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Di(ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant to which humans are exposed via multiple routes. Human health risk assessments for this substance have recently been updated, focusing on reproductive toxicity, including DEHP, in the list of chemicals classified as carcinogenic, mutagenic, or toxic to reproduction (CMR). Moreover, DEHP has also been defined as probably and possibly carcinogenic to humans based on its carcinogenicity in rodents. However, the mechanism of action of DEHP and its relevance in humans remain unclear. Rodent data suggests that DEHP induces cancer through non-genotoxic mechanisms related to multiple molecular signals, including PPARα activation, perturbation of fatty acid metabolism, induction of cell proliferation, decreased apoptosis, production of reactive oxygen species, and oxidative stress. According to the DEHP toxicological dataset, several in vitro cell transformation assays have been performed using different protocols and cellular models to produce different results. This study aimed to evaluate the carcinogenic potential of DEHP by using the A31-1-1 BALB/c-3T3 cell line in a standard cell transformation assay. Additionally, transcriptomic analysis was performed to explore the molecular responses and identify the affected toxicological pathways. Although DEHP treatment did not induce transformation in BALB/c-3T3 cells, the transcriptomic results revealed significant modulation of several pathways associated with DEHP metabolism, tissue-specific functions related to systemic metabolism, and basal cellular signaling with pleiotropic outcomes. Among these signaling pathways, modulation of cell-regulating signaling pathways, such as Notch, Wnt, and TGF-ß, can be highlighted. More specific modulation of such genes and pathways with double functions in metabolism and neurophysiology underlies the well-known crosstalk that may be crucial for the mechanism of action of DEHP. Our findings offer evidence to support the notion that these models are effective in minimizing the use of animal testing for toxicity assessment.
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Background: There are still certain gaps in the research that need to be filled despite the fact that numerous studies have looked into the transformation of odontogenic cysts into neoplastic lesions. To identify pertinent research that had been published and to synthesise the available data and provide an overview of the current body of knowledge, this review also sought to do so. Materials and Methods: Adopting the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a search strategy was implemented across several online databases to search for relevant articles as per the defined selection criterion. Results: After the search strategy was complete, 31 studies were chosen. Men tended to have more cancer than women. Swelling and discomfort were the primary pathology-related complaints. Although two cases were not detailed, radiologically, well-defined and poorly defined borders were reported in 18 and 11 participants, respectively. Squamous cell carcinoma with good differentiation (n = 12) was the most common cancer kind. More than 74% of patients were still living 6 months to 10 years following follow-up, four (12.90%) experienced recurrences and/or metastases and two (6.45%) experienced a disease-related mortality between 2 months and a year. Conclusion: Prompt surgical follow-ups and cautious excision of odontogenic cysts are essential to avoiding neoplastic change and recurrence. Future research is required to look at possible reasons why odontogenic cysts can convert neoplastically.
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Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N6-methyladenosine (m6A) modification is known to modulate pri-miRNA processing. However, whether m6A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m6A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5⯵M arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m6A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m6A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m6A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What's more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m6A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.
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Adenosina , Bronquios , Células Epiteliales , Metiltransferasas , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Adenosina/análogos & derivados , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Metiltransferasas/genética , Metiltransferasas/metabolismo , Bronquios/efectos de los fármacos , Bronquios/patología , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/efectos de los fármacos , Arsénico/toxicidad , Arsenitos/toxicidad , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Línea Celular , FenotipoRESUMEN
AIMS: Vascular smooth muscle cell (VSMC) plasticity is a state in which VSMCs undergo phenotypic switching from a quiescent contractile phenotype into other functionally distinct phenotypes. Although emerging evidence suggest that VSMC plasticity plays critical roles in the development of vascular diseases, little is known about the key determinant for controlling VSMC plasticity and fate. METHODS AND RESULTS: We found that smooth muscle cell-specific deletion of Lkb1 in tamoxifen-inducible Lkb1flox/flox; Myh11-Cre/ERT2 mice spontaneously and progressively induced aortic/arterial dilation, aneurysm, rupture, and premature death. Single-cell RNA sequencing and imaging-based lineage tracing showed that Lkb1-deficient VSMCs transdifferentiated gradually from early modulated VSMCs to fibroblast-like and chondrocyte-like cells, leading to ossification and blood-vessel rupture. Mechanistically, Lkb1 regulates polypyrimidine tract binding protein 1 (Ptbp1) expression and controls alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2. Lkb1 loss in VSMC results in an increased PKM2/PKM1 ratio and alters the metabolic profile by promoting aerobic glycolysis. Treatment with PKM2 activator TEPP-46 rescues VSMC transformation and aortic dilation in Lkb1flox/flox; Myh11-Cre/ERT2 mice. Furthermore, we found that Lkb1 expression decreased in human aortic aneurysm tissue compared to control tissue, along with changes in markers of VSMC fate. CONCLUSIONS: Lkb1, via its regulation of Ptbp1-dependent alterative splicing of PKM, maintains VSMC in contractile states by suppressing VSMC plasticity.
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Lung cancer is a leading cause of cancer deaths worldwide, consisting of two major histological subtypes: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). In some cases, NSCLC patients may undergo a histological transformation to SCLC during clinical treatments, which is associated with resistance to targeted therapy, immunotherapy, or chemotherapy. The review provides a comprehensive analysis of SCLC transformation from NSCLC, including biological mechanism, clinical relevance, and potential treatment options after transformation, which may give a better understanding of SCLC transformation and provide support for further research to define better therapy options.
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BACKGROUND AND OBJECTIVE: Cutaneous T-cell lymphomas (CTCL) such as mycosis fungoides (MF) and Sézary syndrome (SS) are rare lymphomas with varying prognoses. The aim of the study was to describe the survival of a cohort of patients with MF/SS and evaluate the prognostic factors impacting disease survival. MATERIALS AND METHODS: All cases of MF/SS diagnosed from 2008 through 2022 were retrospectively analyzed. The demographic variables, histological parameters, and analytical data were analyzed too. Progression-free survival (PFS) and disease-specific survival (DSS) were calculated. RESULTS: A total of 148 cases were included. A total of 121 (82%) and 27 cases were diagnosed with MF, and SS, respectively. A total of 37 patients (25%) experienced progression at some point disease progression. The median PFS and median DSS were 127 and 135 months, respectively. Age >60 years, diagnosis of SS, the presence of large cell transformation (LCT) at diagnosis, folliculotropism in early stages, high Ki-67 expression, the presence of the clonal T-cell receptor (TCR) in blood, elevated LDH and B2M levels, and advanced stages (IIB, IVA, T3, T4, N3/Nx) were associated with worse prognosis across the entire cohort. CONCLUSIONS: Stage IVA and the presence of LCT at diagnosis stood out as independent factors of unfavorable prognosis. LCT was the variable that most significantly impacted the patients' survival and was closely associated with tumor skin involvement and stage IIB.
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Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Masculino , Femenino , Anciano , Síndrome de Sézary/mortalidad , Síndrome de Sézary/patología , Micosis Fungoide/mortalidad , Micosis Fungoide/patología , Micosis Fungoide/diagnóstico , Adulto , Anciano de 80 o más Años , Linfoma Cutáneo de Células T/mortalidad , Linfoma Cutáneo de Células T/patología , Análisis de Supervivencia , Adulto Joven , Supervivencia sin Progresión , Progresión de la EnfermedadRESUMEN
With the exponential growth of the nanotechnology field, the global nanotechnology market is on an upward track with fast-growing jobs. Nickel (Ni)-containing nanoparticles (NPs), an important class of transition metal nanoparticles, have been extensively used in industrial and biomedical fields due to their unique nanostructural, physical, and chemical properties. Millions of people have been/are going to be exposed to Ni-containing NPs in occupational and non-occupational settings. Therefore, there are increasing concerns over the hazardous effects of Ni-containing NPs on health and the environment. The respiratory tract is a major portal of entry for Ni-containing NPs; thus, the adverse effects of Ni-containing NPs on the respiratory system, especially the lungs, have been a focus of scientific study. This review summarized previous studies, published before December 1, 2023, on cytotoxic, genotoxic, and carcinogenic effects of Ni-containing NPs on humans, lung cells in vitro, and rodent lungs in vivo, and the potential underlying mechanisms were also included. In addition, whether these adverse effects were induced by NPs themselves or Ni ions released from the NPs was also discussed. The extra-pulmonary effects of Ni-containing NPs were briefly mentioned. This review will provide us with a comprehensive view of the pulmonary effects of Ni-containing NPs and their underlying mechanisms, which will shed light on our future studies, including the urgency and necessity to produce engineering Ni-containing NPs with controlled and reduced toxicity, and also provide the scientific basis for developing nanoparticle exposure limits and policies.
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Antioxidants exert a paradoxical influence on cancer prevention. The latest explanation for this paradox is the different target sites of antioxidants. However, it remains unclear how mitochondria-targeted antioxidants trigger specific p53-dependent pathways in malignant transformation models. Our study revealed that overexpression of mitochondria-targeted catalase (mCAT) instigated such malignant transformation via mouse double minute 2 homolog (MDM2) -mediated p53 degradation. In mouse epithelial JB6 Cl41 cells, the stable expression of mCAT resulted in MDM2-mediated p53 degradation, unlike in catalase-overexpressed Cl41 cells. Further, we demonstrated that mCAT overexpression upregulated ubiquitin-specific protease 28 (USP28) expression, which in turn stabilized c-Jun protein levels. This alteration initiated the activation of the miR-200b promoter transcription activity and a subsequent increase in miR-200b expression. Furthermore, elevated miR-200b levels then promoted its binding to the 3'-untranslated region of protein phosphatase 2A catalytic subunit (PP2A-C) α-isoform mRNA, consequently resulting in PP2A-C protein downregulation. This cascade of events ultimately contributed to increased MDM2 phosphorylation and p53 protein degradation. Thus, the mCAT overexpression triggers MDM2/p53-dependent malignant transformation through USP28/miR-200b/PP2A-Cα pathway, which may provide a new information for understanding mitochondria-targeted antioxidants facilitate the progression to the tumorigenic state.
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Catalasa , Transformación Celular Neoplásica , Regulación hacia Abajo , MicroARNs , Mitocondrias , Proteína Fosfatasa 2 , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor , Ubiquitina Tiolesterasa , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , MicroARNs/metabolismo , MicroARNs/genética , Animales , Ratones , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/genética , Catalasa/metabolismo , Catalasa/genética , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/genética , Humanos , Línea Celular , Transducción de Señal , Regulación Neoplásica de la Expresión GénicaRESUMEN
INTRODUCTION: Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98-BPTF (NB) fusion in patients with T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing. The FG-repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown. MATERIALS AND METHODS: To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline-inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T-ALL cells. RESULTS: NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto-oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB-induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T-ALL cells by inactivating the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). CONCLUSION: We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.
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Transformación Celular Neoplásica , Proteínas de Complejo Poro Nuclear , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas c-pim-1 , Animales , Humanos , Ratones , Apoptosis , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Células Jurkat , Células 3T3 NIH , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación hacia ArribaRESUMEN
The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Carcinoma Endometrioide , Metilación de ADN , Hiperplasia Endometrial , Neoplasias Endometriales , Epigénesis Genética , Fosfohidrolasa PTEN , Femenino , Humanos , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Fosfohidrolasa PTEN/genética , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patología , Hiperplasia Endometrial/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Mutación , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Islas de CpG/genética , AncianoRESUMEN
BACKGROUND: Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. RESULTS: We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. CONCLUSIONS: We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.
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Ingeniería Metabólica , Saccharomyces cerevisiae , Sesterterpenos , Sesterterpenos/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genéticaRESUMEN
Epstein-Barr Virus (EBV) is associated with a range of B-cell malignancies, including Burkitt, Hodgkin, post-transplant, and AIDS-related lymphomas. Studies highlight EBV's transformative capability to induce oncometabolism in B-cells to support energy, biosynthetic precursors, and redox equivalents necessary for transition from quiescent to proliferation. Mitochondrial dysfunction presents an intrinsic barrier to EBV B-cell immortalization. Yet, how EBV maintains B-cell mitochondrial function and metabolic fluxes remains unclear. Here we show that EBV boosts cardiolipin(CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBNA2-induced CL enzyme transactivation. Pharmaceutical and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B-cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis, all vital for EBV-transformed B-cells. Targeting CL biosynthesis destabilizes mitochondrial one-carbon enzymes, causing synthetic lethality when coupled with a SHMT1/2 inhibitor. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering new strategies against EBV-associated B-cell malignancies.
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Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the major components of long-chain per- and polyfluorinated alkyl substances (PFAS), known for their chemical stability and environmental persistence. Even if PFOA and PFOS have been phased out or are limited in use, they still represent a concern for human and environmental health. Several studies have been performed to highlight the toxicological behavior of these chemicals and their mode of action (MoA). Data have suggested a causal association between PFOA or PFOS exposure and carcinogenicity in humans, but the outcomes of epidemiological studies showed some inconsistency. Moreover, the hypothesized MoA based on animal studies is considered not relevant for human cancer. To improve the knowledge on PFAS toxicology and contribute to the weight of evidence for the regulatory classification of PFAS, we used the BALB/c 3T3 cell transformation assay (CTA), an in vitro model under consideration to be included in an integrated approach to testing and assessment for non-genotoxic carcinogens (NGTxCs). PFOS and PFOA were tested at several concentrations using a validated experimental protocol. Our results demonstrate that PFOA does not induce cell transformation, whereas PFOS exposure induced a concentration-related increase of type III foci. Malignant foci formation was triggered at PFOS concentrations equal to or higher than 50 ppm and was not directly associated with cytotoxicity or proliferation induction. The divergent CTA outcomes suggest that different molecular events could be responsible for the toxicological profiles of PFOS and PFOA, which were not fully captured in our study.
PFAS chemicals are known for their durability and resistance to heat, water, and oil. They are persistent in the environment and may pose health risks despite decreased use. This study explored PFOS and PFOA, two common PFAS chemicals, to understand their potential harm and cancer risk. To better understand how they might be harmful, we conducted a cell-based test that can resemble the carcinogenesis process in experimental animals. The test revealed PFOS, but not PFOA, can cause cancer-like changes, at levels of 50 parts per million or higher. This result suggests different PFAS chemicals affect cells differently, but we need more research to understand exactly how they work and how they might cause cancer. Understanding this could help regulate and reduce PFAS harmful effects. This research aligns with 3R principles by using cell-based tests as an alternative to animal testing, thereby promoting ethical research practices.
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Ácidos Alcanesulfónicos , Caprilatos , Carcinógenos , Fluorocarburos , Fluorocarburos/toxicidad , Animales , Caprilatos/toxicidad , Ácidos Alcanesulfónicos/toxicidad , Ratones , Carcinógenos/toxicidad , Pruebas de Carcinogenicidad , Células 3T3 BALB , Humanos , Alternativas a las Pruebas en AnimalesRESUMEN
The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.
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Pruebas de Carcinogenicidad , Transformación Celular Neoplásica , Neoplasias Colorrectales , Contaminantes Ambientales , Organoides , Animales , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/efectos de los fármacos , Pruebas de Carcinogenicidad/métodos , Organoides/efectos de los fármacos , Organoides/patología , Ratones , Contaminantes Ambientales/toxicidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inducido químicamente , Humanos , Carcinógenos/toxicidad , Intestinos/efectos de los fármacos , Intestinos/patología , Neoplasias Intestinales/inducido químicamente , Neoplasias Intestinales/patología , Relación Dosis-Respuesta a DrogaRESUMEN
Although endometriosis is a common condition, both extrapelvic endometriosis and endometriosis associated malignancy (EAM) are rare. We describe the first reported case of a patient with Müllerian-type carcinosarcoma arising in gastric endometriosis.
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Continuous exposure to plastic pollutants may have serious consequences on human health. However, most toxicity assessments focus on non-environmentally relevant particles and rarely investigate long-term effects such as cancer induction. The present study assessed the carcinogenic potential of two secondary nanoplastics: polyethylene terephthalate (PET) particles generated from plastic bottles, and a biodegradable polylactic acid material, as respective examples of environmentally existing particles and new bioplastics. Pristine polystyrene nanoplastics were also included for comparison. A broad concentration range (6.25-200 µg/mL) of each nanoplastic was tested in both the initiation and promotion conditions of the regulatory assessment-accepted in vitro Bhas 42 cell transformation assay. Parallel cultures allowed confirmation of the efficient cellular internalisation of the three nanoplastics. Cell growth was enhanced by polystyrene in the initiation assay, and by PET in both conditions. Moreover, the number of transformed foci was significantly increased only by the highest PET concentration in the promotion assay, which also showed dose-dependency, indicating that nano PET can act as a non-genotoxic tumour promotor. Together, these findings support the carcinogenic risk assessment of nanoplastics and raise concerns regarding whether real-life co-exposure of PET nanoplastics and other environmental pollutants may result in synergistic transformation capacities.
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Contaminantes Ambientales , Poliésteres , Contaminantes Químicos del Agua , Humanos , Poliestirenos/toxicidad , Poliestirenos/análisis , Tereftalatos Polietilenos/toxicidad , Microplásticos/toxicidad , Plásticos/toxicidad , Contaminantes Químicos del Agua/análisis , PolietilenoRESUMEN
Tumor cells gain advantages in growth and survival by acquiring genotypic and phenotypic heterogeneity. Interactions with bystander cells in the tumor microenvironment contribute to the progression of heterogeneity. We have shown that fusion between tumor and bystander cells is one form of interaction, and that tumor-bystander cell fusion has contrasting effects. By trapping fusion hybrids in the heterokaryon or synkaryon state, tumor-bystander cell fusion prevents the progression of heterogeneity. However, if trapping fails, fusion hybrids will resume replication to form derivative clones with diverse genomic makeups and behavioral phenotypes. To determine the characteristics of bystander cells that influence the fate of fusion hybrids, we co-cultured prostate mesenchymal stromal cell lines and their spontaneously transformed sublines with LNCaP as well as HPE-15 prostate cancer cells. Subclones derived from cancer-stromal fusion hybrids were examined for genotypic and phenotypic diversifications. Both stromal cell lines were capable of fusing with cancer cells, but only fusion hybrids with the transformed stromal subline generated large numbers of derivative subclones. Each subclone had distinct cell morphologies and growth behaviors and was detected with complete genomic hybridization. The health conditions of the bystander cell compartment play a crucial role in the progression of tumor cell heterogeneity.
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Nickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIß. Notably, artificially increasing RhoGDIß levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIß contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c-Jun activity, which in turn promoted miR-200c transcription. High levels of miR-200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR-137, SP-1 protein translation, and the suppression of RhoGDIß mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co-regulation of RhoGDIß expression by long noncoding RNA MEG3, multiple microRNAs (miR-200c and miR-137), and RNA-regulated transcription factors (c-Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIß pathway.
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Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Humanos , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Regulación hacia Abajo , Células Epiteliales/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , MicroARNs/genética , MicroARNs/metabolismo , Níquel , Inhibidor beta de Disociación del Nucleótido Guanina rho/antagonistas & inhibidores , Inhibidor beta de Disociación del Nucleótido Guanina rho/genética , Inhibidor beta de Disociación del Nucleótido Guanina rho/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero , Factores de Transcripción SOXB1/genética , Ribonucleoproteína Nuclear Heterogénea D0/genética , Ribonucleoproteína Nuclear Heterogénea D0/metabolismoRESUMEN
Bilirubin, a key active ingredient of bezoars with extensive clinical applications in China, is produced through a chemical process. However, this method suffers from inefficiency and adverse environmental impacts. To address this challenge, we present a novel and efficient approach for bilirubin production via whole-cell transformation. In this study, we employed Corynebacterium glutamicum ATCC13032 to express a ß-glucuronidase (StGUS), an enzyme from Staphylococcus sp. RLH1 that effectively hydrolyzes conjugated bilirubin to bilirubin. Following the optimization of the biotransformation conditions, a remarkable conversion rate of 79.7% in the generation of bilirubin was obtained at temperate 40 °C, pH 7.0, 1 mM Mg2+ and 6 mM antioxidant NaHSO3 after 12 h. These findings hold significant potential for establishing an industrially viable platform for large-scale bilirubin production.
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Bilirrubina , Corynebacterium glutamicum , Glucuronidasa/genética , Glucuronidasa/metabolismo , Corynebacterium glutamicum/metabolismo , Staphylococcus , ChinaRESUMEN
One of the extracellular matrix proteins, tenascin-C (TN-C), is known to be upregulated in age-related inflammatory diseases such as cancer and cardiovascular diseases. Expression of this molecule is frequently detected, especially in the macrophage-rich areas of atherosclerotic lesions; however, the role of TN-C in mechanisms underlying the progression of atherosclerosis remains obscure. Previously, we found a hidden bioactive sequence termed TNIIIA2 in the TN-C molecule and reported that the exposure of this sequence would be carried out through limited digestion of TN-C by inflammatory proteases. Thus, we hypothesized that some pro-atherosclerotic phenotypes might be elicited from macrophages when they were stimulated by TNIIIA2. In this study, TNIIIA2 showed the ability to accelerate intracellular lipid accumulation in macrophages. In this experimental condition, an elevation of phagocytic activity was observed, accompanied by a decrease in the expression of transporters responsible for lipid efflux. All these observations were mediated through the induction of excessive ß1-integrin activation, which is a characteristic property of the TNIIIA2 sequence. Finally, we demonstrated that the injection of a drug that targets TNIIIA2's bioactivity could rescue mice from atherosclerotic plaque expansion. From these observations, it was shown that TN-C works as a pro-atherosclerotic molecule through an internal TNIIIA2 sequence. The possible advantages of clinical strategies targeting TNIIIA2 are also indicated.