scholarly journals Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

2021 ◽  
Vol 7 (23) ◽  
pp. eabf9141
Author(s):  
Valentin J. A. Barthet ◽  
Martina Brucoli ◽  
Marcus J. G. W. Ladds ◽  
Christoph Nössing ◽  
Christos Kiourtis ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Liver Parenchyma ◽  
Genetically Engineered ◽  
Lineage Tracing ◽  
Binding Motif ◽  
Cell Of Origin ◽  
Ductular Reaction ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Genetically Engineered Mouse Model

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention.

scholarly journals Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Chee Wai Chua ◽  
Nusrat J Epsi ◽  
Eva Y Leung ◽  
Shouhong Xuan ◽  
Ming Lei ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Progenitor Cells ◽  
Neuroendocrine Differentiation ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Cell Of Origin ◽  
Genetically Engineered Mouse Models ◽  
Pten Deletion ◽  
A Cell

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer.

Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells

2020 ◽  
Vol 12 (536) ◽  
pp. eaaw6003 ◽  
Author(s):  
Anna Julie Peired ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Marco Allinovi ◽  
Francesco Guzzi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Progenitor Cells ◽  
Renal Cell ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Renal Progenitor Cells ◽  
Renal Progenitor

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.

scholarly journals Diversity of Epithelial Stem Cell Types in Adult Lung

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Feng Li ◽  
Jinxi He ◽  
Jun Wei ◽  
William C. Cho ◽  
Xiaoming Liu
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Genetically Engineered ◽  
Lineage Tracing ◽  
Epithelial Stem Cells ◽  
Epithelial Stem Cell ◽  
Genetically Engineered Mice ◽  
Airway Tree

Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays,in vitroand/orex vivomodels, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer.

scholarly journals High Throughput Screen Identifies the DNMT1 (DNA Methyltransferase-1) Inhibitor, 5-Azacytidine, as a Potent Inducer of PTEN (Phosphatase and Tensin Homolog)

2020 ◽  
Vol 40 (8) ◽  
pp. 1854-1869
Author(s):  
Keith A. Strand ◽  
Sizhao Lu ◽  
Marie F. Mutryn ◽  
Linfeng Li ◽  
Qiong Zhou ◽  
...  
Keyword(s):  
Protein Expression ◽  
High Throughput ◽  
Knockout Mice ◽  
Vascular Remodeling ◽  
Dna Methyltransferase ◽  
Dna Methyltransferase 1 ◽  
Protective Effects ◽  
High Throughput Screen ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Objective: Our recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Ang II (angiotensin II)-induced pathological vascular remodeling, suggesting that pharmacological PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Approach and Results: To identify novel PTEN activators, we conducted a high-throughput screen using a fluorescence based PTEN promoter-reporter assay. After screening ≈3400 compounds, 11 hit compounds were chosen based on level of activity and mechanism of action. Following in vitro confirmation, we focused on 5-azacytidine, a DNMT1 (DNA methyltransferase-1) inhibitor, for further analysis. In addition to PTEN upregulation, 5-azacytidine treatment increased expression of genes associated with a differentiated SMC phenotype. 5-Azacytidine treatment also maintained contractile gene expression and reduced inflammatory cytokine expression after PDGF (platelet-derived growth factor) stimulation, suggesting 5-azacytidine blocks PDGF-induced SMC de-differentiation. However, these protective effects were lost in PTEN-deficient SMCs. These findings were confirmed in vivo using carotid ligation in SMC-specific PTEN knockout mice treated with 5-azacytidine. In wild type controls, 5-azacytidine reduced neointimal formation and inflammation while maintaining contractile protein expression. In contrast, 5-azacytidine was ineffective in PTEN knockout mice, indicating that the protective effects of 5-azacytidine are mediated through SMC PTEN upregulation. Conclusions: Our data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.

miR-139-5p promotes neovascularization in diabetic retinopathy by regulating the phosphatase and tensin homolog

2021 ◽  
Vol 44 (2) ◽  
pp. 205-218
Author(s):  
Zhongwei Zhang ◽  
Caiping Song ◽  
Tao Wang ◽  
Lei Sun ◽  
Ling Qin ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Photic Regulation of Circadian Rhythms and Voluntary Ethanol Intake: Role of Melanopsin-expressing Intrinsically Photosensitive Retinal Ganglion Cells

2020 ◽  
pp. 074873042098122
Author(s):  
Matthew C. Hartmann ◽  
Walter D. McCulley ◽  
Samuel T. Johnson ◽  
Corey S. Salisbury ◽  
Nikhil Vaidya ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Circadian System ◽  
Genetically Engineered ◽  
Ethanol Intake ◽  
Constant Darkness ◽  
Retinal Ganglion ◽  
Retinal Photoreceptors ◽  
Genetically Engineered Mouse Model ◽  
Lighting Regimen

“Non-image-forming” (NIF) effects of light are mediated primarily by a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment, melanopsin (OPN4). These NIF functions include circadian entrainment, pupillary reflexes, and photic effects on sleep, mood, and cognition. We recently reported that mice of multiple genotypes exhibit reduced voluntary ethanol intake under both constant darkness (DD) and constant light (LL) relative to standard light-dark (LD) conditions. In the present study, we sought to determine whether these effects are mediated by melanopsin-expressing ipRGCs and their potential relationship to photic effects on the circadian system. To this end, we examined the effects of environmental lighting regimen on both ethanol intake and circadian activity rhythms in a genetically engineered mouse model ( Opn4aDTA/aDTA) in which melanopsin expression is completely blocked while ipRGCs are progressively ablated due to activation of attenuated diphtheria toxin A (aDTA) transgene under the control of the Opn4 promoter. As expected from previous studies, Opn4aDTA/aDTA mice displayed dramatic attenuation of circadian photosensitivity, but surprisingly, showed identical suppression of ethanol intake under both DD and LL as that seen in controls. These results demonstrate that the effects of lighting regimen on voluntary ethanol intake are independent of melanopsin-expressing ipRGCs and ipRGC-mediated photic effects on the circadian system. Rather, these effects are likely mediated by classical retinal photoreceptors and central pathways.

scholarly journals The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1525
Author(s):  
Chunling Huang ◽  
Ji Bian ◽  
Qinghua Cao ◽  
Xin-Ming Chen ◽  
Carol A. Pollock
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Mitochondrial Protein ◽  
Physiological Role ◽  
Close Link ◽  
Promising Alternative ◽  
Diabetic Kidney ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.

scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Mi Tian ◽  
Jingjing Wang ◽  
Shangming Liu ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Mrna ◽  
Normal Chow ◽  
Mice Liver

AbstractThe liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuRLKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3′ untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuRLKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

scholarly journals An Immunohistochemical Study of the PTEN/AKT Pathway Involvement in Canine and Feline Mammary Tumors

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 365
Author(s):  
Pietro Asproni ◽  
Francesca Millanta ◽  
Lorenzo Ressel ◽  
Fabio Podestà ◽  
Francesca Parisi ◽  
...  
Keyword(s):  
Immunohistochemical Study ◽  
Lymphatic Invasion ◽  
Pten Expression ◽  
Akt Pathway ◽  
Phosphatase And Tensin Homolog ◽  
Mammary Carcinomas ◽  
Tensin Homolog ◽  
Aggressive Tumors ◽  
Aggressive Subtype ◽  
Viral Oncogene Homolog

Phosphatase and tensin homolog deleted on chromosome10 (PTEN), phospho-v-Akt murine thymoma viral oncogene homolog (AKT), and the Rapamycin-Insensitive Companion of mTOR (Rictor) expression was investigated by immunohistochemistry in 10 canine mammary adenomas (CMAs), 40 canine mammary carcinomas (CMCs), and 30 feline mammary carcinomas (FMCs). All the CMAs, 25 of 40 CMCs (63%) and 7 of 30 FMCs (23%), were PTEN-positive. In dogs, no CMAs and 15 of 25 CMCs (37%) expressed phospho-AKT (p-AKT), while 24 of 30 FMCs (82%) were p-AKT-positive. One of 10 CMAs (10%), 24 of 40 CMCs (60%) and 20 of 30 FMCs (67%) were Rictor-positive. In the dog, PTEN expression correlated with less aggressive tumors, absence of lymphatic invasion, and longer survival. P-AKT expression correlated with more aggressive subtype, lymphatic invasion, and poorer survival and Rictor expression with lymphatic invasion. In cats, PTEN correlated with less aggressive carcinomas, absence of lymphatic invasion, and better survival. P-AKT and Rictor expression correlated with poorer survival. PTEN expression was inversely correlated with p-AKT and Rictor in both species, while p-AKT positively correlated with Rictor expression. A strong PTEN/AKT pathway involvement in behavior worsening of CMT and FMTs is demonstrated, providing a rationale for further studies of this pathway in veterinary oncology.

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