to November 4, 2021. The patients (n = 497) were randomized in a 7:3 ratio into the training cohort (TC, n = 349) and the validation cohort (VC, n = 148). We performed Least Absolute Shrinkage and Selection Operator (LASSO) and univariate as well as multivariate logistic regression analyses (ULRA, MRLA) on patients in the TC to identify factors independently predicting MVI.
RESULTS
Preoperative FIB-4, AFU, AFP levels, liver cirrhosis, and non-smooth tumor margin were independent risk factors for preoperative MVI prediction. The C-index of the TC, VC, and the entire cohort was 0.846, 0.786, and 0.829, respectively. The calibration curves demonstrated the outstanding agreement between predicted MVI incidences by our model and the actual MVI risk. Decision curve analysis (DCA) confirmed the significance of our predictive model in clinical settings. The Kaplan-Meier (KM) survival curve showed that the recurrence-free survival (RFS) and overall survival (OS) of patients in the high-MVI risk group were poor compared to those in the low-MVI risk group.
CONCLUSIONS
We constructed and evaluated the performance of the novel nomogram for predicting MVI risk. Our predictive model could adequately predict MVI risk and aid clinicians in selecting appropriate therapeutic strategies for patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Nomograms; Female; Male; Middle Aged; Retrospective Studies; Neoplasm Invasiveness; Hepatectomy; Microvessels; Risk Factors; Aged; Prognosis; Predictive Value of Tests; Risk Assessment
PubMed: 37479060
DOI: 10.1016/j.aohep.2023.101136 -
Cancer Letters Feb 2024Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells....
Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin β1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin β1/RhoA/ROCK1/MLC2 and Piezo1/Ca/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.
Topics: Humans; Carcinoma, Hepatocellular; Cortactin; Podosomes; Liver Neoplasms; Integrin beta1; Extracellular Matrix; Cell Line, Tumor; Neoplasm Invasiveness; rho-Associated Kinases
PubMed: 38145655
DOI: 10.1016/j.canlet.2023.216597 -
Annals of Hepatology 2024Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B, Chronic; Neoplasm Recurrence, Local; Hepatitis C; Hepatitis B virus; Hepatitis B
PubMed: 37734662
DOI: 10.1016/j.aohep.2023.101153 -
Molecular Biology Reports Sep 2023Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several... (Review)
Review
Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several technological advances. The poor prognosis of HCC and the few available treatments are to blame for the low survival rate, which emphasizes the importance of creating new, effective diagnostic markers and innovative therapy strategies. In-depth research is being done on the potent biomarker miRNAs, a special class of non-coding RNA and has shown encouraging results in the early identification and treatment of HCC in order to find more viable and successful therapeutics for the disease. It is beyond dispute that miRNAs control cell differentiation, proliferation, and survival and, depending on the genes they target, can either promote tumorigenesis or suppress it. Given the vital role miRNAs play in the biological system and their potential to serve as ground-breaking treatments for HCC, more study is required to fully examine their theranostic potential.
Topics: Carcinoma, Hepatocellular; Humans; MicroRNAs; Apoptosis; Cell Proliferation; Neoplasm Metastasis; Neovascularization, Physiologic; Liver Neoplasms; Biomarkers, Tumor
PubMed: 37418086
DOI: 10.1007/s11033-023-08586-z -
International Journal of Biological... 2023Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently...
Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently expressed in HCC. However, the capabilities and underlying mechanisms of lnc-ZEB2-19 remain uncertain. In this study, we verified that the downregulation of lnc-ZEB2-19 was prevalent in HCC and significantly correlated with the unfavorable prognosis. Further in vitro and in vivo verified that lnc-ZEB2-19 notably inhibited the proliferation, metastasis, stemness, and lenvatinib resistance (LR) of HCC cells. Mechanistically, lnc-ZEB2-19 inhibited HCC progression and LR by specifically binding to transformer 2α (TRA2A) and promoting its degradation, which resulted in the instability of RSPH14 mRNA, leading to the downregulation of Rela(p65) and p-Rela(p-p65). Furthermore, rescue assays showed that silencing RSPH14 partially restrained the effect of knockdown expression of lnc-ZEB2-19 on HCC cell metastatic ability and stemness. The findings describe a novel regulatory axis, lnc-ZEB2-19/TRA2A/RSPH14, downregulating the nuclear factor kappa B to inhibit HCC progression and LR.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Liver Neoplasms; NF-kappa B; Signal Transduction; Zinc Finger E-box Binding Homeobox 2; Drug Resistance, Neoplasm; RNA, Long Noncoding
PubMed: 37564197
DOI: 10.7150/ijbs.85270 -
Current Opinion in Organ Transplantation Apr 2024The increasing success of liver transplantation in hepatocellular carcinoma (HCC) drives an ever-evolving search for innovative strategies to broaden eligible patients'... (Review)
Review
PURPOSE OF REVIEW
The increasing success of liver transplantation in hepatocellular carcinoma (HCC) drives an ever-evolving search for innovative strategies to broaden eligible patients' pools. Recent advances in immuno-oncology have turned the spotlight on immune checkpoint inhibitors (ICIs). This review offers an updated overview of ICIs in liver transplantation for HCC, exploring neoadjuvant and adjuvant approaches and addressing unanswered questions on safety, patients' selection, and response predictors.
RECENT FINDINGS
ICIs have transitioned from being a last-chance therapeutic hope to becoming an integral cornerstone in the treatment of advanced HCC, holding great promise as a compelling option not only to downstage patients for transplantation but also as an alternative strategy in addressing posttransplantation disease recurrence. Despite ongoing refinements in immunotherapeutic agents, the complex molecular pathways involved emphasize the need for a comprehensive approach to integrate immunotherapy in liver transplantation.
SUMMARY
Initial concerns about graft rejection, with ICIs as a bridging therapy to liver transplantation, were successfully addressed using adequate immunosuppressants strategies and minimized with a sufficient washout period. Post-liver transplantation disease recurrence remains challenging, requiring a balance between effective therapy and preserving graft function. Emphasis should be placed on clinical trials validating the risk-benefit ratio of ICIs for liver transplantation, guiding appropriate patients' selection, and establishing clear management pathways.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasm Recurrence, Local; Immunotherapy; Liver Transplantation
PubMed: 38164882
DOI: 10.1097/MOT.0000000000001133 -
Aging Jul 2023Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all...
Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Neoplasm; Ferroptosis; Galectin 1; Liver Neoplasms; Receptor Protein-Tyrosine Kinases; Sorafenib
PubMed: 37433225
DOI: 10.18632/aging.204867