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Hepatology Communications Dec 2022Liver cancer, comprised primarily of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We...
Liver cancer, comprised primarily of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor zinc fingers and homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2-deficient mice using the diethylnitrosamine (DEN)-induced liver tumor model. Our study using whole-body Zhx2 knockout (Zhx2 ) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure. Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme cytochrome P450 2E1 (CYP2E1) and DNA polymerase delta 2, or in the numbers of phosphorylated histone variant H2AX foci between Zhx2 and wild-type (Zhx2 ) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2 livers showed fewer positive foci for Ki67 staining and reduced interleukin-6 and AKT serine/threonine kinase 2 expression compared with Zhx2 livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN-treated liver-specific Zhx2 knockout mice, suggesting that Zhx2 acts in both hepatocytes and nonparenchymal cells to inhibit tumor formation. Analysis of data from the Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 messenger RNA and protein levels were significantly higher in patients with HCC and associated with clinical pathological parameters. Conclusion: In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN-induced HCC model and is consistent with the higher ZHX2 expression in patients with HCC.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Diethylnitrosamine; Genes, Homeobox; Homeodomain Proteins; Liver Neoplasms; Mice, Inbred C57BL; Mice, Knockout; Proteomics; Transcription Factors; Zinc Fingers
PubMed: 36194180
DOI: 10.1002/hep4.2106 -
Life Sciences Jan 2021Most hepatocellular carcinoma cases are diagnosed at late stages of the disease, which makes it the second cause of cancer mortality worldwide. For advanced-stage...
BACKGROUND
Most hepatocellular carcinoma cases are diagnosed at late stages of the disease, which makes it the second cause of cancer mortality worldwide. For advanced-stage patients, chemotherapeutic drugs are the best treatment option; however, their adverse effects and high cost are still major obstacles for effective treatment. Spirulina microalga is a rich source of nutritional and bioactive elements and potential pharmaceuticals, which has an -proliferative effect against several cancer cell lines. It also has a prophylactic effect against the early stages of some cancer models, including hepatocellular carcinoma.
AIMS
The present study was carried out to evaluate the therapeutic anticarcinogenic effect of spirulina against advanced murine hepatocellular carcinoma.
MAIN METHODS
Hepatocarcinoma was induced by a single injection of diethylnitrosamine (100 mg/kg, intraperitoneally) followed by 22 weekly injections of carbon-tetrachloride (0.5 mg/kg, i.p). Spirulina (250 and 500 mg/kg bw) was given orally, from week 25 to 28, after the establishment of hepatocellular carcinoma.
KEY FINDINGS
Spirulina inhibited HCC structural and functional alterations, manifested by improving the survival rate, significantly decreasing the tumor marker AFP, and the count and size of the hepatic nodules, as well as downstaging HCC. This was accompanied with the augmentation of the endogenous antioxidant capacity, apoptosis (Bax) and the tumor suppressor protein (p53), as well as the suppression of tissue levels of the lipid peroxidation marker (MDA) and neoangiogenesis marker (VEGF).
SIGNIFICANCE
In conclusion, spirulina has an anticarcinogenic effect against advanced hepatocellular carcinoma exerted through activating the tumor suppressor protein p53 and apoptosis, and suppressing oxidative stress and angiogenesis.
Topics: Animals; Anticarcinogenic Agents; Antioxidants; Apoptosis; Carcinoma, Hepatocellular; Diethylnitrosamine; Dose-Response Relationship, Drug; Lipid Peroxidation; Liver Neoplasms; Male; Mice; Neovascularization, Pathologic; Oxidative Stress; Spirulina; Survival Rate; Tumor Suppressor Protein p53
PubMed: 33253720
DOI: 10.1016/j.lfs.2020.118827 -
Biochemical and Biophysical Research... Feb 2020Two-stage rat hepatocarcinogenesis model was used to induce early carcinogenesis in which thioacetamide (TAA) promotes diethylnitrosamine (DEN) initiated carcinogenesis....
Two-stage rat hepatocarcinogenesis model was used to induce early carcinogenesis in which thioacetamide (TAA) promotes diethylnitrosamine (DEN) initiated carcinogenesis. Dimethyl fumarate (DMF) used to treat multiple sclerosis, activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway during oxidative stress, and maintains antioxidant levels. Glibenclamide (GLB), a sulphonylurea drug used to treat type II diabetes, possesses anti-inflammatory properties and inhibits NLRP3 inflammasomes. The present study was designed to investigate the concurrent intervention of DMF and GLB on DEN + TAA-induced early hepatic carcinogenesis. DMF and GLB treatment improved DEN + TAA-induced decrease in body weight, increase in liver weight and plasma transaminases, histopathological alterations, DNA damage, and apoptosis. DMF and GLB intervention significantly ameliorated the DEN + TAA-induced alterations in the antioxidant (Nrf2, HO-1, SOD-1, catalase), inflammatory (NF-κB, NLRP3, ASC, caspase-1), fibrogenic (TGF-β1, collagen) and regenerative proliferative stress (GST-p, HGF, c-MET, TGFα, EGF, AFP) markers. The present results indicate that Nrf2/ARE activation and NLRP3 inhibition might be a rational approach to attenuate oxidative stress and chronic inflammation associated progression of hepatocarcinogenesis.
Topics: Animals; Body Weight; Carcinogenesis; DNA Damage; Diethylnitrosamine; Dimethyl Fumarate; Glyburide; Liver; Male; NF-E2-Related Factor 2; Organ Size; Rats, Wistar; Thioacetamide
PubMed: 31761320
DOI: 10.1016/j.bbrc.2019.11.100 -
Carcinogenesis Jun 2016The liver is a key metabolic organ that is essential for production of blood proteins, lipid and sugar metabolism and detoxification of naturally occurring and foreign... (Review)
Review
The liver is a key metabolic organ that is essential for production of blood proteins, lipid and sugar metabolism and detoxification of naturally occurring and foreign harmful chemicals. To maintain its mass and many essential functions, the liver possesses remarkable regenerative capacity, but the latter also renders it highly susceptible to carcinogenesis. In fact, liver cancer often develops in the context of chronic liver injury. Currently, primary liver cancer is the second leading cause of cancer-related deaths, and as the rates of other cancers have been declining, the incidence of liver cancer continues to rise with an alarming rate. Although much remains to be accomplished in regards to liver cancer therapy, we have learned a great deal about the molecular etiology of the most common form of primary liver cancer, hepatocellular carcinoma (HCC). Much of this knowledge has been obtained from studies of mouse models, using either toxic chemicals, a combination of fatty foods and endoplasmic reticulum stress or chronic activation of specific metabolic pathways. Surprisingly, NRF2, a transcription factor that was initially thought to protect the liver from oxidative stress, was found to play a key role in promoting HCC pathogenesis.
Topics: Animals; Carcinoma, Hepatocellular; Diet, High-Fat; Diethylnitrosamine; Disease Models, Animal; Hepatitis; Humans; Liver Neoplasms; Mice; Mutation; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents
PubMed: 27207669
DOI: 10.1093/carcin/bgw060 -
Asian Pacific Journal of Cancer... Aug 2022Hepatocellular carcinoma (HCC) is one of the leading drivers of cancer-related mortality in the world. As a result, researchers are constantly looking for ways to...
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the leading drivers of cancer-related mortality in the world. As a result, researchers are constantly looking for ways to optimize the screening and diagnosis of the said malignancy.
OBJECTIVE
To establish the mice model of hepatocellular carcinoma with the administration of a suitable dose of diethylnitrosamine (DEN) and examine the utility of EphA7 and pEphA7 as ideal diagnostic markers in HCC.
METHODS
Swiss Albino (BALB/c) mice of around 10-12 weeks old were exposed to a known hepatocarcinogen-diethylnitrosamine at a dose of 20 mg/kg body weight at weekly intervals for a period of 4, 8, 12, & 16 weeks. Blood was collected from mice of different experimental groups, and age-matched control and serum were separated from whole blood samples. The liver homogenate was prepared after completion of treatment, and the resulting supernatant was used for enzyme assays. A range of liver biomarker enzyme assays such as Gamma-glutamyl transpeptidase (GGT), Acetylcholine esterase (AChE), GPx activity and GSH level, Heme oxygenase-1 (HO-1), GPC3 and alpha-fetoprotein (AFP) level along with the expression of Caspase-3, EphA7 and pEphA7 were evaluated.
RESULTS
An elevation in body weight and relative liver weight across the treatment period (4, 8, 12, 16 weeks) was observed in DEN-treated mice. Significant differences in GGT levels between control and DEN treated mice were noted in the present study (P < 0.005). In the 16th week of the treatment period, a significant difference in AchE level was noted between the treated and control group (P < 0.001). However, there was no statistically significant difference in the levels of SGOT and SGPT levels between the control and DEN treated groups (P > 0.001). Lower GSH and GPx levels were demonstrated in the treated mice as compared to control over all the treatment period. Loss of Caspase-3 expression and significant differences in expression of HO-1 activity in treated vs. non-treated group of mice were observed. Significant differences in EphA7 and pEphA7 protein expression levels were noted in the DEN-treated vs. control groups across all the treatment periods (4 weeks: P < 0.05; 8 weeks: P < 0.05; 12 weeks: P < 0.005; 16 weeks: P < 0.05).
CONCLUSION
The present study indicated that EphA7 and phosphoEphA7 over-expression might contribute to the malignancy transition, invasion development, and metastasis of HCC. As a result, along with the known markers such as AFP and others, EphA7 and pEphA7 could be a very putative biomarkers of HCC, particularly at a very early stage of cancer development.
Topics: Animals; Body Weight; Carcinoma, Hepatocellular; Caspase 3; Diethylnitrosamine; Early Detection of Cancer; Liver Neoplasms; Liver Neoplasms, Experimental; Mice; Mice, Inbred BALB C; alpha-Fetoproteins
PubMed: 36037142
DOI: 10.31557/APJCP.2022.23.8.2843 -
The Yale Journal of Biology and Medicine Dec 2023Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes....
Identifying new hepatocellular carcinoma (HCC)-driven signaling molecules and discovering their molecular mechanisms are crucial for efficient and better outcomes. Recently, OMA1 and YME1L, the inner mitochondrial proteases, were displayed to be associated with tumor progression in various cancers; however, their role in HCC has not yet been studied. Therefore, we evaluated the possible role of OMA1/YME1L in HCC staging and discussed their potential role in cellular apoptosis and proliferation. Our study was performed using four groups of male albino rats: a normal control and three diethyl nitrosamine-treated groups for 8, 16, and 24 weeks. The OMA1 and YME1L, matrix-metalloproteinase-9 (MMP-9), and cyclin D1 content were measured in liver tissues, while alpha-fetoprotein (AFP) level was assessed in serum. Additionally, Ki-67 expression was evaluated by immunohistochemistry. The relative hepatic expression of Bax, and tissue inhibitor matrix metalloproteinase (TIMP-3) was measured. Herein, we confirmed for the first time that OMA1 is down-regulated while YME1L is up-regulated in HCC in the three studied stages with subsequent inhibition of apoptosis and cell cycle progression. Furthermore, these proteases have a possible role in metastasis. These newly recognized results suggested OMA1 and YME1L as possible diagnostic tools and therapeutic targets for HCC management.
Topics: Male; Animals; Rats; Diethylnitrosamine; Metalloproteases; Mitochondrial Proteins; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasm Staging; ATPases Associated with Diverse Cellular Activities; Apoptosis; Neoplasm Metastasis; Oxidative Stress; Liver; Biomarkers, Tumor
PubMed: 38161580
DOI: 10.59249/BWBY8971 -
Cancer Research Sep 2017Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of...
Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that -deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. .
Topics: Alkylating Agents; Animals; Apoptosis; Cell Proliferation; Diethylnitrosamine; Female; Humans; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagens; NF-E2 Transcription Factor, p45 Subunit; Signal Transduction; Tumor Cells, Cultured
PubMed: 28655791
DOI: 10.1158/0008-5472.CAN-16-3538 -
Journal of Hazardous Materials May 2023N-nitrosamines are formed during different industrial processes and are of significant concern due to their carcinogenic and mutagenic properties. This study reports...
N-nitrosamines are formed during different industrial processes and are of significant concern due to their carcinogenic and mutagenic properties. This study reports concentrations of N-nitrosamines in eight different industrial wastewater treatment plants in Switzerland and the variability of their abundance. Only four N-nitrosamines species, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodibutylamine (NDPA) and N-nitrosomorpholine (NMOR) were above the limit of quantification in this campaign. Remarkably high concentrations (i.e. up to 975 μg NDMA/L, 90.7 μg NDEA/L, 1.6 μg NDPA/L and 710 μg NMOR/L) of these N-nitrosamines were detected at seven of eight sites. These concentrations are two to five orders of magnitude higher than those typically detected in municipal wastewater effluents. These results suggest that industrial effluents may be a major source of N-nitrosamines. Although very high concentrations of N-nitrosamine have been detected in industrial discharges, various processes in surface water can partially mitigate their concentrations (e.g. photolysis, biodegradation and volatilization) and hence the risk to human health and aquatic ecosystems. Nevertheless, there is little information on long-term effects on aquatic organisms and therefore the discharge of N-nitrosamines to the environment should be avoided until the impact on ecosystems is assessed. During winter a less efficient mitigation of N-nitrosamines can be expected (lower biological activity, less sunlight) and therefore, emphasis should be put on this season in future risk assessment studies.
Topics: Humans; Switzerland; Ecosystem; Nitrosamines; Dimethylnitrosamine; Diethylnitrosamine
PubMed: 36867906
DOI: 10.1016/j.jhazmat.2023.131094 -
Human & Experimental Toxicology 2022Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory...
BACKGROUND
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Piperlongumine (PL) has been claimed to have cytotoxic and HCC inhibitory effects in various cancer cell lines and xenograft models, but the chemopreventive potential of PL has not been studied in experimentally induced HCC yet.
RESEARCH DESIGN
Twenty-four Wistar male rats were divided into four groups of six each, Group A: untreated control; Group B: Diethylnitrosamine (DEN) control (200 mg/kg), Group C: DEN + PL 10 mg/kg; and Group D: DEN + PL 20 mg/kg. Rats from all groups were assessed for liver cancer progression or inhibition by evaluating biochemical, cytokines, tumor markers, lipid peroxidation, and histological profiles.
RESULTS
The liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) levels, and lipid peroxidation were significantly decreased in Group C and Group D compared to Group B. Upregulation in the level of pro-inflammatory cytokines IL-1B, TNF-α, inflammatory mediator (NF-κB) and tumour marker alpha-fetoprotein (AFP) in Group B were brought down upon treatment with piperlongumine in a dose-dependent manner. Antitumor cytokine (IL-12) was upregulated in PL-treated rats compared to DEN control rats. DEN treated group (Group B) showed histological features of HCC, and in rats treated with PL (Groups C, D) partial to complete reversal to normal liver histoarchitecture was observed.
CONCLUSIONS
The potential chemopreventive actions of piperlongumine may be due to its free radical scavenging and antiproliferative effect. Therefore, piperlongumine may serve as a novel therapeutic agent for the treatment of hepatocellular carcinoma.
Topics: Animals; Carcinoma, Hepatocellular; Diethylnitrosamine; Dioxolanes; Disease Models, Animal; Humans; Liver Neoplasms; Male; Rats
PubMed: 35113675
DOI: 10.1177/09603271211073593 -
Frontiers in Immunology 2023Liver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to...
INTRODUCTION
Liver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model.
METHODS
We first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy.
RESULTS
Human data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups.
DISCUSSION
CD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one.
Topics: Humans; Mice; Animals; Infant; Diethylnitrosamine; Liver Neoplasms; MicroRNAs; Hypoxia; Tumor Microenvironment
PubMed: 37795103
DOI: 10.3389/fimmu.2023.1245708