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Nature Communications Jun 2024RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in...
RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in the Hippo pathway are substrates of RNF214. RNF214 induces non-proteolytic ubiquitylation at a conserved lysine residue of TEADs, enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling. Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a signaling axis of RNF214-TEAD-YAP and suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Ubiquitination; Animals; Transcription Factors; Signal Transduction; Mice; DNA-Binding Proteins; Cell Proliferation; YAP-Signaling Proteins; Cell Line, Tumor; TEA Domain Transcription Factors; Adaptor Proteins, Signal Transducing; Disease Progression; Mice, Nude; Cell Movement; Male; Gene Expression Regulation, Neoplastic; Hippo Signaling Pathway; HEK293 Cells; Ubiquitin-Protein Ligases; Female; Nuclear Proteins
PubMed: 38862474
DOI: 10.1038/s41467-024-49045-y -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the prognostic value of M2 macrophage-related genes (MRG) in hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC).
OBJECTIVE
To investigate the prognostic value of M2 macrophage-related genes (MRG) in hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC).
METHODS
The transcriptome data of 73 patients with HBV-related HCC were obtained from TCGA database, and the MRG modules were identified by WGCNA. The MRG-based risk scoring model was constructed by LASSO regression analysis and validated using an external dataset. The correlation of the risk score with immune cell infiltration and drug sensitivity of HCC were analyzed with CIBERSORT and R. pRRophetic. The signaling pathways of the differential genes between the high- and low-risk groups were investigated using GSVA and GSEA enrichment analyses, and MRG expressions at the single cell level were validated using R.Seurat. The cell interaction intensity was analyzed by R.Cellchat to identify important cell types related to HCC progression. MRG expression levels were detected by RT-qPCR in THP-1 cells with HCC-conditioned medium-induced M2 polarization and in HBV-positive HCC cells.
RESULTS
A high M2 macrophage infiltration level was significantly correlated with a poor prognosis of HCC, and 5 hub MRG (VTN, GCLC, PARVB, TRIM27, and GMPR) were identified. The overall survival of HCC patients was significantly lower in the high-risk than in the low-risk group. The high- and the low-risk groups showed significant enrichment of M2 macrophages and na?ve B cells, respectively, and were sensitive to BI. 2536 and to AG. 014699, AKT. inhibitor. Ⅷ, AZD. 0530, AZD7762, and BMS. 708163, respectively. The proliferation-related and metabolism-related pathways were enriched in the high-risk group, where monocytes showed the most active cell interactions during HCC progression. VTN was significantly upregulated in HCC cell lines, while GCLC, PARVB, TRIM27, and GMPR were upregulated in M2 THP-1 cells.
CONCLUSION
The MRG-based risk scoring model can accurately predict the prognosis of HBV-related HCC and reveal the differences in tumor microenvironment to guide precision treatment of the patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Macrophages; Hepatitis B virus; Transcriptome; Hepatitis B; Gene Expression Regulation, Neoplastic; Tumor Microenvironment
PubMed: 38862440
DOI: 10.12122/j.issn.1673-4254.2024.05.04 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To investigate the effects of an adeno-associated virus (AAV2) vector expressing secretory transforming growth factor-β (TGF-β) type Ⅱ receptor (sTβRⅡ)...
[A recombinant adeno-associated virus expressing secretory TGF-β type Ⅱ receptor inhibits triple-negative murine breast cancer 4T1 cell proliferation and lung metastasis in mice].
OBJECTIVE
To investigate the effects of an adeno-associated virus (AAV2) vector expressing secretory transforming growth factor-β (TGF-β) type Ⅱ receptor (sTβRⅡ) extracellular domain-IgG2a Fc fusion protein (sTβRⅡ-Fc) on proliferation and migration of triple-negative murine breast cancer 4T1 cells in mice.
METHODS
The pAAV-sTβRⅡ-Fc vector expressing sTβRⅡ-Fc fusion protein constructed by molecular cloning, the capsid protein-expressing vector pAAV2 and the helper vector were co-transfected into HEK 293T cells to prepare the recombinant AAV2-sTβRⅡ virus, which was purified by density gradient centrifugation with iodixanol. Western blotting was used to examine the effects of AAV-sTβRⅡ virus on Smad2/3 phosphorylation in 4T1 cells and on expression levels of E-cadherin, vimentin and p-Smad2/3 in 4T1 cell xenografts in mice. BALB/c mice bearing subcutaneous xenografts of luciferase-expressing 4T1 cells received intravenous injections of AAV-sTβRⅡ virus, AAV-GFP virus or PBS (=6) through the tail vein, and the proliferation and migration of 4T1 cells were analyzed with in vivo imaging. Ki67 expression in the tumor tissues and sTβRⅡ protein expressions in mouse livers were detected with immunohistochemistry and immunofluorescence staining, and tumor metastases in the vital organs were examined with HE staining.
RESULTS
The recombinant pAAV-sTβRⅡ-Fc vector successfully expressed sTβRⅡ in HEK 293T cells. Infection with AAV2-sTβRⅡ virus significantly reduced TGF-β1-induced Smad2/3 phosphorylation in 4T1 cells and effectively inhibited proliferation and lung metastasis of 4T1 xenografts in mice (<0.05). In the tumor-bearing mice, intravenous injection of AAV-sTβRⅡ virus significantly increased E-cadherin expression, reduced vimentin and Ki67 protein expressions and Smad2/3 phosphorylation level in the tumor tissues (<0.05 or 0.01), and induced liver-specific sTβRⅡ expression without causing body weight loss or heart, liver, spleen or kidney pathologies.
CONCLUSION
The recombinant AVV2 vector encoding sTβRⅡ extracellular domain is capable of blocking the TGF-β signaling pathway to inhibit the proliferation and lung metastasis of 4T1 cells in mice.
Topics: Animals; Mice; Dependovirus; Cell Proliferation; Mice, Inbred BALB C; Humans; HEK293 Cells; Genetic Vectors; Lung Neoplasms; Female; Receptor, Transforming Growth Factor-beta Type II; Cell Line, Tumor; Triple Negative Breast Neoplasms; Cadherins; Smad3 Protein; Cell Movement; Smad2 Protein
PubMed: 38862439
DOI: 10.12122/j.issn.1673-4254.2024.05.03 -
Redox Report : Communications in Free... Dec 2024Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We...
Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.
Topics: Animals; Emodin; Carcinoma, Hepatocellular; Rats; Thioacetamide; Liver Neoplasms; Antioxidants; ADAMTS4 Protein; Male; Protein Kinase C; Oxidative Stress; Antineoplastic Agents; Signal Transduction; Cell Proliferation
PubMed: 38861483
DOI: 10.1080/13510002.2024.2365590 -
Journal of Cancer Research and Clinical... Jun 2024Human MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests...
BACKGROUND
Human MARCH5 is a mitochondria-localized E3 ubiquitin-protein ligase that is essential for the regulation of mitochondrial dynamics. A large body of evidence suggests that imbalances in mitochondrial dynamics are strongly associated with cancer. However, the expression, biological function and prognostic significance of MARCH5 in hepatocellular carcinoma (HCC) have not been determined.
MATERIALS AND METHODS
The mRNA and protein expression of MARCH5 in HCC cell lines and tumor tissues was assessed by real-time quantitative PCR, Western blot analysis and immunohistochemistry. The clinical prognostic significance of MARCH5 was evaluated in 135 HCC patients. Knockdown or overexpression of MARCH5 in HCC cells was determined by in vitro cell proliferation, migration and invasion assays, and in vivo tumor growth and metastasis assays. In addition, the intrinsic mechanisms by which MARCH5 regulates HCC cell growth and metastasis were explored.
RESULTS
MARCH5 was significantly overexpressed in HCC cells and was closely associated with patients' poor postoperative prognosis. In vivo and in vitro experiments revealed that MARCH5 significantly promoted the increase and invasive and migratory ability of hepatocellular carcinoma cells, which was mainly due to the promotion of autophagy by MARCH5. Mechanistic studies revealed that MARCH5 promoted autophagy through ubiquitination degradation of p53 leading to malignant progression of hepatocellular carcinoma.
CONCLUSION
Our findings suggest that MARCH5 plays a critical oncogenic role in HCC cells, which provides experimental evidence for the use of MARCH5 as a potential target for HCC therapy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Ubiquitination; Ubiquitin-Protein Ligases; Tumor Suppressor Protein p53; Disease Progression; Male; Animals; Mice; Female; Prognosis; Mice, Nude; Cell Proliferation; Middle Aged; Cell Line, Tumor; Mice, Inbred BALB C; Cell Movement
PubMed: 38861187
DOI: 10.1007/s00432-024-05782-7 -
Technology in Cancer Research &... 2024To compare the ability of gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) and gadobenate dimeglumine (Gd-BOPTA) to display the 3 major features recommended by the... (Comparative Study)
Comparative Study
Comparison of the Ability of Gadobenate Dimeglumine and Gadolinium Ethoxybenzyl Dimeglumine to Display the major Features for Noninvasively Diagnosing Hepatocellular Carcinoma According to the LI-RADS 2018v.
OBJECTIVE
To compare the ability of gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) and gadobenate dimeglumine (Gd-BOPTA) to display the 3 major features recommended by the Liver Imaging Reporting and Data System (LI-RADS 2018v) for diagnosing hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
In this retrospective study, we included 98 HCC lesions that were scanned with either Gd-EOB-DTPA-MR or Gd-BOPTA-M.For each lesion, we collected multiple variables, including size and enhancement pattern in the arterial phase (AP), portal venous phase (PVP), transitional phase (TP), delayed phase (DP), and hepatobiliary phase (HBP). The lesion-to-liver contrast (LLC) was measured and calculated for each phase and then compared between the 2 contrast agents. A value < .05 was considered statistically significant. The display efficiency of the LLC between Gd-BOPTA and Gd-EOB-DTPA for HCC features was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS
Between Gd-BOPTA and Gd-EOB-DTPA, significant differences were observed regarding the display efficiency for capsule enhancement and the LLC in the AP/PVP/DP ( < .05), but there was no significant difference regarding the LLC in the TP/HBP. Both Gd-BOPTA and Gd-EOB-DTPA had good display efficiency in each phase (AUC> 0.750). When conducting a total evaluation of the combined data across the 5 phases, the display efficiency was excellent (AUC > 0.950).
CONCLUSION
Gd-BOPTA and Gd-EOB-DTPA are liver-specific contrast agents widely used in clinical practice. They have their own characteristics in displaying the 3 main signs of HCC. For accurate noninvasive diagnosis, the choice of agent should be made according to the specific situation.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Contrast Media; Magnetic Resonance Imaging; Male; Organometallic Compounds; Gadolinium DTPA; Female; Meglumine; Middle Aged; Aged; Retrospective Studies; ROC Curve; Adult; Image Enhancement; Aged, 80 and over
PubMed: 38860337
DOI: 10.1177/15330338241260331 -
European Journal of Medical Research Jun 2024Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene...
BACKGROUND
Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene transcription and translation to influence the progression of HCC. However, the regulatory relationship that exists between E3 ligases, which is a class of post-translational modifying proteins, and circRNA remains unclear.
METHODS
Based on the E3 ubiquitin ligase in the competitive endogenous RNA (ceRNA) network, a circRNA-regulated E3 ubiquitin ligase signature (CRE3UL) was developed. A CRE3UL signature was created using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis and merged it with clinicopathologic characteristics to generate a nomogram for prognosis prediction. The pRRophetic algorithm was utilized and immunological checkpoints were analyzed to compare the responses of patients in the high-risk group (HRG) and low-risk group (LRG) to targeted therapy and immunotherapy. Finally, experimental research will further elucidate the relationship between E3 ubiquitin ligase signature and HCC.
RESULTS
HRG patients were found to have a worse prognosis than LRG patients. Furthermore, significant variations in prognosis were observed among different subgroups based on various clinical characteristics. The CRE3UL signature was identified as being an independent prognostic indicator. The nomogram that combined clinical characteristics and the CRE3UL signature was found to accurately predict the prognosis of HCC patients and demonstrated greater clinical utility than the current TNM staging approach. According to anticancer medication sensitivity predictions, the tumors of HRG patients were more responsive to gefitinib and nilotinib. From immune-checkpoint markers analysis, immunotherapy was identified as being more probable to assist those in the HRG.
CONCLUSIONS
We found a significant correlation between the CRE3UL signature and the tumor microenvironment, enabling precise prognosis prediction for HCC patients. Additionally, a nomogram was developed that performs well in predicting the overall survival (OS) of HCC patients. This provides valuable guidance for clinicians in devising specific personalized treatment strategies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Nomograms; Prognosis; RNA, Circular; Ubiquitin-Protein Ligases; Immunotherapy; Male; Female; Biomarkers, Tumor; Middle Aged; Gene Expression Regulation, Neoplastic
PubMed: 38858746
DOI: 10.1186/s40001-024-01893-6 -
Journal of Nanobiotechnology Jun 2024Cancer stem cells (CSCs) play a vital role in the occurrence, maintenance, and recurrence of solid tumors. Although, miR-145-5p can inhibit CSCs survival, poor...
BACKGROUND
Cancer stem cells (CSCs) play a vital role in the occurrence, maintenance, and recurrence of solid tumors. Although, miR-145-5p can inhibit CSCs survival, poor understanding of the underlying mechanisms hamperes further therapeutic optimization for patients. Lentivirus with remarkable transduction efficiency is the most commonly used RNA carrier in research, but has shown limited tumor-targeting capability.
METHODS
We have applied liposome to decorate lentivirus surface thereby yielding liposome-lentivirus hybrid-based carriers, termed miR-145-5p-lentivirus nanoliposome (MRL145), and systematically analyzed their potential therapeutic effects on liver CSCs (LCSCs).
RESULTS
MRL145 exhibited high delivery efficiency and potent anti-tumor efficacy under in vitro and in vivo. Mechanistically, the overexpressed miR-145-5p can significantly suppress the self-renewal, migration, and invasion abilities of LCSCs by targeting Collagen Type IV Alpha 3 Chain (COL4A3). Importantly, COL4A3 can promote phosphorylating GSK-3β at ser 9 (p-GSK-3β S9) to inactivate GSK3β, and facilitate translocation of β-catenin into the nucleus to activate the Wnt/β-catenin pathway, thereby promoting self-renewal, migration, and invasion of LCSCs. Interestingly, COL4A3 could attenuate the cellular autophagy through modulating GSK3β/Gli3/VMP1 axis to promote self-renewal, migration, and invasion of LCSCs.
CONCLUSIONS
These findings provide new insights in mode of action of miR-145-5p in LCSCs therapy and indicates that liposome-virus hybrid carriers hold great promise in miRNA delivery.
Topics: MicroRNAs; Liposomes; Humans; Animals; Mice; Lentivirus; Cell Line, Tumor; Neoplastic Stem Cells; Mice, Nude; Liver Neoplasms; Mice, Inbred BALB C; Cell Movement; Glycogen Synthase Kinase 3 beta; beta Catenin; Wnt Signaling Pathway
PubMed: 38858736
DOI: 10.1186/s12951-024-02534-0 -
BMJ Open Jun 2024Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such...
Efficacy and safety of SBRT combined with sintilimab and IBI305 in patients with advanced HCC and previously failed immunotherapy: study protocol of a phase 2 clinical trial.
INTRODUCTION
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in China. The combination of immune checkpoint inhibitors (ICIs) and antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors, has been recommended as first-line treatment for advanced HCC. However, two-thirds of patients did not benefit from this form of immunotherapy. Currently, data on the subsequent regimen for patients previously treated with ICIs are lacking. Studies have shown that the combination of radiotherapy (RT) and ICIs is a potentially effective second-line therapy for HCC. This study aims to assess the efficacy and safety of combined therapy with stereotactic body RT (SBRT), sintilimab and IBI305 (a biosimilar of bevacizumab) in patients with HCC following the progression of first-line ICI therapy.
METHODS AND ANALYSIS
This study is an open-label, single-arm, single-centre, phase 2 trial of 21 patients with advanced HCC in whom previous ICI therapy has failed. Participants will receive approximately 30-40 Gy/5-8F SBRT, followed by 200 mg sintilimab and 15 mg/kg IBI305 intravenously every 3 weeks. Treatment will continue until the development of unacceptable toxicity or disease progression. We will use Simon's two-stage design, with the objective response rate (ORR) as the primary endpoint. Secondary endpoints include ORR of lesions without RT, disease control rate, progression-free survival, overall survival and safety.
ETHICS AND DISSEMINATION
The study was authorised by the Medical Ethics Committee. Dissemination of results will occur via a peer-reviewed publication and other relevant media.
TRIAL REGISTRATION NUMBER
ChiCTR2200056068.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Radiosurgery; Antibodies, Monoclonal, Humanized; Male; Female; Middle Aged; Immune Checkpoint Inhibitors; Adult; Aged; Combined Modality Therapy; Clinical Trials, Phase II as Topic; Immunotherapy
PubMed: 38858156
DOI: 10.1136/bmjopen-2023-077903 -
PloS One 2024Environmental risk factors are significant contributors to cancer mortality, which are neglected.
Population attributable fractions of cancer mortality related to indoor air pollution, animal contact, and water source as environmental risk factors: Findings from the Golestan Cohort Study.
BACKGROUND
Environmental risk factors are significant contributors to cancer mortality, which are neglected.
PURPOSE
This study aimed to estimate the population attributable fraction of cancer mortality due to the environmental risk factors.
METHODS
Golestan cohort study is a population-base cohort on 50045 participants between 40-75 with about 18 years of follow up. We detected 2,196 cancer mortality and applied a multiple Cox model to compute the hazard ratio of environmental risk factor on all cancer and cancer-specific mortality. The population attributable fraction was calculated, accordingly.
RESULTS
Biomass fuels for cooking, as an indoor air pollution, increased the risk of colorectal, esophageal, gastric cancer, and all-cancer mortality by 84%, 66%, 37%, and 17% respectively. Using gas for cooking, particularly in rural areas, could save 6% [Population Attributable Fraction: 6.36(95%CI: 1.82, 10.70)] of esophageal cancer, 3% [Population Attributable Fraction: 3.43 (0, 7.33)] of gastric cancer, and 6% [Population Attributable Fraction: 6.25 (1.76, 13.63)] of colorectal cancer mortality. Using a healthy tap water source could save 5% [Population Attributable Fraction:5.50(0, 10.93)] of esophageal cancer mortality, particularly in rural areas. There was no significant association between indoor air pollution for heating purposes and animal contact with cancer mortality.
CONCLUSION
Considering the results of this study, eliminating solid fuel for most daily usage, among the population with specific cancer types, is required to successfully reduce cancer related mortality. Adopting appropriate strategies and interventions by policymakers such as educating the population, allocating resources for improving the healthy environment of the community, and cancer screening policies among susceptible populations could reduce cancer related mortalities.
Topics: Humans; Air Pollution, Indoor; Middle Aged; Male; Female; Risk Factors; Adult; Animals; Neoplasms; Aged; Cohort Studies; Cooking; Environmental Exposure; Proportional Hazards Models
PubMed: 38857263
DOI: 10.1371/journal.pone.0304828