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1.
Cancer Treat Rev ; 88: 102060, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32619863

RESUMO

Phenotypic plasticity of malignant melanoma is a well-known phenomenon. Several translational studies and small case series have reported this clinical and biological entity, particularly in metastatic melanoma, showing frequent aberrant expression of non-melanocytic differentiation markers of different lineages, posing remarkable challenges due to several alternative differential diagnoses including undifferentiated carcinoma and sarcomas. When melanoma loses its typical morpho-phenotype by routinely used diagnostic immunohistochemical markers, it is defined as "dedifferentiated melanoma". Historically, this process was closely related to diagnostic interpretative difficulties. In recent years, however, dedifferentiation has been increasingly recognized as an important biological phenomenon that demonstrates the phenotypic and genetic plasticity of melanoma, and specifically the non-irreversibility of the multistep cancerogenesis. Furthermore, dedifferentiation emerged as a general hallmark of cancer evolution and a common denominator of cross-resistance to both targeted and immunotherapy. In this review, we summarize the histopathological features, the genetic and epigenetic bases underlying the dedifferentiated phenotype in melanomas and provide additional support that dedifferentiation is a mechanism of resistance to immunotherapy and targeted therapy.


Assuntos
Melanoma/genética , Melanoma/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Animais , Desdiferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Epigênese Genética , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia
2.
PLoS One ; 15(3): e0229892, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32231396

RESUMO

The specification of cell identity depends on the exposure of cells to sequences of bioactive ligands. All-trans retinoic acid (ATRA) affects neuronal development in the early stage, and it is involved in neuronal lineage reprogramming. We previously established a fibroblast-like dedifferentiated fat cells (DFATs) derived from highly homogeneous mature adipocytes, which are more suitable for the study of cellular reprogramming. Canine cognitive dysfunction is similar to human cognitive dysfunction, suggesting that dogs could be a pathological and pharmacological model for human neuronal diseases. However, the effect of ATRA on neuronal reprogramming in dogs has remained unclear. Therefore, in this study, we investigated the effect of ATRA on the neuronal reprogramming of canine DFATs. ATRA induced the expression of neuronal marker mRNA/protein. The neuron-like cells showed Ca2+ influx with depolarization (50 mM KCl; 84.75 ± 4.05%) and Na+ channel activation (50 µM veratridine; 96.02 ± 2.02%). Optical imaging of presynaptic terminal activity and detection of neurotransmitter release showed that the neuron-like cells exhibited the GABAergic neuronal property. Genome-wide RNA-sequencing analysis shows that the transcriptome profile of canine DFATs is effectively reprogrammed towards that of cortical interneuron lineage. Collectively, ATRA can produce functional GABAergic cortical interneuron-like cells from canine DFATs, exhibiting neuronal function with > 80% efficiency. We further demonstrated the contribution of JNK3 to ATRA-induced neuronal reprogramming in canine DFATs. In conclusion, the neuron-like cells from canine DFATs could be a powerful tool for translational research in cell transplantation therapy, in vitro disease modeling, and drug screening for neuronal diseases.


Assuntos
Desdiferenciação Celular/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Cães , Neurogênese/genética , RNA Mensageiro/genética , Sinapses/efeitos dos fármacos , Sinapses/genética
3.
PLoS One ; 15(4): e0231963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320444

RESUMO

Severely damaged adult zebrafish extraocular muscles (EOMs) regenerate through dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. Members of the Twist family of basic helix-loop-helix transcription factors (TFs) are key regulators of the epithelial-mesenchymal transition (EMT) and are also involved in craniofacial development in humans and animal models. During zebrafish embryogenesis, twist family members (twist1a, twist1b, twist2, and twist3) function to regulate craniofacial skeletal development. Because of their roles as master regulators of stem cell biology, we hypothesized that twist TFs regulate adult EOM repair and regeneration. In this study, utilizing an adult zebrafish EOM regeneration model, we demonstrate that inhibiting twist3 function using translation-blocking morpholino oligonucleotides (MOs) impairs muscle regeneration by reducing myocyte dedifferentiation and proliferation in the regenerating muscle. This supports our hypothesis that twist TFs are involved in the early steps of dedifferentiation and highlights the importance of twist3 during EOM regeneration.


Assuntos
Desdiferenciação Celular , Músculos Oculomotores/citologia , Músculos Oculomotores/fisiologia , Regeneração , Fatores de Transcrição Twist/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia , Animais , Proliferação de Células , Técnicas de Silenciamento de Genes , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética
4.
J Cancer Res Clin Oncol ; 146(7): 1847-1855, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32157438

RESUMO

PURPOSE: Ligand-dependent corepressor (LCoR) and receptor-interacting protein 140 (RIP140/NRIP1) play an important role in the regulation of multiple oncogenic signaling pathways and the development of cancer. LCoR and RIP140 form a nuclear complex in breast cancer cells and are of prognostic value in further prostate and cervical cancer. The purpose of this study was to analyze the regulation of these proteins in the development of cervical intraepithelial neoplasia (CIN I-III). METHODS: Immunohistochemical analysis was obtained to quantify RIP140 and LCoR expression in formalin-fixed paraffin embedded tissue sections of cervical intraepithelial neoplasia samples. Tissue (n = 94) was collected from patients treated in the Department of Gynecology and Obstetrics, Ludwig-Maximilians-University of Munich, Germany, between 2002 and 2014. Correlations of expression levels with clinical outcome were carried out to assess for prognostic relevance in patients with CIN2 progression. Kruskal-Wallis test and Mann-Whitney U test were used for data analysis. RESULTS: Nuclear LCoR overexpression correlates significantly with CIN II progression. Nuclear RIP140 expression significantly increases and nuclear LCoR expression decreases with higher grading of cervical intraepithelial neoplasia. Cytoplasmic RIP140 expression is significantly higher in CIN III than in CIN I or CIN II. CONCLUSION: A decrease of nuclear LCoR expression in line with an increase of dedifferentiation of CIN can be observed. Nuclear LCoR overexpression correlates with CIN II progression indicating a prognostic value of LCoR in cervical intraepithelial neoplasia. Nuclear and cytoplasmic RIP140 expression increases significantly with higher grading of cervical intraepithelial neoplasia underlining its potential role in the development of pre-cancerous lesions. These findings support the relevance of LCoR and RIP140 in the tumorigenesis indicating a possible role of LCoR and RIP140 as targets for novel therapeutic approaches in cervical intraepithelial neoplasia and cervical cancer.


Assuntos
Desdiferenciação Celular , Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/patologia , Proteína 1 de Interação com Receptor Nuclear/metabolismo , Proteínas Repressoras/metabolismo , Biomarcadores Tumorais , Desdiferenciação Celular/genética , Neoplasia Intraepitelial Cervical/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Gradação de Tumores , Proteína 1 de Interação com Receptor Nuclear/genética , Proteínas Repressoras/genética
5.
Cell Stem Cell ; 26(3): 301-302, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142658

RESUMO

The existence of "active" and "reserve" stem cell populations in the intestinal epithelium has been debated since 1977. Now in Cell Stem Cell, Murata et al. (2020) show that all intestinal regeneration arises from daughter cell dedifferentiation, marking the coming-of-age of the regenerative stem cell plasticity model.


Assuntos
Desdiferenciação Celular , Intestinos , Plasticidade Celular , Mucosa Intestinal , Células-Tronco
6.
FASEB J ; 34(1): 333-349, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914629

RESUMO

Kidney fibrosis is a common process of various kidney diseases leading to end-stage renal failure irrespective of etiology. Myofibroblasts are crucial mediators in kidney fibrosis through production of extracellular matrix (ECM), but their origin has not been clearly identified. Many study proposed that epithelial and endothelial cells become myofibroblasts by epithelial dedifferentiation and endothelial-mesenchymal transition (EndoMT). TGF-ß1/Smad signaling plays a crucial role in partly epithelial-mensencymal transition (EMT) and EndoMT. Thus, we designed the TGF-ß1/Smad oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequence for Smad transcription factor and TGF-ß1 mRNA. Therefore, this study investigated the anti-fibrotic effect of synthetic TGF-ß1/Smad ODN on UUO-induced kidney fibrosis in vivo model and TGF-ß1-induced in vitro model. To examine the effect of TGF-ß1/Smad ODN, we performed various experiments to evaluate kidney fibrosis. The results showed that UUO induced inflammation, ECM accumulation, epithelial dedifferentiation and EndoMT processes, and tubular atrophy. However, synthetic TGF-ß1/Smad ODN significantly suppressed UUO-induced fibrosis. Furthermore, synthetic ODN attenuated TGF-ß1-induced epithelial dedifferentiation and EndoMT program via blocking TGF-ß1/Smad signaling. In conclusion, this study demonstrated that administration of synthetic TGF-ß1/Smad ODN attenuates kidney fibrosis, epithelial dedifferentiation, and EndoMT processes. The findings propose the possibility of synthetic ODN as a new effective therapeutic tool for kidney fibrosis.


Assuntos
Desdiferenciação Celular , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Fibrose/prevenção & controle , Nefropatias/prevenção & controle , Oligodesoxirribonucleotídeos/farmacologia , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética , Animais , Células Epiteliais/metabolismo , Fibrose/genética , Fibrose/patologia , Técnicas In Vitro , Nefropatias/genética , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , Obstrução Ureteral/prevenção & controle
7.
Am J Physiol Renal Physiol ; 318(2): F375-F387, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813251

RESUMO

Protein arginine methyltransferase 1 (PRMT1), which primarily causes asymmetric arginine methylation of histone and nonhistone proteins, has been found to activate gene expression and mediate multiple pathological processes. Its role in renal fibrosis, however, remains unclear. In the present study, we observed that PRMT1 and its specific epigenetic marker, asymmetric di-methylated histone 4 arginine 3 (H4R3Me2a), were highly expressed in cultured renal interstitial fibroblasts. Treatment of PRMT1 with AMI-1, a selective inhibitor of PRMT1, or silencing PRMT1 with siRNA inhibited serum-induced and transforming growth factor (TGF)-ß1-induced expression of α-smooth muscle actin (α-SMA) and collagen type I, two hallmarks of renal fibroblast activation, in a dose-dependent and time-dependent manner. In a murine model of renal fibrosis induced by unilateral ureteral obstruction, PRMT1 expression and H4R3Me2a were also upregulated, which was coincident with increased expression of α-SMA, collagen type I, and fibronectin. Administration of AMI-1 reduced PRMT1 and H4R3Me2a expression, attenuated extracellular matrix protein deposition, and inhibited renal fibroblast activation and proliferation. Moreover, AMI-1 treatment inhibited Smad3 phosphorylation and TGF-ß receptor I expression but prevented Smad7 downregulation both in the kidney after unilateral ureteral obstruction injury and in cultured renal interstitial fibroblasts exposed to TGF-ß1. Collectively, these results demonstrate that PRMT1 may mediate renal fibroblast activation and renal fibrosis development through activation of the TGF-ß/Smad3 signaling pathway. They also suggest that PRMT1 inhibition may be a potential therapeutic approach for the treatment of fibrotic kidney disease.


Assuntos
Desdiferenciação Celular , Fibroblastos/enzimologia , Nefropatias/enzimologia , Rim/enzimologia , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína Smad3/metabolismo , Animais , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Miofibroblastos/enzimologia , Miofibroblastos/patologia , Naftalenossulfonatos/farmacologia , Fosforilação , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Obstrução Ureteral/complicações
8.
Dev Cell ; 52(2): 167-182.e7, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31866203

RESUMO

Dedifferentiation of mature cells is an intriguing cellular process associated with regeneration of several organs. During zebrafish fin regeneration, osteoblasts dedifferentiate to osteogenic progenitors that provide source cells for bone restoration. We performed a high-content in vivo chemical screen for regulators of osteoblast dedifferentiation and fin regenerative growth. NF-κB signaling emerged as a specific regulator of dedifferentiation. The pathway is active in mature osteoblasts and downregulated prior to dedifferentiation. Pathway activation blocked osteoblast dedifferentiation, while NF-κB signaling inhibition enhanced dedifferentiation. Conditional Cre-lox-mediated NF-κB signaling manipulation specifically in osteoblasts showed that the pathway acts cell autonomously to interfere with osteoblast dedifferentiation. NF-κB signaling acts upstream of retinoic acid (RA) signaling, which also needs to be downregulated for dedifferentiation to occur, via suppression of the RA-degrading enzyme cyp26b1. Our findings shed light on the molecular regulation of regenerative cellular plasticity.


Assuntos
Regeneração Óssea , Desdiferenciação Celular , Diferenciação Celular , NF-kappa B/metabolismo , Osteoblastos/citologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tretinoína/farmacologia , Nadadeiras de Animais , Animais , Proliferação de Células , Ensaios de Triagem em Larga Escala , Ceratolíticos/farmacologia , NF-kappa B/genética , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese , Transdução de Sinais , Cicatrização , Peixe-Zebra
9.
Int J Mol Sci ; 20(24)2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31847447

RESUMO

A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a "progenitor phenotype" during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.


Assuntos
Desdiferenciação Celular/fisiologia , Epitélio/fisiologia , Túbulos Renais/citologia , Regeneração/fisiologia , Células-Tronco/citologia , Animais , Células Epiteliais/citologia , Humanos
10.
Plast Reconstr Surg ; 144(6): 1323-1333, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31764645

RESUMO

BACKGROUND: Mature adipocytes dedifferentiate in vivo on application of a soft-tissue expander. Dedifferentiated adipocytes can proliferate and redifferentiate. This study used tissue expanders to pretreat adipose flaps, to increase the retention rate after fat graft. METHODS: A soft-tissue expander and silicone sheet were implanted beneath the left and right inguinal fat pads of rats, respectively. After 7 days of expansion, the adipose tissue derived from the pads was transplanted beneath dorsal skin. Samples were harvested at various time points, and histologic, immunohistochemical, and gene expression analyses were conducted. Mature adipocytes were cultured in vitro under a pressure of 520 Pa. Changes in cell morphology, the cytoskeleton, and expression of mechanical signal-related proteins were investigated. RESULTS: Pressure in adipose flaps increased to 25 kPa on expansion. Mature adipocytes dedifferentiated following expansion. At 1 week after transplantation, the expression of vascular endothelial growth factor (p < 0.05) was higher in the expanded group. The retention rate at 12 weeks after transplantation was higher in the expanded group (56 ± 3 percent) than in the control group (32 ± 3 percent) (p < 0.05), and the surviving/regenerating zones (p < 0.01) were wider. The lipid content of mature adipocytes gradually decreased on culture under increased pressure, and these cells regained a proliferative capacity. This was accompanied by increased expression of mechanical signal--related proteins (p < 0.05). CONCLUSIONS: Mechanical signals may induce dedifferentiation of mature adipocytes. Dedifferentiated adipocytes increase the retention rate of fat grafts by acting as seed cells.


Assuntos
Adipócitos/citologia , Tecido Adiposo/transplante , Desdiferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Actinas/metabolismo , Tecido Adiposo/citologia , Animais , Biomarcadores/metabolismo , Fenômenos Biomecânicos , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Sobrevivência de Enxerto , Antígeno Ki-67/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Retalhos Cirúrgicos/fisiologia , Expansão de Tecido/instrumentação , Dispositivos para Expansão de Tecidos , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Biomater Sci ; 8(1): 485-496, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31755497

RESUMO

Liver is pivotal in organism metabolism. This organ is receiving nutriments from the portal vein and then storing, metabolizing, distributing in the circulation or excreting excess and xenobiotics in bile. Liver architecture and hepatocyte polarization are crucial to achieve these functions. To study these mechanisms in details, relevant cell culture systems are required, which is not the case with standard 2D cell culture. Besides, primary hepatocytes rapidly de-differenciate making them inefficient in forming physiological system. Herein, we used an hepatoma-derived cell line to produce matrix-free hepatic spheroids and developed an integrated structural cell biology methodology by combining light sheet fluorescence microscopy and 3D electron microscopy to study their function and structure. Within these spheroids, hepatocytes polarize and organize to form bile canaliculi active for both organics and inorganics excretion. Besides, live imaging revealed the high dynamic of actin networks in basal membranes compared to their high stability in the apical pole that constitutes bile canaliculi. Finally, the first structure of active bile canaliculi was solved at nm resolution and showed the very high density of microvilli coming from all cells constituting the canaliculus. Therefore, this study is the first comprehensive and in-depth functional and structural study of bile canaliculi in a physiological-relevant context.


Assuntos
Canalículos Biliares/metabolismo , Hepatócitos/citologia , Esferoides Celulares/citologia , Técnicas de Cultura de Células , Desdiferenciação Celular , Polaridade Celular , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Microscopia de Fluorescência , Esferoides Celulares/metabolismo
12.
Nat Med ; 25(11): 1739-1747, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700183

RESUMO

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.


Assuntos
Complemento C3a/genética , Fator D do Complemento/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fosfatases de Especificidade Dupla/genética , Células Secretoras de Insulina/efeitos dos fármacos , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Animais , Índice de Massa Corporal , Desdiferenciação Celular/efeitos dos fármacos , Fator D do Complemento/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/patologia , Insulina/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD
13.
Nucleic Acids Res ; 47(20): 10645-10661, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31598691

RESUMO

The glucocorticoid and progesterone receptors (GR and PR) are closely related members of the steroid receptor family. Despite sharing similar structural and functional characteristics; the cognate hormones display very distinct physiological responses. In mammary epithelial cells, PR activation is associated with the incidence and progression of breast cancer, whereas the GR is related to growth suppression and differentiation. Despite their pharmacological relevance, only a few studies have compared GR and PR activities in the same system. Using a PR+/GR+ breast cancer cell line, here we report that either glucocorticoid-free or dexamethasone (DEX)-activated GR inhibits progestin-dependent gene expression associated to epithelial-mesenchymal-transition and cell proliferation. When both receptors are activated with their cognate hormones, PR and GR can form part of the same complex according to co-immunoprecipitation, quantitative microscopy and sequential ChIP experiments. Moreover, genome-wide studies in cells treated with either DEX or R5020, revealed the presence of several regions co-bound by both receptors. Surprisingly, GR also binds novel genomic sites in cells treated with R5020 alone. This progestin-induced GR binding was enriched in REL DNA motifs and located close to genes coding for chromatin remodelers. Understanding GR behavior in the context of progestin-dependent breast cancer could provide new targets for tumor therapy.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Sequência de Bases , Sítios de Ligação , Neoplasias da Mama/patologia , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cromatina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Progestinas/farmacologia , Promegestona/farmacologia , Ligação Proteica/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
14.
Rejuvenation Res ; 22(5): 439-446, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31578938

RESUMO

Reversal of aging by factors or drugs that reprogram adult cells to induced pluripotent stem cells suggests that at least at the cellular level aging may be reversible by resetting somatic cell state to a "ground state." An open question has been whether such rejuvenation is possible in whole organisms, especially in mammals. A related key question is whether rejuvenation can be dissociated from dedifferentiation. Several recent reports suggest that one prominent biomarker of mammalian aging, age-associated DNA methylation (DNAm) state that has been used to create DNAm age (DNAma) clocks, can be partially reversed by intrinsic treatment of cells with sets of reprogramming factors without affecting cell fate. Partial reprogramming using a superset of reprogramming factors applied transiently or subset of Yamanaka factors applied continually can increase regenerative potential, and reverse DNAma, while maintaining cell identity. Alternatively, a cell-extrinsic manipulation can accomplish something similar. A small preliminary clinical trial in humans suggests that systemic treatment with a cocktail of growth hormone, dehydroepiandrosterone, and metformin could also partially reverse DNAma and at the same time regenerate the thymus, which shrinks with age. Important questions are raised: How completely does reversing DNAma clocks embody a reversal of other age-related phenotypes, such as functional decline in strength, cognition, or immunity? How universal are these epigenetic changes at the tissue and cell levels? For example, do populations of younger stem cells exist that respond to these manipulations and then only confer the appearance of decreasing DNAma as they proliferate and differentiate? Together, these studies have profound implications for the development of antiaging and healthspan-enhancing therapies. A combination of both intrinsic and extrinsic modalities will most likely provide an optimal benefit.


Assuntos
Senescência Celular/genética , Epigênese Genética , Envelhecimento/genética , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Desdiferenciação Celular/genética , Reprogramação Celular/genética , Metilação de DNA , Humanos , Medicina Regenerativa , Rejuvenescimento , Timo/efeitos dos fármacos , Timo/patologia , Timo/fisiopatologia
15.
Mol Med Rep ; 20(6): 5249-5256, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31661132

RESUMO

Gallotannin (GT) is a class of polyphenols with antioxidant, anticancer, and antiviral activities. 2­Deoxy­D­glucose (2DG), a glucose­derived molecule, can inhibit glucose metabolism and induce endoplasmic reticulum (ER) stress. GT in primary­cultured chondrocytes enhances expression of type II collagen, an indicator of differentiation, and cyclooxygenase­2 (COX­2), which mediates inflammatory reactions. In contrast, 2DG reduces type II collagen and COX­2 expression while driving ER­stress­induced unglycosylation. In the present study, it was investigated whether GT could attenuate 2DG­induced dedifferentiation and ER­stress. Following treatment with GT and 2DG, chondrocytes were assessed using western blotting, RT­PCR, immunofluorescence, and alcian blue staining. GT restored type II collagen expression that was reduced by 2DG, inhibited ER­stress­induced COX­2 unglycosylation, and induced COX­2 expression. The expression of a glucose­regulated protein, GRP78, which is an indicator of reduced ER­stress, was decreased. To link the GT signaling pathway with pathways that inhibit 2DG­induced dedifferentiation and ER­stress, inhibitors were treated in chondrocytes. The results revealed that, among the different signaling pathways triggered by ER­stress, the p38 kinase pathway was involved in the inositol­requiring enzyme 1 (IRE1) downstream signaling pathway. Following inhibition of the IRE1 pathway, type II collagen expression was increased and COX­2 expression was decreased. In addition, after examining the splicing of X­box binding protein 1 (XBP­1) which is dependent on IRE1 activation induced by ER­stress, it was revealed that GT inhibited the increase of XBP­1s after splicing due to 2DG­induced ER stress. GT in chondrocytes inhibited 2DG­induced dedifferentiation and ER­stress­induced COX­2 unglycosylation while regulating differentiation and inflammation via the ER­stress­induced p38 kinase pathway downstream from the IRE1 pathway.


Assuntos
Desdiferenciação Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/metabolismo , Desoxiglucose/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células Cultivadas , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Glucose/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Coelhos , Transdução de Sinais
16.
Clin Sci (Lond) ; 133(20): 2107-2119, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31654064

RESUMO

Adipose tissues collectively as an endocrine organ and energy storage are crucial for systemic metabolic homeostasis. The major cell type in the adipose tissue, the adipocytes or fat cells, are remarkably plastic and can increase or decrease their size and number to adapt to changes in systemic or local metabolism. Changes in adipocyte size occur through hypertrophy or atrophy, and changes in cell numbers mainly involve de novo generation of new cells or death of existing cells. Recently, dedifferentiation, whereby a mature adipocyte is reverted to an undifferentiated progenitor-like status, has been reported as a mechanism underlying adipocyte plasticity. Dedifferentiation of mature adipocytes has been observed under both physiological and pathological conditions. This review covers several aspects of adipocyte dedifferentiation, its relevance to adipose tissue function, molecular pathways that drive dedifferentiation, and the potential of therapeutic targeting adipocyte dedifferentiation in human health and metabolic diseases.


Assuntos
Adipócitos/citologia , Desdiferenciação Celular/fisiologia , Doenças Metabólicas/patologia , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiologia , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Comunicação Celular/fisiologia , Desdiferenciação Celular/efeitos dos fármacos , Plasticidade Celular/fisiologia , Células Cultivadas , Microambiente Celular/fisiologia , Humanos , Lactação/fisiologia , Doenças Metabólicas/metabolismo
17.
Indian J Pathol Microbiol ; 62(4): 549-555, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611438

RESUMO

Context: C-Cbl is an important negative regulator of the cell signaling that acts as an adaptor protein and E3 ubiquitin ligase. The role of c-Cbl in development and regulation of human cancer has aroused intensive attention. Aims: In this study, we aimed to assess the correlation between the expression of c-Cbl and clinicopathological parameters and explored the role of c-Cbl in the development and progression of GC. Settings and Design: This is a Pilot study. Methods and Materials: In total, 84 tissue samples including 44 gastric cancers (GC) and 40 matched adjacent normal tissues were collected after surgery. Then tissue microarray (TMA) and immunohistochemistry (IHC) technology were combined to detect the protein expression of c-Cbl. Statistical Analysis Used: Statistical analysis was performed using SPSS 22.0 (IBM Corporation, Armonk, NY, USA). Results: We have studied the correlation between c-Cbl expression and clinicopathological parameters. Our study showed that c-Cbl has a low expression in 61.4% (27/44) of GC tissues, and the incidence of cases was significantly higher than that in adjacent normal tissues (P < 0.0001). In addition, the correlation between c-Cbl expression and gastric carcinoma subtype (P = 0.027), histological type (P = 0.033), Borrmann classification (P = 0.009), histological differentiation (P = 0.0005), lymph node metastasis (P = 0.007), and intravascular tumor thrombus (P = 0.036) has also been revealed. Conclusions: Our results show that c-Cbl is down-regulated in GC tissues compared with normal gastric tissue, which may play an important role in the development and progression of GC.


Assuntos
Desdiferenciação Celular , Metástase Linfática/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Neoplasias Gástricas/genética , Idoso , Idoso de 80 Anos ou mais , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Transdução de Sinais , Análise Serial de Tecidos
18.
Pathol Res Pract ; 215(11): 152640, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31570279

RESUMO

AIMS: Genomic instability has been indicated during the dedifferentiation process from leiomyoma (LM) to leiomyosarcoma (LMS). Previously, we have described that nuclear expression pattern of DNA damage response protein p53-binding protein 1 (53BP1), detected by immunofluorescence, reflects the magnitude of genomic instability during malignancy. Here, we present a case of LMS arising from LM with molecular analysis of 53BP1, which showed transitional magnitude of DNA damage response within a tumor. METHODS AND RESULTS: A fifty-year-old female with abdominal mass underwent hysterectomy. Histologically, the tumor consisted of LMS with highly atypical multinucleated giant cells as well as an LM component with transitional atypical spindle cells in the border area. LMS showed diffuse nuclear staining of 53BP1 expression, which has been previously described as high DNA damage response pattern. In contrast, the LM component lacked 53BP1 immunoreactivity and focal expression was observed in transitional lesion. Furthermore, double-labelled immunofluorescence revealed co-localization of 53BP1 with p53 and Ki-67 in the LMS component, which indicated abnormal DNA damage response in proliferative state. CONCLUSIONS: This study revealed that diffuse-type 53BP1 expression may be beneficial to estimate genomic instability during dedifferentiation from LM to DLMS.


Assuntos
Leiomioma/patologia , Leiomiossarcoma/patologia , Neoplasias Primárias Múltiplas/patologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/análise , Neoplasias Uterinas/patologia , Desdiferenciação Celular/genética , Transformação Celular Neoplásica/genética , Feminino , Imunofluorescência , Instabilidade Genômica/genética , Humanos , Leiomiossarcoma/genética , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Neoplasias Uterinas/genética
19.
Int J Oncol ; 55(4): 938-948, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485600

RESUMO

Liposarcoma (LPS) is one of the most frequently reported type of soft­tissue sarcoma (STS). Well­differentiated (WD) LPS and dedifferentiated (DD) LPS are the two most common subtypes. Chemotherapy has been considered to be ineffective in LPS, and novel treatment agents are thus necessary. In this study, we reanalyzed two published microarray data sets of LPS. By comparing the top 50 upregulated genes in DD LPS in both sets of data, we identified 12 overlapping genes. Of note, the top five gene sets enriched in DD LPS in both sets of data were involved in cell cycle regulation. Among the 12 overlapping genes, aurora kinase A (AURKA) is a well­known gene involved in cell cycle regulation; we thus further investigated this gene. AURKA was significantly upregulated in DD LPS, compared with WD LPS. Among 40 cases of DD LPS in GSE30929, patients with high AURKA expression in tumors had significantly worse distant recurrence­free survival than those with low expression. In an in vitro model, MLN8237, an AURKA inhibitor, could inhibit AURKA in LPS cell lines with a resultant G2/M arrest. MLN8237 was also reported to exert a cytotoxic effect by inducing apoptosis in LPS cell lines. Furthermore, except for cisplatin, MLN8237 had a significantly synergistic effect with chemotherapy agents against LPS. MLN8237 induced cellular senescence in LPS cell lines with increased expression of DcR2, a senescence biomarker, and upregulated expression of cytokines associated with the senescence­associated secretory phenotype, including interleukin (IL)­1α, IL­6 and IL­8. Our study identified AURKA as a potential biomarker for predicting poor prognosis in LPS. The findings of the present study suggested the potential of AURKA as a therapeutic target in LPS cell line models, while the novel combination of AURKA inhibitors and chemotherapy requires further investigation.


Assuntos
Aurora Quinase A/genética , Azepinas/farmacologia , Perfilação da Expressão Gênica/métodos , Lipossarcoma/genética , Pirimidinas/farmacologia , Aurora Quinase A/antagonistas & inibidores , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Tratamento Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipossarcoma/tratamento farmacológico , Análise de Sequência com Séries de Oligonucleotídeos , Regulação para Cima/efeitos dos fármacos
20.
World J Gastroenterol ; 25(31): 4300-4319, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31496615

RESUMO

Methionine adenosyltransferases (MATs) are essential enzymes for life as they produce S-adenosylmethionine (SAMe), the biological methyl donor required for a plethora of reactions within the cell. Mammalian systems express two genes, MAT1A and MAT2A, which encode for MATα1 and MATα2, the catalytic subunits of the MAT isoenzymes, respectively. A third gene MAT2B, encodes a regulatory subunit known as MATß which controls the activity of MATα2. MAT1A, which is mainly expressed in hepatocytes, maintains the differentiated state of these cells, whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver (e.g., hepatic stellate and Kupffer cells). The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1. A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation, but this change in the expression pattern of MATs results in reduced hepatic SAMe level. Decades of study have utilized the Mat1a-knockout (KO) mouse that spontaneously develops non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis. An increasing volume of work indicates that MATs have SAMe-independent functions, distinct interactomes and multiple subcellular localizations. Here we aim to provide an overview of MAT biology including genes, isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation. We will highlight recent breakthroughs in the field and underscore the importance of MAT's in liver tumorigenesis as well as their potential as targets for cancer therapy.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Metionina Adenosiltransferase/metabolismo , S-Adenosilmetionina/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Desdiferenciação Celular , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Fígado/citologia , Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Metionina Adenosiltransferase/genética , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/patologia
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