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1.
Int J Mol Sci ; 25(7)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38612397

RESUMO

Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS's characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.


Assuntos
Síndrome de Beckwith-Wiedemann , Neoplasias , Humanos , Autofagia/genética , Síndrome de Beckwith-Wiedemann/genética , Linhagem Celular , Quinase 3 da Glicogênio Sintase
2.
Haematologica ; 107(9): 2183-2194, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35263984

RESUMO

Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the protumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not only rely on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2-dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the protumorigenic role of EV in MM as well as other tumors.


Assuntos
Vesículas Extracelulares , Mieloma Múltiplo , Medula Óssea/patologia , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Mieloma Múltiplo/patologia , Microambiente Tumoral
3.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077111

RESUMO

Cutaneous lesions are one of the hallmarks of tuberous sclerosis complex (TSC), a genetic disease in which mTOR is hyperactivated due to the lack of hamartin or tuberin. To date, novel pharmacological treatments for TSC cutaneous lesions that are benign but still have an impact on a patient's life are needed, because neither surgery nor rapamycin administration prevents their recurrence. Here, we demonstrated that primary TSC2-/meth cells that do not express tuberin for an epigenetic event caused cutaneous lesions and follicular neogenesis when they were subcutaneously injected in nude mice. Tuberin-null cells localized in the hair bulbs and alongside mature hairs, where high phosphorylation of S6 and Erk indicated mTOR hyperactivation. Interestingly, 5-azacytidine treatment reduced hair follicles, indicating that chromatin remodeling agents might be effective on TSC lesions in which cells lack tuberin for an epigenetic event. Moreover, we demonstrated that the primary TSC2-/meth cells had metastatic capability: when subcutaneously injected, they reached the bloodstream and lymphatics and invaded the lungs, causing the enlargement of the alveolar walls. The capability of TSC2-/meth cells to survive and migrate in vivo makes our mouse model ideal to follow the progression of the disease and test potential pharmacological treatments in a time-dependent manner.


Assuntos
Esclerose Tuberosa , Animais , Camundongos , Camundongos Nus , Serina-Treonina Quinases TOR , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
4.
Int J Mol Sci ; 23(13)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35806041

RESUMO

Senescence is a stress-response process characterized by the irreversible inhibition of cell proliferation, associated to the acquisition of a senescence-associated secretory phenotype (SASP), that may drive pathological conditions. Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells, featuring the hyperactivation of the mammalian Target of Rapamycin Complex 1 (mTORC1) for the absence of tuberin expression, cause the disruption of the lung parenchyma. Considering that LAM cells secrete SASP factors and that mTOR is also a driver of senescence, we deepened the contribution of senescence in LAM cell phenotype. We firstly demonstrated that human primary tuberin-deficient LAM cells (LAM/TSC cells) have senescent features depending on mTOR hyperactivation, since their high positivity to SA-ß galactosidase and to phospho-histone H2A.X are reduced by inducing tuberin expression and by inhibiting mTOR with rapamycin. Then, we demonstrated the capability of LAM/TSC cells to induce senescence. Indeed, primary lung fibroblasts (PLFs) grown in LAM/TSC conditioned medium increased the positivity to SA-ß galactosidase and to phospho-histone H2A.X, as well as p21WAF1/CIP1 expression, and enhanced the mRNA expression and the secretion of the SASP component IL-8. Taken together, these data make senescence a novel field of study to understand LAM development and progression.


Assuntos
Linfangioleiomiomatose , Humanos , beta-Galactosidase/metabolismo , Senescência Celular/genética , Histonas , Linfangioleiomiomatose/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Microambiente Tumoral
5.
Haematologica ; 105(7): 1925-1936, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31582544

RESUMO

Multiple myeloma is still incurable due to an intrinsic aggressiveness or, more frequently, to the interactions of malignant plasma cells with the bone marrow (BM) microenvironment. Myeloma cells educate BM cells to support neoplastic cell growth, survival, acquisition of drug resistance resulting in disease relapse. Myeloma microenvironment is characterized by Notch signaling hyperactivation due to the increased expression of Notch1 and 2 and the ligands Jagged1 and 2 in tumor cells. Notch activation influences myeloma cell biology and promotes the reprogramming of BM stromal cells. In this work we demonstrate, in vitro, ex vivo and by using a zebrafish multiple myeloma model, that Jagged inhibition causes a decrease in both myeloma-intrinsic and stromal cell-induced resistance to currently used drugs, i.e. bortezomib, lenalidomide and melphalan. The molecular mechanism of drug resistance involves the chemokine system CXCR4/SDF1α. Myeloma cell-derived Jagged ligands trigger Notch activity in BM stromal cells. These, in turn, secrete higher levels of SDF1α in the BM microenvironment increasing CXCR4 activation in myeloma cells, which is further potentiated by the concomitant increased expression of this receptor induced by Notch activation. Consistently with the augmented pharmacological resistance, SDF1α boosts the expression of BCL2, Survivin and ABCC1. These results indicate that a Jagged-tailored approach may contribute to disrupting the pharmacological resistance due to intrinsic myeloma cell features or to the pathological interplay with BM stromal cells and, conceivably, improve patients' response to standard-of-care therapies.


Assuntos
Proteína Jagged-1/genética , Proteína Jagged-2/genética , Mieloma Múltiplo , Animais , Medula Óssea , Linhagem Celular Tumoral , Resistência a Medicamentos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Receptores Notch , Microambiente Tumoral , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
6.
EMBO J ; 34(9): 1214-30, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25770584

RESUMO

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che-1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress-induced autophagy. Strikingly, Che-1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Mieloma Múltiplo/patologia , Proteínas Repressoras/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos Nus , Mieloma Múltiplo/metabolismo , Complexos Multiproteicos/metabolismo , Fosforilação , Proteínas Repressoras/genética , Estresse Fisiológico , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
Int J Mol Sci ; 20(13)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266187

RESUMO

Extracellular vesicles (EVs) represent a heterogeneous group of membranous structures shed by all kinds of cell types, which are released into the surrounding microenvironment or spread to distant sites through the circulation. Therefore, EVs are key mediators of the communication between tumor cells and the surrounding microenvironment or the distant premetastatic niche due to their ability to transport lipids, transcription factors, mRNAs, non-coding regulatory RNAs, and proteins. Multiple myeloma (MM) is a hematological neoplasm that mostly relies on the bone marrow (BM). The BM represents a highly supportive niche for myeloma establishment and diffusion during the formation of distant bone lesions typical of this disease. This review represents a survey of the most recent evidence published on the role played by EVs in supporting MM cells during the multiple steps of metastasis, including travel and uptake at distant premetastatic niches, MM cell engraftment as micrometastasis, and expansion to macrometastasis thanks to EV-induced angiogenesis, release of angiocrine factors, activation of osteolytic activity, and mesenchymal cell support. Finally, we illustrate the first evidence concerning the dual effect of MM-EVs in promoting both anti-tumor immunity and MM immune escape, and the possible modulation operated by pharmacological treatments.


Assuntos
Neoplasias Ósseas/secundário , Vesículas Extracelulares/metabolismo , Mieloma Múltiplo/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Comunicação Celular , Progressão da Doença , Vesículas Extracelulares/genética , Humanos , Mieloma Múltiplo/genética , Evasão Tumoral , Microambiente Tumoral
8.
BMC Pulm Med ; 17(1): 107, 2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754097

RESUMO

BACKGROUND: Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome, lymphangioleiomyomatosis/tuberous sclerosis complex (LAM-TSC), and sarcoidosis are three rare diseases. Here we present, to the best of our knowledge, the first description of a patient with the coexistence of these three diseases. CASE PRESENTATION: A 47-year-old woman affected by LAM-TSC and primary biliary cirrosis/autoimmune hepatitis overlap syndrome. During her follow up a high resolution chest CT scan (HRTC) confirmed the presence of both multiple cysts and micronodular opacities consistent with multifocal micronodular pneumocytes hyperlasia (MMPH), and revealed multiple hilar-mediastinal symmetrical lymphadenopathies suggestive of sarcoidosis. Simultaneously, subcutaneous nodules appeared on her forearm bilaterally. Cutaneous biopsy showed granulomatous dermatitis with sarcoid-like granulomas. A diagnosis of stage I pulmonary sarcoidosis was made. No treatment for sarcoidosis was initiated since the patient had neither systemic involvement, nor respiratory impairment. CONCLUSIONS: The presence of more than one rare disease should challenge the concept of a potential common underlying mechanism, since the a priori probability of the concomitant presence of different conditions with different pathogenic mechanisms - especially if rare diseases - is low. We speculate that the dysregulation of the pathway involving mTOR and MAPK and their interaction might play a role in the pathogenesis of other diseases, including sarcoidosis.


Assuntos
Hepatite Autoimune/complicações , Cirrose Hepática Biliar/complicações , Neoplasias Pulmonares/complicações , Linfangioleiomiomatose/complicações , Sarcoidose Pulmonar/complicações , Esclerose Tuberosa/complicações , Células Epiteliais Alveolares/patologia , Feminino , Humanos , Hiperplasia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Linfangioleiomiomatose/diagnóstico por imagem , Pessoa de Meia-Idade , Sarcoidose Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Esclerose Tuberosa/diagnóstico por imagem
9.
Am J Med Genet A ; 167A(10): 2388-93, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25946256

RESUMO

Tuberous Sclerosis Complex (TSC) is characterized by the presence of benign tumors in the brain, kidneys, heart, eyes, lungs, and skin. The typical brain lesions are cortical tubers, subependimal nodules and subependymal giant-cell astrocytomas. The occurrence of malignant astrocytomas such as glioblastoma is rare. We report on a child with a clinical diagnosis of TSC and a rapidly evolving glioblastoma multiforme. Genetic analysis identified a de novo mutation in TSC2. Molecular characterization of the tumor was performed and discussed, as well as a review of the literature where cases of TSC and glioblastoma multiforme are described. Although the co-occurrence of TSC and glioblastoma multiforme seems to be rare, this possible association should be kept in mind, and proper clinical and radiological follow up should be recommended in these patients.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Mutação , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Antineoplásicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Evolução Fatal , Raios gama/uso terapêutico , Expressão Gênica , Glioblastoma/complicações , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Esclerose Tuberosa/terapia , Proteína 2 do Complexo Esclerose Tuberosa
10.
J Cell Mol Med ; 18(5): 766-79, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24606538

RESUMO

Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes. Lymphangioleiomyomatosis (LAM) can be sporadic or associated with TSC and is characterized by widespread pulmonary proliferation of abnormal α-smooth muscle (ASM)-like cells. We investigated the features of ASM cells isolated from chylous thorax of a patient affected by LAM associated with TSC, named LAM/TSC cells, bearing a germline TSC2 mutation and an epigenetic defect causing the absence of tuberin. Proliferation of LAM/TSC cells is epidermal growth factor (EGF)-dependent and blockade of EGF receptor causes cell death as we previously showed in cells lacking tuberin. LAM/TSC cells spontaneously detach probably for the inactivation of the focal adhesion kinase (FAK)/Akt/mTOR pathway and display the ability to survive independently from adhesion. Non-adherent LAM/TSC cells show an extremely low proliferation rate consistent with tumour stem-cell characteristics. Moreover, LAM/TSC cells bear characteristics of stemness and secrete high amount of interleukin (IL)-6 and IL-8. Anti-EGF receptor antibodies and rapamycin affect proliferation and viability of non-adherent cells. In conclusion, the understanding of LAM/TSC cell features is important in the assessment of cell invasiveness in LAM and TSC and should provide a useful model to test therapeutic approaches aimed at controlling their migratory ability.


Assuntos
Epigênese Genética , Linfangioleiomiomatose/genética , Linfangioleiomiomatose/patologia , Proteínas Supressoras de Tumor/genética , Anticorpos/farmacologia , Sequência de Bases , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fator de Crescimento Epidérmico/farmacologia , Epigênese Genética/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/imunologia , Feminino , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Dados de Sequência Molecular , Sirolimo/farmacologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 2 do Complexo Esclerose Tuberosa
11.
J Pharmacol Exp Ther ; 345(2): 180-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23426956

RESUMO

Tuberous sclerosis complex (TSC) is a multi-systemic syndrome caused by mutations in TSC1 or TSC2 gene. In TSC2-null cells, Rheb, a member of the Ras family of GTPases, is constitutively activated. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase and block the synthesis of isoprenoid lipids with inhibition of Rheb farnesylation and RhoA geranylgeranylation. The effects of rosuvastatin on the function of human TSC2(-/-) and TSC2(-/meth) α-actin smooth muscle (ASM) cells have been investigated. The TSC2(-/-) and TSC2(-/meth) ASM cells, previously isolated in our laboratory from the renal angiomyolipoma of two TSC patients, do not express tuberin and bear loss of heterozigosity caused by a double hit on TSC2 and methylation of TSC2 promoter, respectively. Exposure to rosuvastatin affected TSC2(-/meth) ASM cell growth and promoted tuberin expression by acting as a demethylating agent. This occurred without changes in interleukin release. Rosuvastatin also reduced RhoA activation in TSC2(-/meth) ASM cells, and it required coadministration with the specific mTOR (mammalian target of rapamycin) inhibitor rapamycin to be effective in TSC2(-/-) ASM cells. Rapamycin enhanced rosuvastatin effect in inhibiting cell proliferation in TSC2(-/-) and TSC2(-/meth) ASM cells. Rosuvastatin alone did not alter phosphorylation of S6 and extracellular signal-regulated kinase (ERK), and at the higher concentration, rosuvastatin and rapamycin slightly decreased ERK phosphorylation. These results suggest that rosuvastatin may potentially represent a treatment adjunct to the therapy with mTOR inhibitors now in clinical development for TSC. In particular, rosuvastatin appears useful when the disease is originated by epigenetic defects.


Assuntos
Anti-Inflamatórios , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Fluorbenzenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Actinas/metabolismo , Adulto , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Guanosina Trifosfato/metabolismo , Humanos , Masculino , Ácido Mevalônico/metabolismo , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Rosuvastatina Cálcica , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteína 2 do Complexo Esclerose Tuberosa , Proteína rhoA de Ligação ao GTP/metabolismo
12.
Am J Pathol ; 181(3): 947-60, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22770663

RESUMO

Lymphangioleiomyomatosis (LAM) is an interstitial lung disease characterized by invasion and proliferation of abnormal smooth muscle (ASM) cells in lung parenchyma and axial lymphatics. LAM cells bear mutations in tuberous sclerosis (TSC) genes. TSC2(-/-) ASM cells, derived from a human renal angiomyolipoma, require epidermal growth factor (EGF) for proliferation. Blockade of EGF receptors (EGFR) causes cell death. TSC2(-/-) ASM cells, previously labeled with PKH26-GL dye, were endonasally administered to 5-week-old immunodeficient female nude mice, and 4 or 26 weeks later anti-EGFR antibody or rapamycin was administered twice a week for 4 consecutive weeks. TSC2(-/-) ASM cells infiltrated lymph nodes and alveolar lung walls, causing progressive destruction of parenchyma. Parenchymal destruction was efficiently reversed by anti-EGFR treatment and partially by rapamycin treatment. Following TSC2(-/-) ASM cell administration, lymphangiogenesis increased in lungs as indicated by more diffuse LYVE1 expression and high murine VEGF levels. Anti-EGFR antibody and rapamycin blocked the increase in lymphatic vessels. This study shows that TSC2(-/-) ASM cells can migrate and invade lungs and lymph nodes, and anti-EGFR antibody is more effective than rapamycin in promoting lung repair and reducing lymphangiogenesis. The development of a model to study metastasis by TSC cells will also help to explain how they invade different tissues and metastasize to the lung.


Assuntos
Modelos Animais de Doenças , Linfangioleiomiomatose/patologia , Miócitos de Músculo Liso/transplante , Proteínas Supressoras de Tumor/deficiência , Administração Intranasal , Animais , Anticorpos/farmacologia , Contagem de Células , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Camundongos , Camundongos Nus , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Fosforilação/efeitos dos fármacos , Condicionamento Físico Animal , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Sirolimo/farmacologia , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismo
13.
Front Med (Lausanne) ; 10: 1124008, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36744130

RESUMO

A chronic inflammatory condition characterizes various lung diseases. Interestingly, a great contribution to inflammation is made by altered lipids metabolism, that can be caused by the deregulation of the mammalian target of rapamycin complex-1 (mTORC1) activity. There is evidence that one of mTOR downstream effectors, the sterol regulatory element-binding protein (SREBP), regulates the transcription of enzymes involved in the de novo fatty acid synthesis. Given its central role in cell metabolism, mTOR is involved in several biological processes. Among those, mTOR is a driver of senescence, a process that might contribute to the establishment of chronic lung disease because the characteristic irreversible inhibition of cell proliferation, associated to the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP) supports the loss of lung parenchyma. The deregulation of mTORC1 is a hallmark of lymphangioleiomyomatosis (LAM), a rare pulmonary disease predominantly affecting women which causes cystic remodeling of the lung and progressive loss of lung function. LAM cells have senescent features and secrete SASP components, such as growth factors and pro-inflammatory molecules, like cancer cells. Using LAM as a paradigm of chronic and metastatic lung disease, here we review the published data that point out the role of dysregulated lipid metabolism in LAM pathogenesis. We will discuss lipids' role in the development and progression of the disease, to hypothesize novel LAM biomarkers and to propose the pharmacological regulation of lipids metabolism as an innovative approach for the treatment of the disease.

14.
Genes (Basel) ; 13(3)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35328068

RESUMO

KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann-Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin-Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein-Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.


Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Animais , Epigênese Genética , Humanos , Deficiência Intelectual/genética , Lisina , Fenótipo
15.
Front Oncol ; 11: 644109, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869035

RESUMO

Bone is the most common site of cancer metastasis and the spread of cancer cells to the bone is associated with poor prognosis, pain, increased risk of fractures, and hypercalcemia. The bone marrow microenvironment is an attractive place for tumor dissemination, due to the dynamic network of non-malignant cells. In particular, the alteration of the bone homeostasis favors the tumor homing and the consequent osteolytic or osteoblastic lesions. Extracellular vesicles (EVs) are reported to be involved in the metastatic process, promoting tumor invasion, escape from immune surveillance, extravasation, extracellular matrix remodeling, and metastasis, but the role of EVs in bone metastases is still unclear. Current results suggest the ability of tumor derived EVs in promoting bone localization and metastasis formation, altering the physiological balance between bone destruction and new bone depositions. Moreover, EVs from the bone marrow niche may support the onset of tumor metastasis. This review summarizes recent findings on the role of EVs in the pathological alterations of homeostasis that occur during bone metastasis to show novel potential EV-based therapeutic options to inhibit metastasis formation.

16.
Biomedicines ; 9(12)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34944575

RESUMO

Matrix metalloproteinase (MMP) dysregulation is implicated in several diseases, given their involvement in extracellular matrix degradation and cell motility. In lymphangioleiomyomatosis (LAM), a pulmonary rare disease, MMP-2 and MMP-9 have been detected at high levels in serum and urine. LAM cells, characterized by a mutation in the tuberous sclerosis complex (TSC)1 or TSC2, promote cystic lung destruction. The role of MMPs in invasive and destructive LAM cell capability has not yet been fully understood. We evaluated MMP-2 and MMP-7 expression, secretion, and activity in primary LAM/TSC cells that bear a TSC2 germline mutation and an epigenetic modification and depend on epidermal growth factor (EGF) for survival. 5-azacytidine restored tuberin expression with a reduction of MMP-2 and MMP-7 levels and inhibits motility, similarly to rapamycin and anti-EGFR antibody. Both drugs reduced MMP-2 and MMP-7 secretion and activity during wound healing and decreased their expression in lung nodules of a LAM mouse model. In LAM/TSC cells, MMP-2 and MMP-7 are dependent on tuberin expression, cellular adhesion, and migration. MMPs appears sensitive to rapamycin and anti-EGFR antibody only during cellular migration. Our data indicate a complex and differential modulation of MMP-2 and MMP-7 in LAM/TSC cells, likely critical for lung parenchyma remodeling during LAM progression.

17.
Front Med (Lausanne) ; 8: 605909, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981713

RESUMO

Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM. Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls. Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively. Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.

18.
J Neurochem ; 114(2): 397-407, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20456005

RESUMO

Spinal cord injury (SCI) triggers a complex ischemic and inflammatory reaction, involving activation of neurotransmitter systems, in particular glutamate, culminating in cell death. We hypothesized that SCI might lead to alteration in the RNA editing of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors that govern critical determinants of neuronal survival. To this end, we examined the molecular changes set in motion by SCI that affect the channel properties of AMPA receptors. SCI strongly reduced the level of AMPA receptor R/G editing, involving not only the site of the lesion but also adjacent areas of the cord spared by the lesion. The effects, with changes for some subunits and loci, were observed as long as 30 days after lesioning and may correlate with a partial decrease in enzymatic activity of adenosine deaminase acting on RNA 2 (ADAR2), as deduced from the analysis of ADAR2 self-editing. The reduced editing at the R/G site of glutamate receptor subunits (GluRs) is likely to reduce post-synaptic excitatory responses to glutamate, thus limiting the progression of cell death; however, prolonged suppression of GluR function in later stages may hinder synaptic plasticity. These observations provide the first direct evidence of the potential contribution of RNA editing to excitatory neural injury and recovery after SCI.


Assuntos
Edição de RNA , Receptores de AMPA/genética , Traumatismos da Medula Espinal/metabolismo , Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Processamento Alternativo , Animais , Atividade Motora , RNA Mensageiro/biossíntese , Proteínas de Ligação a RNA , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/biossíntese , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
19.
Am J Pathol ; 174(6): 2150-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19443708

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal-dominant disease that is caused by mutations in either the TSC1 or TSC2 gene. Smooth muscle-like cells (ASMs) were isolated from an angiomyolipoma of a patient with TSC. These cells lacked tuberin, were labeled by both HMB45 and CD44v6 antibodies, and had constitutive S6 phosphorylation. The cells bear a germline TSC2 intron 8-exon 9 junction mutation, but DNA analysis and polymerase chain reaction amplification failed to demonstrate loss of heterozygosity. Testing for an epigenetic alteration, we detected methylation of the TSC2 promoter. Its biological relevance was confirmed by tuberin expression and a reduction in HMB45 labeling and S6 constitutive phosphorylation after exposure to the chromatin-remodeling agents, trichostatin A and 5-azacytidine. These cells were named TSC2(-/meth) ASMs. Their proliferation required epidermal growth factor in the medium as previously described for TSC2(-/-) ASMs. Blockade of epidermal growth factor with monoclonal antibodies caused the death of TSC2(-/meth) ASMs. In addition, rapamycin effectively blocked the proliferation of these cells. Our data show for the first time that methylation of the TSC2 promoter might cause a complete loss of tuberin in TSC2 cells, and that the pathogenesis of angiomyolipomas might also originate from epigenetic defects in smooth muscle cells. Additionally, the effect of chromatin-remodeling agents in these cells suggests a further avenue for the treatment of TSC as well as lymphangioleiomyomatosis.


Assuntos
Angiomiolipoma/genética , Angiomiolipoma/patologia , Metilação de DNA/genética , Miócitos de Músculo Liso/patologia , Proteínas Supressoras de Tumor/genética , Adulto , Angiomiolipoma/etiologia , Antibióticos Antineoplásicos/farmacologia , Antígenos de Neoplasias , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Análise Mutacional de DNA , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Antígenos Específicos de Melanoma , Microscopia de Fluorescência , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas de Neoplasias , Regiões Promotoras Genéticas/genética , Sirolimo/farmacologia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 2 do Complexo Esclerose Tuberosa
20.
Cancers (Basel) ; 12(9)2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32932949

RESUMO

Multiple myeloma (MM) is an incurable plasma cell malignancy arising primarily within the bone marrow (BM). During MM progression, different modifications occur in the tumor cells and BM microenvironment, including the angiogenic shift characterized by the increased capability of endothelial cells to organize a network, migrate and express angiogenic factors, including vascular endothelial growth factor (VEGF). Here, we studied the functional outcome of the dysregulation of Notch ligands, Jagged1 and Jagged2, occurring during disease progression, on the angiogenic potential of MM cells and BM stromal cells (BMSCs). Jagged1-2 expression was modulated by RNA interference or soluble peptide administration, and the effects on the MM cell lines' ability to induce human pulmonary artery cells (HPAECs) angiogenesis or to indirectly increase the BMSC angiogenic potential was analyzed in vitro; in vivo validation was performed on a zebrafish model and MM patients' BM biopsies. Overall, our results indicate that the MM-derived Jagged ligands (1) increase the tumor cell angiogenic potential by directly triggering Notch activation in the HPAECs or stimulating the release of angiogenic factors, i.e., VEGF; and (2) stimulate the BMSCs to promote angiogenesis through VEGF secretion. The observed pro-angiogenic effect of Notch activation in the BM during MM progression provides further evidence of the potential of a therapy targeting the Jagged ligands.

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