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Nature Genetics Jun 2020During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the...
During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.
Topics: ADAM10 Protein; Amyloid Precursor Protein Secretases; Animals; Cell Lineage; Diethylnitrosamine; Epithelium; Esophagus; Female; High-Throughput Nucleotide Sequencing; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Receptor, Notch1; Receptor, Notch2; Reproducibility of Results; Tumor Suppressor Protein p53
PubMed: 32424351
DOI: 10.1038/s41588-020-0624-3 -
Frontiers in Oncology 2022The extracellular matrix proteoglycan SPOCK1 is increasingly recognized as a contributor to the development and progression of cancers. Here, we study how SPOCK1, which...
The extracellular matrix proteoglycan SPOCK1 is increasingly recognized as a contributor to the development and progression of cancers. Here, we study how SPOCK1, which is present in non-tumorous hepatocytes at low concentrations, promotes the development and progression of malignant hepatocellular tumors. Although SPOCK1 is an extracellular matrix proteoglycan, its concentration increases in the cytoplasm of hepatocytes starting with very low expression in the normal cells and then appearing in much higher quantities in cells of cirrhotic human liver and hepatocellular carcinoma. This observation is similar to that observed after diethylnitrosamine induction of mouse hepatocarcinogenesis. Furthermore, syndecan-1, the major proteoglycan of the liver, and SPOCK1 are in inverse correlation in the course of these events. In hepatoma cell lines, the cytoplasmic SPOCK1 colocalized with mitochondrial markers, such as MitoTracker and TOMM20, a characteristic protein of the outer membrane of the mitochondrion and could be detected in the cell nucleus. SPOCK1 downregulation of hepatoma cell lines by siRNA inhibited cell proliferation, upregulated p21 and p27, and interfered with pAkt and CDK4 expression. A tyrosine kinase array revealed that inhibition of SPOCK1 in the liver cancer cells altered MAPK signaling and downregulated several members of the Sarc family, all related to the aggressivity of the hepatoma cell lines. These studies support the idea that SPOCK1 enhancement in the liver is an active contributor to human and rodent hepatocarcinogenesis and cancer progression. However, its mitochondrial localization raises the possibility that it has a currently unidentified physiological function in normal hepatocytes.
PubMed: 35186754
DOI: 10.3389/fonc.2022.819883 -
Hepatology (Baltimore, Md.) Oct 2021HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently...
BACKGROUND AND AIMS
HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC.
APPROACH AND RESULTS
Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC.
CONCLUSIONS
This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of "immune-cold" tumor to ICT.
Topics: Adult; Aged; Aged, 80 and over; Alkylating Agents; Animals; Arginine; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Diethylnitrosamine; Enzyme Inhibitors; Female; Histocompatibility Antigens Class II; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Liver Neoplasms, Experimental; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Transgenic; Middle Aged; Protein-Arginine N-Methyltransferases; Proto-Oncogene Proteins c-myc; Pyrimidines; Quinolines; Up-Regulation; Young Adult
PubMed: 33896016
DOI: 10.1002/hep.31864 -
JHEP Reports : Innovation in Hepatology Feb 2024The mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated...
BACKGROUND & AIMS
The mechanism behind the progressive pathological alteration in metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH)-associated hepatocellular carcinoma (HCC) is poorly understood. In the present study, we investigated the role of the polyol pathway enzyme AKR1B1 in metabolic switching associated with MASLD/MASH and in the progression of HCC.
METHODS
AKR1B1 expression was estimated in the tissue and plasma of patients with MASLD/MASH, HCC, and HCC with diabetes mellitus. The role of AKR1B1 in metabolic switching assessed through media conditioning, lentiviral transfection, and pharmacological probes. A proteomic and metabolomic approach was applied for the in-depth investigation of metabolic pathways. Preclinically, mice were subjected to a high-fructose diet and diethylnitrosamine to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching characteristic of MASLD-HCC.
RESULTS
A significant increase in the expression of AKR1B1 was observed in tissue and plasma samples from patients with MASLD/MASH, HCC, and HCC with diabetes mellitus compared to normal samples. Mechanistically, assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, the tricarboxylic acid cycle, and lipogenesis to promote hyperglycemia-mediated MASLD and cancer progression. A pathological increase in the expression of AKR1B1 was observed in experimental MASLD-HCC, and expression was positively correlated with high blood glucose levels. High-fructose diet + diethylnitrosamine-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. AKR1B1 inhibition with epalrestat or NARI-29 inhibited cellular metabolism in and models.
CONCLUSIONS
Pathological AKR1B1 modulates hepatic metabolism to promote MASLD-associated hepatocarcinogenesis. Aldose reductase inhibition modulates the glycolytic pathway to prevent precancerous hepatocyte formation.
IMPACT AND IMPLICATIONS
This research work highlights AKR1B1 as a druggable target in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), which could provide the basis for the development of new chemotherapeutic agents. Moreover, our results indicate the potential of plasma AKR1B1 levels as a prognostic marker and diagnostic test for MASLD and associated HCC. Additionally, a major observation in this study was that AKR1B1 is associated with the promotion of the Warburg effect in HCC.
PubMed: 38283757
DOI: 10.1016/j.jhepr.2023.100974 -
Biologics : Targets & Therapy 2016Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. HCC is usually asymptomatic at potential curative stages, and it has very poor prognosis if... (Review)
Review
Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. HCC is usually asymptomatic at potential curative stages, and it has very poor prognosis if detected later. Thus, the identification of early biomarkers and novel therapies is essential to improve HCC patient survival. Ion channels have been proposed as potential tumor markers and therapeutic targets for several cancers including HCC. Especially, the ether à-go-go-1 (Eag1) voltage-gated potassium channel has been suggested as an early marker for HCC. Eag1 is overexpressed during HCC development from the cirrhotic and the preneoplastic lesions preceding HCC in a rat model. The channel is also overexpressed in human HCC. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including Eag1. Actually, in vivo studies have shown that astemizole may have clinical utility for HCC prevention and treatment. Here, we will review first some general aspects of HCC including the current biomarkers and therapies, and then we will focus on Eag1 channels as promising tools in the early diagnosis of HCC.
PubMed: 27703327
DOI: 10.2147/BTT.S87402 -
Open Access Macedonian Journal of... Jun 2018This study was designated to evaluate the frequency of anatomic variations of the pancreaticobiliary union.
AIM
This study was designated to evaluate the frequency of anatomic variations of the pancreaticobiliary union.
MATERIALS AND METHODS
Our research was observational, comparative and analytical. The investigation was conducted from January 2016-May 2017. This study included 63 patients from Clinic of Gastroenterology and Hepatology - Prishtina, assessed pancreaticobiliary union with Magnetic Resonance cholangiopancreatography.
RESULTS
Union of the common bile duct and the major pancreas was biliary-pancreatic type The angle between common bile duct and the major pancreas duct had different sizes average 35.6°. We did not distinguish significant statistical significance in the size of the pancreaticobiliary angle. In men, the union angle was from the average 36.9°, while in females was average 34.3°. No correlation between the age and size of the angle between common bile duct and the major pancreas duct.
CONCLUSIONS
The union of the common bile duct and the major pancreas duct was in most cases B-P Type. The common channel and angle between common bile duct and the major pancreas duct were normal in most cases.
PubMed: 29983789
DOI: 10.3889/oamjms.2018.196 -
Cancers Aug 2023Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular...
Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular mechanisms involved in PLC development and phenotype decision are still not well understood. Complete deletion of encoding the B56δ subunit of Protein Phosphatase 2A (PP2A) results in spontaneous HCC development in mice via a c-MYC-dependent mechanism. In the present study, we aimed to examine the role of in an independent mouse model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. deletion (heterozygous and homozygous) accelerated HCC development, corroborating its tumor-suppressive function in liver and suggesting may be haploinsufficient. -deficient HCCs stained positively for c-MYC, consistent with increased AKT activation in pre-malignant and tumor tissues of -deficient mice. We also found increased YAP activation in -deficient tumors. Remarkably, in older mice, deletion resulted in cHCC-CCA development in this model, with the CCA component showing increased expression of progenitor markers (SOX9 and EpCAM). Finally, we observed an upregulation of in tumors from wildtype and heterozygous mice, revealing a tumor-specific control mechanism of expression, and suggestive of the involvement of in a negative feedback regulation restricting tumor growth. Our study highlights the tumor-suppressive role of mouse PP2A-B56δ in both HCC and cHCC-CCA, which may have important implications for human PLC development and targeted treatment.
PubMed: 37627221
DOI: 10.3390/cancers15164193 -
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 -
Translational Oncology May 2024The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce...
BACKGROUND
The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore.
METHODS
We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 μM) and Sorafenib (1-10 μM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done.
RESULTS
The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4.
CONCLUSIONS
In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.
PubMed: 38394865
DOI: 10.1016/j.tranon.2024.101920 -
Cancers Mar 2021ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly...
ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.
PubMed: 33807672
DOI: 10.3390/cancers13051110