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Scientific Reports Mar 2024Hepatocellular carcinoma (HCC) progression is associated with dysfunctional mitochondria and bioenergetics impairment. However, no data about the relationship between...
An adenosine derivative promotes mitochondrial supercomplexes reorganization and restoration of mitochondria structure and bioenergetics in a diethylnitrosamine-induced hepatocellular carcinoma model.
Hepatocellular carcinoma (HCC) progression is associated with dysfunctional mitochondria and bioenergetics impairment. However, no data about the relationship between mitochondrial supercomplexes (hmwSC) formation and ATP production rates in HCC are available. Our group has developed an adenosine derivative, IFC-305, which improves mitochondrial function, and it has been proposed as a therapeutic candidate for HCC. We aimed to determine the role of IFC-305 on both mitochondrial structure and bioenergetics in a sequential cirrhosis-HCC model in rats. Our results showed that IFC-305 administration decreased the number and size of liver tumors, reduced the expression of tumoral markers, and reestablished the typical architecture of the hepatic parenchyma. The livers of treated rats showed a reduction of mitochondria number, recovery of the mtDNA/nDNA ratio, and mitochondrial length. Also, IFC-305 increased cardiolipin and phosphatidylcholine levels and promoted hmwSC reorganization with changes in the expression levels of hmwSC assembly-related genes. IFC-305 in HCC modified the expression of several genes encoding elements of electron transport chain complexes and increased the ATP levels by recovering the complex I, III, and V activity. We propose that IFC-305 restores the mitochondrial bioenergetics in HCC by normalizing the quantity, morphology, and function of mitochondria, possibly as part of its hepatic restorative effect.
Topics: Rats; Animals; Carcinoma, Hepatocellular; Diethylnitrosamine; Liver Neoplasms; Mitochondria; Adenosine; Energy Metabolism; Adenosine Triphosphate
PubMed: 38491051
DOI: 10.1038/s41598-024-56306-9 -
Oncogene Nov 2021Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and...
Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and subsequent proliferation after colonization. However, it has long been recognized that cancer cell migration and proliferation can be uncoupled; but the mechanism underlying this paradox is not well understood. Here we report that TNFAIP8 (tumor necrosis factor-α-induced protein 8), a "professional" transfer protein of phosphoinositide second messengers, promotes cancer cell migration or metastasis but inhibits its proliferation or cancer growth. TNFAIP8-deficient mice developed larger tumors, but TNFAIP8-deficient tumor cells completely lost their ability to migrate toward chemoattractants and were defective in colonizing lung tissues as compared to wild-type counterparts. Mechanistically, TNFAIP8 served as a cellular "pilot" of tumor cell migration by locally amplifying PI3K-AKT and Rac signals on the cell membrane facing chemoattractant; at the same time, TNFAIP8 also acted as a global inhibitor of tumor cell growth and proliferation by regulating Hippo signaling pathway. These findings help explain the migration-proliferation paradox of cancer cells that characterizes many cancers.
Topics: Animals; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diethylnitrosamine; Female; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Hippo Signaling Pathway; Humans; Lung Neoplasms; Male; Methylcholanthrene; Mice; Phosphatidylinositol 3-Kinases; Skin Neoplasms
PubMed: 34608264
DOI: 10.1038/s41388-021-02035-6 -
Scientific Reports Sep 2017The aryl hydrocarbon receptor (AhR) has roles in cell proliferation, differentiation and organ homeostasis, including the liver. AhR depletion induces undifferentiation...
The aryl hydrocarbon receptor (AhR) has roles in cell proliferation, differentiation and organ homeostasis, including the liver. AhR depletion induces undifferentiation and pluripotency in normal and transformed cells. Here, AhR-null mice (AhR-/-) were used to explore whether AhR controls liver regeneration and carcinogenesis by restricting the expansion of stem-like cells and the expression of pluripotency genes. Short-term CCl liver damage was earlier and more efficiently repaired in AhR-/- than in AhR+/+ mice. Stem-like CK14 + and TBX3 + and pluripotency-expressing OCT4 + and NANOG + cells expanded sooner in AhR-/- than in AhR+/+ regenerating livers. Stem-like side population cells (SP) isolated from AhR-/- livers had increased β-catenin (β-Cat) signaling with overexpression of Axin2, Dkk1 and Cyclin D1. Interestingly, β-Cat, Axin2 and Dkk1 also increased during regeneration but more notably in AhR-null livers. Liver carcinogenesis induced by diethylnitrosamine (DEN) produced large carcinomas in all AhR-/- mice but mostly premalignant adenomas in less than half of AhR+/+ mice. AhR-null tumoral tissue, but not their surrounding non-tumoral parenchyma, had nuclear β-Cat and Axin2 overexpression. OCT4 and NANOG were nevertheless similarly expressed in AhR+/+ and AhR-/- lesions. We suggest that AhR may serve to adjust liver repair and to block tumorigenesis by modulating stem-like cells and β-Cat signaling.
Topics: Animals; Biomarkers; Cell Transformation, Neoplastic; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Disease Models, Animal; Disease Progression; Immunophenotyping; Liver; Liver Neoplasms; Liver Regeneration; Male; Mice; Mice, Knockout; Receptors, Aryl Hydrocarbon
PubMed: 28874739
DOI: 10.1038/s41598-017-10984-w -
BMC Cancer Nov 2018Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and...
BACKGROUND
Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes.
METHODS
Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs).
RESULTS
OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment.
CONCLUSIONS
ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.
Topics: Angiotensin Receptor Antagonists; Animals; Biomarkers; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; DNA Damage; Diethylnitrosamine; Disease Models, Animal; Drug Synergism; Humans; Lipid Peroxidation; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Oxidative Stress; Protective Agents; Rats; Rats, Inbred OLETF; Tretinoin
PubMed: 30477453
DOI: 10.1186/s12885-018-5099-6 -
Journal of Cancer Research and... 2021Hepatocellular carcinoma (HCC), a primary liver malignancy, represents a continuous challenge to clinicians as it is a leading cause of death due to cancer widely. Early...
BACKGROUND AND AIM
Hepatocellular carcinoma (HCC), a primary liver malignancy, represents a continuous challenge to clinicians as it is a leading cause of death due to cancer widely. Early detection is the only hope to cure patients from this deadly disease or possibly increase life expectancy. Mouse models are most acceptable studies as they have ability to manipulate their genome and transcriptome to evaluate mechanistic changes. In addition, system biology can improvise the understanding of molecular mechanism of HCC and also can reveal the protein hub involved in every stage of HCC.
MATERIALS AND METHODS
Herein, diethylnitrosamine and thioacetamide (TAA) were used to develop stage-specific HCC in Wistar rats. Histopathological changes, biochemical parameters, and the oxidative stress were measured in hepatocytes. We have reanalyzed the microarray dataset to identify the complex signaling pathways involved in hepatocarcinogenesis induced by TAA. GSE45050 dataset was downloaded from Gene Expression Omnibus database, and the gene expression profile of nontumor, cirrhosis, and HCC was compared.
RESULTS
The study reveals stage-specific development of chronic HCC rat model and promising stage-specific targets (EHMT2, GMPS, and SPRY2) of HCC.
CONCLUSIONS
EHMT2, GMPS, and SPRY found as high centrality nodes in protein-protein interaction studies using high-throughput microarray data which tend to be present in signaling pathways and co-occur in a biological state of HCC. These genes can be targeted to understand the possible pathology, molecular changes, and target strategy under cirrhosis and HCC condition.
Topics: Alkylating Agents; Animals; Biomarkers, Tumor; Carcinoma, Hepatocellular; Diethylnitrosamine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Liver Neoplasms, Experimental; Male; Protein Interaction Maps; Rats; Rats, Wistar; Thioacetamide; Transcriptome
PubMed: 34528568
DOI: 10.4103/jcrt.JCRT_948_20 -
Scientific Reports Feb 2019Hepatitis and hepatocellular carcinoma are serious human diseases. Here, we examined the in vivo and in vitro inhibitory effect of extracts of Qizhu decoction (a...
Hepatitis and hepatocellular carcinoma are serious human diseases. Here, we examined the in vivo and in vitro inhibitory effect of extracts of Qizhu decoction (a traditional Chinese medicine) on hepatitis caused by diethylnitrosamine or hepatitis B virus and on diethylnitrosamine-induced hepatocellular carcinoma. The results showed that both the aqueous and ethanol extracts (QC and QS, respectively) of Qizhu decoction significantly inhibited hepatic inflammation and liver cancer induced by diethylnitrosamine or hepatitis B virus by suppressing NF-κB signaling and decreasing the levels of TNF-α and IL-1β. Both QC and QS inhibited the proliferation and migration of primary cancer hepatocytes by reducing cyclin B1, cyclin D1 and N-cadherin expression and increasing E-cadherin expression. QC and QS also promoted the apoptosis of primary cancer hepatocytes by upregulating caspase-3 and downregulating BCL-2 expression. The knockdown of p65 in NF-κB signaling inhibited the ability of QC and QS to significantly reduce the colony formation ability of liver cancer cells. Additionally, QC and QS might significantly inhibit the DNA replication of hepatitis B virus in vivo and in vitro, and we found that corilagin and polydatin were the active compounds of QC and QS. Taken together, our in vitro findings and our results in C57BL/6 mice showed that extracts of Qizhu decoction might inhibit hepatitis and hepatocellular carcinoma by suppressing NF-κB signaling.
Topics: Animals; Carcinoma, Hepatocellular; Diethylnitrosamine; Disease Models, Animal; Drugs, Chinese Herbal; Gene Knockdown Techniques; Hep G2 Cells; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis, Animal; Humans; Liver Neoplasms; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Mice, Transgenic; Signal Transduction; Transcription Factor RelA; Transfection
PubMed: 30723284
DOI: 10.1038/s41598-018-38391-9 -
Cell Biology International Jul 2016N-nitrosodiethylamine (NDEA), a nitrosamine compound, is known to cause liver damage through the generation of reactive oxygen species (ROS), resulting in oxidative...
UNLABELLED
N-nitrosodiethylamine (NDEA), a nitrosamine compound, is known to cause liver damage through the generation of reactive oxygen species (ROS), resulting in oxidative damage to macromolecules such as DNA, and the consequent development of cancer. The present study examines the protective effects of two antioxidant coumarin compounds umbelliferone (Umb) and esculetin (Esc) against NDEA-induced hepatotoxicity when administered in the diet to male Wistar rats. The results show that treatment with Umb (0.5% w/w) and Esc (0.5% w/w) in the diet for 7 days significantly attenuates NDEA-induced liver damage, lowering serum alanine transaminase (ALT) levels, decreasing hepatic lipid peroxidation, and restoring total glutathione levels. To investigate the mechanism for the observed protective effect, the levels of the key protective enzymes
NAD(P)H
quinone oxidoreductase 1 (NQO1), heme oxygenase (HO1), and glutathione S-transferase Pi (GSTP1) were measured by Western blotting following Umb and Esc administration. The results showed that Umb and Esc administration significantly increased the expression of NQO1 by 3.6- and 2.7-fold, HO1 by 2.7- and 3.2-fold, and GSTP1 by 2.8- and 3.2-fold, respectively. In conclusion, Umb and Esc are capable of protecting liver from NDEA-induced hepatotoxicity, and this is associated with the induction of protective enzymes.
Topics: Alanine Transaminase; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Glutathione; Lipid Peroxidation; Liver; Liver Neoplasms, Experimental; Male; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Umbelliferones
PubMed: 27080985
DOI: 10.1002/cbin.10611 -
Biomedicine & Pharmacotherapy =... Sep 2023Dichloromethane extract of Cleistocalyx nervosum var. paniala seeds exhibited an anticarcinogenicity against chemically-induced the early stages of carcinogenesis in...
2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone from Cleistocalyx nervosum var. paniala seeds attenuated the early stage of diethylnitrosamine and 1,2-dimethylhydrazine-induced colorectal carcinogenesis.
BACKGROUND
Dichloromethane extract of Cleistocalyx nervosum var. paniala seeds exhibited an anticarcinogenicity against chemically-induced the early stages of carcinogenesis in rats. This study aimed to identify anticarcinogenic compounds from C. nervosum seed extract (CSE).
METHODS
Salmonella mutation assay was performed to determine mutagenicity and antimutagenicity of partially purified and purified compounds of CSE. The anticarcinogenic enzyme-inducing activity was measured in Hepa1c1c7. Moreover, the anticancer potency was examined on various human cancer cell lines. The anticarcinogenicity of DMC was investigated using dual-organ carcinogenicity model. The number of preneoplastic lesions was evaluated in the liver and colon. The inhibitory mechanisms of DMC on liver- and colorectal carcinogenesis were investigated.
RESULTS
Six partially purified fractions (MK1 - MK6) and purified compounds, including 2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) and hariganetin, were obtained from CSE. Among these fractions, MK4 and DMC presented the greatest antimutagenicity against indirect mutagens in bacterial model. Moreover, MK5 possessed an effective anticarcinogenic enzyme inducer in Hepa1c1c7. The MK4, DMC and CSE showed greater anticancer activity on all cell lines and exhibited the most effective toxicity on colon cancer cells. Furthermore, DMC inhibited the formation of colonic preneoplastic lesions in carcinogens-treated rats. It reduced PCNA-positive cells and frequency of BCAC in rat colon. DMC also enhanced the detoxifying enzyme, GST, in rat livers.
CONCLUSIONS
DMC obtained from CSE may be a promising cancer chemopreventive compound of colorectal cancer process in rats. It could increase detoxifying enzymes and suppress the cell proliferation process resulting in prevention of post-initiation stage of colorectal carcinogenesis.
Topics: Humans; Rats; Animals; Syzygium; Diethylnitrosamine; 1,2-Dimethylhydrazine; Seeds; Carcinogenesis; Colorectal Neoplasms
PubMed: 37517291
DOI: 10.1016/j.biopha.2023.115221 -
Hepatology (Baltimore, Md.) Oct 2011Hepatocyte death and proliferation contribute to hepatocellular carcinoma development after carcinogen exposure or chronic liver inflammation. However, the role and the... (Comparative Study)
Comparative Study
UNLABELLED
Hepatocyte death and proliferation contribute to hepatocellular carcinoma development after carcinogen exposure or chronic liver inflammation. However, the role and the molecular targets of hepatocyte death in relation to compensatory proliferation have not been fully characterized. In this study, we investigated the role of p53 up-regulated modulator of apoptosis (PUMA), a BH3-only protein important for both p53-dependent and -independent apoptosis, in a diethylnitrosamine (DEN)-induced liver carcinogenesis model. PUMA deficiency significantly decreased the multiplicity and size of liver tumors. DEN treatment induced p53-independent PUMA expression, PUMA-dependent hepatocyte death, and compensatory proliferation. Furthermore, inhibition or deletion of c-jun N-terminal kinase 1 (JNK1) abrogated PUMA induction, hepatocyte death, and compensatory proliferation.
CONCLUSION
These results provide direct evidence that JNK1/PUMA-dependent apoptosis promotes chemical hepatocarcinogenesis through compensatory proliferation, and suggest apoptotic inducers as potential therapeutic targets in liver injury and cancer.
Topics: Alanine Transaminase; Animals; Apoptosis; Apoptosis Regulatory Proteins; Biopsy, Needle; Blotting, Western; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cells, Cultured; Diethylnitrosamine; Disease Models, Animal; Hepatocytes; Immunohistochemistry; Liver Neoplasms; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 8; Random Allocation; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation
PubMed: 21725994
DOI: 10.1002/hep.24516 -
Biomedicine & Pharmacotherapy =... Jun 2019Pretreatment of mesenchymal stem cells (MSCs) with melatonin (Mel) improves their potential therapeutic effect on chronic diseases and cancers. However, this...
Pretreatment of mesenchymal stem cells (MSCs) with melatonin (Mel) improves their potential therapeutic effect on chronic diseases and cancers. However, this preconditioning strategy may direct the effect of Mel toward MSCs alone and deprive cancer cells of the oncostatic effect of Mel. Herein, we hypothesized that Mel given before transplantation of non-preconditioned MSCs may maximize the therapeutic outcome via the oncostatic effect of Mel by preparing a suitable tumor microenvironment for MSCs. Female rats (n = 60) were equally divided into 6 groups; normal control, diethylnitrosamine (DEN), DEN + Mel, DEN + MSCs, DEN + MSCs preconditioned with Mel, and DEN + MSCs + Mel. The obtained data revealed that administration of Mel before MSCs treatment without preconditioning yielded a better ameliorative effect against DEN-induced hepatocellular carcinoma (HCC) as evidenced by: 1) reduced serum levels of alpha fetoprotein and gamma-glutamyl transferase; 2) decreased number and area of glutathione S-transferase placental positive foci; 3) induced apoptosis (as indicated by increased cleaved caspase-3 activity, upregulated expression of proapoptotic genes Bax and caspase 3 and downregulated expression of anti-apoptotic genes Bcl2, survivin); 4) decreased malondialdehyde level and increased activities of superoxide dismutase, catalase, and glutathione peroxidase enzymes; and 5) reduced inflammation, angiogenesis and metastasis as indicated by downregulated expression of interleukin 1 beta, nuclear factor kappa B, vascular endothelial growth factor, and matrix metallopeptidase 9 genes and upregulated expression of metalloproteinase inhibitor 1 gene. Thus, administration of Mel before MSCs (without preconditioning) fostered the survival and therapeutic potential of MSCs in HCC, possibly through induction of apoptosis and inhibition of inflammation and oxidative stress. This new strategy showed better therapeutic outcomes and may improve MSC-based therapies for HCC.
Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Diethylnitrosamine; Disease Models, Animal; Down-Regulation; Female; Glutathione Peroxidase; Glutathione Transferase; Inflammation; Liver; Liver Neoplasms; Male; Melatonin; Mesenchymal Stem Cells; Oxidative Stress; Rats; Up-Regulation; alpha-Fetoproteins; gamma-Glutamyltransferase
PubMed: 30925457
DOI: 10.1016/j.biopha.2019.108732