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1.
Adv Exp Med Biol ; 1202: 203-222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32034715

RESUMO

STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Transformação Celular Neoplásica , Humanos , Janus Quinases/metabolismo , Fosforilação
2.
Anticancer Res ; 40(1): 101-107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892558

RESUMO

BACKGROUND: Mitochondria are energy-producing organelles, and dysfunction in these organelles causes various types of disease. Although several studies have identified mutations in nuclear DNA that are associated with the etiology of ulcerative colitis (UC), information regarding mitochondrial DNA (mtDNA) in UC is limited. This study aimed to investigate the mitochondrial DNA polymorphism underlying the etiology of UC and UC-associated colorectal cancer. MATERIALS AND METHODS: Next-generation sequencing was performed to assess mitochondrial DNA mutations in 12 patients with UC-associated cancer. The mtDNA mutations in the non-neoplastic mucosa, tumor tissues, and healthy controls were compared. RESULTS: The incidence of mutations of nicotinamide adenine dinucleotide phosphate ubiquinone oxidase subunit, ATP synthetase, and tRNA was higher in non-neoplastic mucosa in those with UC compared with the healthy controls. However, no statistically significant differences were observed in mutations between the tumor tissues and non-neoplastic mucosa in UC. CONCLUSION: Significant mutations in mtDNA were observed in the non-neoplastic mucosa of patients with UC-associated cancer.


Assuntos
Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Neoplasias Colorretais/etiologia , Genes Mitocondriais , Polimorfismo Genético , Transformação Celular Neoplásica/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Suscetibilidade a Doenças , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Mutação
3.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892565

RESUMO

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Assuntos
Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Fluoruracila/farmacologia , Xenoenxertos , Humanos , Receptores de Hialuronatos/genética , Camundongos
4.
Cancer Immunol Immunother ; 69(2): 285-292, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897662

RESUMO

The wide-ranging collection of malignancies arising at the upper aerodigestive tract is categorized as head and neck cancer (HNC), the sixth most prevalent cancer worldwide. Infection with human papillomavirus (HPV) or exposure to carcinogens is the leading causes of HPV+ and HPV- HNCs development, respectively. HPV+ and HPV- HNCs are different in clinical and molecular aspects. Specifically, HPV- HNCs tightly associate with missense mutants of the TP53 gene (encoding for the p53 protein), suggesting a central role for mutant p53 gain-of-function (GOF) in driving tumorigenesis. In contrast, in HPV + HNC, the sequence of TP53 typically remains intact, while the protein is degraded. In tumor cells, the status of the TP53 gene affects the cargo of secreted exosomes. In this review, we describe the accumulated knowledge regarding the involvement of exosomes and p53 on cellular interactions between HPV+ and HPV- HNC cells, and the surrounding tumor microenvironment (TME). Moreover, we envision how TP53 status may determine exosomes cargo in HNC, and, consequently, modify the TME. The potential roles of exosomes described herein are based on both our studies and the studies of others on mutant p53-derived exosomes. Specifically, we showed how exosomes are shed by cancer cells harboring mutant p53 communicate with tumor-associated macrophages in the colon as well as with cancer-associated fibroblasts in the lung, creating immunosuppressive conditions and promoting invasiveness. Altogether, exosomes in HNC in the context of TP53 status are understudied and extensive research is required to shed light on the biology of HPV+ and HPV- HNC.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Exossomos/metabolismo , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Mutação , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/patologia , Humanos
5.
Cancer Immunol Immunother ; 69(2): 315-324, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31915854

RESUMO

There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.


Assuntos
Suscetibilidade a Doenças , Neoplasias Hematológicas/etiologia , Imunomodulação , Evasão Tumoral , Animais , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Calreticulina/genética , Calreticulina/metabolismo , Transformação Celular Neoplásica , Modelos Animais de Doenças , Epitopos/imunologia , Neoplasias Hematológicas/metabolismo , Humanos , Imunomodulação/genética , Mutação , Evasão Tumoral/genética
6.
Lancet Haematol ; 7(1): e73-e81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810765

RESUMO

Diagnosing, surveilling, and understanding the biological consequences of clonal haematopoiesis poses a clinical challenge for both patients and clinicians. The relationship between peripheral blood cytopenias and myeloid neoplasms-such as myelodysplastic syndrome-is an area of active research, and understanding of clonal haematopoiesis has developed markedly on the basis of findings concerning somatic mutations in genes known to be associated with myelodysplastic syndrome. These findings have raised the conundrum of how to appropriately define and follow myelodysplastic syndrome precursor states, such as clonal haematopoiesis of indeterminate potential (CHIP) and clonal cytopenias of undetermined significance (CCUS). Identifying these conditions could allow earlier diagnosis of myelodysplastic syndrome, modify surveillance for myelodysplastic syndrome, and possibly guide therapies, but this information also comes at a cost to patients that might or might not be justified by our present understanding of clonal haematopoiesis. When faced with a diagnosis of clonal haematopoiesis, some patients and providers might be content to let the events unfold naturally, whereas others may insist on intense follow-up and early interventions. This Viewpoint assesses recent developments in clonal haematopoiesis and the related implications for affected patients and their providers.


Assuntos
Hematopoese , Síndromes Mielodisplásicas/diagnóstico , Transformação Celular Neoplásica/genética , Predisposição Genética para Doença , Humanos , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/fisiopatologia
7.
Gut ; 69(2): 355-364, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30979717

RESUMO

OBJECTIVES: Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC. DESIGN: Ploidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections. RESULTS: We first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis. CONCLUSIONS: Our results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Poliploidia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Estudos de Casos e Controles , Diferenciação Celular/genética , Núcleo Celular/patologia , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Feminino , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
8.
BJOG ; 127(3): 377-387, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31631477

RESUMO

OBJECTIVE: To assess the long-term risk factors predicting residual/recurrent cervical intraepithelial neoplasia (CIN 2-3) and time to recurrence after large loop excision of the transformation zone (LLETZ). DESIGN: Retrospective study. SETTING: Colposcopy clinic. POPULATION: 242 women with CIN 2-3 treated between 1996 and 2006 and followed up until June 2016. METHODS: Age, margins, and high-risk human papillomavirus (HR-HPV) were estimated using Cox proportional hazard and unconditional logistic regression models. The cumulative probability of treatment failure was estimated by Kaplan-Meier analysis. MAIN OUTCOME MEASURE: Histologically confirmed CIN 2-3, HR-HPV, margins, age. RESULTS: CIN 2-3 was associated with HR-HPV (HR = 30.5, 95% confidence interval [CI] = 3.80-246.20), age >35 years (HR = 5.53, 95% CI = 1.22-25.13), and margins (HR = 7.31, 95% CI = 1.60-33.44). HR-HPV showed a sensitivity of 88.8% and a specificity of 80%. Ecto+ /endocervical+ (16.7%), uncertain (19.4%) and ecto- /endocervical+ margins (9.1%) showed a higher risk of recurrence (odds ratio [OR] = 13.20, 95% CI = 1.02-170.96; OR = 15.84, 95% CI = 3.02-83.01; and OR = 6.60, 95% CI = 0.88-49.53, respectively). Women with involved margins and/or who were HR-HPV positive had more treatment failure than those who were HR-HPV negative or had clear margins (P-log-rank <0.001). CONCLUSIONS: HR-HPV and margins seem essential for stratifying post-LLETZ risk, and enable personalised management. Given that clear margins present a lower risk, a large excision may be indicated in older women to reduce the risk. TWEETABLE ABSTRACT: After LLETZ for CIN 2-3, recurrences appear more often in women with positive HR-HPV and involved margins and aged over 35.


Assuntos
Neoplasia Intraepitelial Cervical , Efeitos Adversos de Longa Duração , Margens de Excisão , Recidiva Local de Neoplasia/diagnóstico , Neoplasia Residual/diagnóstico , Infecções por Papillomavirus , Traquelectomia , Neoplasias do Colo do Útero , Transformação Celular Neoplásica , Neoplasia Intraepitelial Cervical/epidemiologia , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/cirurgia , Colo do Útero/patologia , Colo do Útero/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/epidemiologia , Pessoa de Meia-Idade , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Estudos Retrospectivos , Medição de Risco/métodos , Espanha/epidemiologia , Traquelectomia/efeitos adversos , Traquelectomia/métodos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia
9.
Gene ; 726: 144223, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669645

RESUMO

TBX3, a member of the ancient and evolutionary conserved T-box transcription factor family, is a critical developmental regulator of several structures including the heart, mammary glands, limbs and lungs. Indeed, mutations in the human TBX3 lead to ulnar mammary syndrome which is characterized by several clinical malformations including hypoplasia of the mammary and apocrine glands, defects of the upper limb, areola, dental structures, heart and genitalia. In contrast, TBX3 has no known function in adult tissues but is frequently overexpressed in a wide range of epithelial and mesenchymal derived cancers. This overexpression greatly impacts several hallmarks of cancer including bypass of senescence, apoptosis and anoikis, promotion of proliferation, tumour formation, angiogenesis, invasion and metastatic capabilities as well as cancer stem cell expansion. The debilitating consequences of having too little or too much TBX3 suggest that its expression levels need to be tightly regulated. While we have a reasonable understanding of the mutations that result in low levels of functional TBX3 during development, very little is known about the factors responsible for the overexpression of TBX3 in cancer. Furthermore, given the plethora of oncogenic processes that TBX3 impacts, it must be regulating several target genes but to date only a few have been identified and characterised. Interestingly, while there is compelling evidence to support oncogenic roles for TBX3, a few studies have indicated that it may also have tumour suppressor functions in certain contexts. Together, the diverse functional elasticity of TBX3 in development and cancer is thought to involve, in part, the protein partners that it interacts with and this area of research has recently received some attention. This review provides an insight into the significance of TBX3 in development and cancer and identifies research gaps that need to be explored to shed more light on this transcription factor.


Assuntos
Doença/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas com Domínio T/genética , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Humanos , Fatores de Transcrição/genética
10.
Gene ; 726: 144224, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669646

RESUMO

MicroRNA-155 (miR-155) has been identified to be overexpressed in various human cancers including osteosarcoma. However, whether the up-regulation of miR-155 is associated with osteosarcoma cancer stem cells (CSCs) is not well understood. In the present study, we showed that miR-155 induced the acquisition of stem-like features in U2OS osteosarcoma cells by increasing the expression of both CSCs surface markers (CD24, CD90, CD133) and CSC-related transcriptional factors (Nanog, SOX2, Oct4, Bim-1). Inflammatory factor TNF-α upregulated the miR-155 expression in U2OS cells and formed a feedback regulatory loop with miR-155. Furthermore, TNF-α/miR-155 axis promoted the cell proliferation, invasion and epithelial-mesenchymal transition (EMT) process in a TP53INP1 independent manner. We also revealed that TNF-α/miR-155 axis induced osteosarcoma CSCs transformation via ERK signaling pathway. These results indicate a crucial role of miR-155 in the acquisition of osteosarcoma CSC phenotype and miR-155 may serve as a potential target in future osteosarcoma therapy.


Assuntos
Proteínas de Transporte/genética , Transformação Celular Neoplásica/genética , Proteínas de Choque Térmico/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Osteossarcoma/genética , Fator de Necrose Tumoral alfa/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/patologia , Transdução de Sinais/genética , Fatores de Transcrição/genética
11.
Toxicol Lett ; 318: 99-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669098

RESUMO

Fluorination preventing metabolic hydroxylation of 17ß-estradiol (E2) was applied to investigate the mechanisms underlying estrogen-induced carcinogenesis. Either 2-fluoro-17ß-estradiol (2-FE2) or 4-fluoro-17ß-estradiol (4-FE2) was administered subcutaneously for 52 weeks to August Copenhagen Irish (ACI) rats, the preferred animal model for human breast cancer. 4-FE2 induced frequent mammary tumors whereas 2-FE2 did not. The cumulative incidence of mammary tumors in rats treated with 4-FE2 was comparable to that observed with E2. The carcinogenic results were supported by histological examination of mammary glands of fluorinated estrogen-treated ACI rats. To evaluate the estrogenic potential of the fluorinated estrogens, 2-FE2 or 4-FE2 was administrated subcutaneously to ovariectomized rats. Both 4-FE2 and 2-FE2 showed high uterotrophic potency. Our results indicate that estrogenic potential may not be the sole factor driving mammary tumorigenesis. Since fluorination inhibits metabolic hydroxylation of E2 at the substituted position, the carcinogenic effect may occur through the metabolic activation of 2-hydroxylated E2, in combination with the compound's estrogenic potency.


Assuntos
Neoplasias da Mama/induzido quimicamente , Transformação Celular Neoplásica/induzido quimicamente , Estradiol/análogos & derivados , Animais , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/patologia , Estradiol/toxicidade , Feminino , Tamanho do Órgão/efeitos dos fármacos , Ratos Endogâmicos ACI , Medição de Risco , Útero/efeitos dos fármacos , Útero/patologia
12.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(11): 806-809, 2019 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-31826542

RESUMO

Objective: To investigate the expression and role of LINC00052 during glycidyl methacrylate (GMA) -induced malignant transformation of 16HBE cells. Methods: Human bronchial epithelial (16HBE) cells were divided into GMA transformation group and corresponding DMSO control group, and the 10th, 20th and 30th generation cells of each group were collected LncRNA microarrays were used to analysis expression of LINC00052 in different stage of malignant transformation. Bioinformatics analysis was applied and the relative expression of LINC00052 and its potentially target genes was detected by real-time quantification PCR (qPCR) . Results: The results of microarray analysis showed that LINC00052 was up-regulated by 1.32-fold, down-regulated by 1.64-fold and down-regulated by 4.92-fold in the malignant transformation early (P10) , middle term (P20) and late (P30) , respectively, The results of qPCR showed that compared with the DMSO control group, the expression of LINC00052 was up-regulated by 1.55 times, down-regulated by 1.20 times and down-regulated by 2.35 times in P10, P20 and P30, respectively, and the difference was statistically significant (P<0.05) . There was a statistically significant difference in the relative expression of NTRK3 between the GMA transformation group of P10 and P30 generations with the corresponding DMSO control group (P<0.05) . Conclusion: LINC00052 is highly expressed in early time of GMA-induced malignant transformation of 16HBE, and down-regulated in the middle and last stage of malignant transformation and may play a protective role in GMA-induced malignant transformation of 16HBE by influencing the expression of its target gene NTRK3.


Assuntos
Transformação Celular Neoplásica , Células Epiteliais , Compostos de Epóxi , Regulação Neoplásica da Expressão Gênica , Metacrilatos , RNA Longo não Codificante , Brônquios/citologia , Linhagem Celular , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , RNA Longo não Codificante/genética
13.
J Contemp Dent Pract ; 20(8): 887-892, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31797842

RESUMO

AIM: Though the exact mechanism of yes-associated protein (YAP) in tumorigenesis is not well understood, studies have shown that YAP plays an imperative role in cancer advancement via the Hippo signaling pathway. The purpose of the present study was to appraise the clinicopathological correlation of YAP expression in various grades and stages along with different parameters like tumor size and nodal metastasis in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Twenty-seven surgically excised specimens from patients with OSCC were selected for the study. Grading of the OSCC specimens was done according to Broder's grading system and staging had been done using tumor-node-metastasis (TNM) system by American Joint Committee on Cancer (AJCC). Comparative analysis of YAP expression and various aforementioned parameters of OSCC was performed and statistically analyzed. RESULTS: Differences in the expression of YAP was observed among well differentiated and moderately differentiated OSCC, with increased YAP expression with successive grades but was statistically insignificant. On evaluating YAP expression among various stages of OSCC, we observed that stages I, II, and IV demonstrated a weak expression of YAP, while stage III showed a strong expression but the differences were insignificant. Insignificant differences were also noted in YAP expression between different tumor sizes, while significant differences were observed between different nodal statuses. CONCLUSION: Our results suggest that YAP could be responsible for extensive proliferation and invasiveness of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Carcinogênese , Transformação Celular Neoplásica , Humanos , Estadiamento de Neoplasias
14.
Pathologe ; 40(Suppl 3): 232-238, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31811372

RESUMO

Inflammatory bowel diseases (IBDs) increase the risk for colorectal cancer (CRC). In IBD, the evolution of potential tumor clones occurs long before neoplastic lesions become evident and these clones can be undetectable by endoscopy and histology at early stages. The spectrum of genomic alterations in IBD-associated colorectal carcinogenesis is distinct from the changes observed in the sporadic adenoma-carcinoma sequence. Predominant alterations include aneuploidies and mutations of TP53, which both occur early in IBD-related tumorigenesis. In some IBD patients, genomic alterations can already be detected in colonic mucosa without any histologic signs of dysplasia. Genomic analysis of multiregional samples from colectomy specimens of IBD patients revealed distinct tumor evolutionary patterns. This suggests an increased genomic instability in the chronically inflamed bowel that enables the emergence of multiple, phylogenetically unrelated neoplastic lesions within the colorectum of a single IBD patient. This article summarizes the genomic alterations underlying IBD-associated colorectal tumorigenesis and the evolutionary patterns from inflamed, not yet dysplastic epithelium to CRC. Furthermore, it is discussed how this knowledge can eventually be exploited for early detection of malignant progression of IBD and thus help to improve the clinical management and surveillance schedule of IBD patients.


Assuntos
Transformação Celular Neoplásica , Neoplasias Colorretais , Doenças Inflamatórias Intestinais , Neoplasias Colorretais/genética , Progressão da Doença , Genômica , Humanos , Doenças Inflamatórias Intestinais/genética
15.
Biol Res ; 52(1): 61, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870440

RESUMO

BACKGROUND: Papillary thyroid cancer (PTC) is the most common malignancy of all thyroid cancers. LncRNA LINC00460 has been proved to play roles in the oncogenesis and progression of various tumors, including papillary thyroid cancer. However, the potential molecular mechanism of LINC00460 in PTC is poorly investigated. RESULTS: LINC00460 was upregulated in PTC tissues and cells. Raf1 was upregulated in PTC tissues, but miR-485-5p was down-regulated. High LINC00460 expression was associated with poor prognosis. LINC00460 knockdown suppressed proliferation, migration, invation and EMT of PTC cells. Bioinformatics prediction revealed that LINC00460 had binding sites with miR-485-5p, which was validated by luciferase reporter assay. In addition, miR-485-5p was confirmed to directly target Raf1 3'-UTR. Moreover, LINC00460 promoted PTC progression by sponging miR-485-5p to elevate the expression of Raf1. Knockdown of LINC00460 restrained tumor growth in vivo. CONCLUSION: LINC00460 induced proliferation, migration, invation and EMT of PTC cells by regulating the LINC00460/miR-485-5p/Raf1 axis, which indicated that LINC00460 may be a potential biomarker and therapeutic target for PTC.


Assuntos
MicroRNAs/genética , RNA Longo não Codificante/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Apoptose , Proliferação de Células , Transformação Celular Neoplásica , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Regulação para Cima
16.
Cell Physiol Biochem ; 53(6): 910-920, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31769258

RESUMO

BACKGROUND/AIMS: Exposure to heavy metals is today a threat to society. The understanding of the molecular processes related to diseases related to exposure to metals mixture involve changes in the expression of microRNAs. Changes on microRNAs expression may alter several cellular processes, among them, DNA repair inhibition has been described as an essential event leading to the initiation of metal-induced carcinogenesis. METHODS: We evaluate the miR-222 expression in the two-stage transformation Balb/c 3T3 cell assay treated with As-Cd-Pb mixture. RESULTS: We could appreciate that up-regulation of miR-222 reduces the expression both gene and as a protein expression of Rad51c by RT-PCR and immunoblot, respectively. CONCLUSION: Here, we demonstrate that the mixture of As-Cd-Pb at epidemiologically relevant concentrations induces miR-222 up-regulation, which directly negatively regulates Rad51c expression and impairs homologous recombination of DNA during the initiation stage of cell transformation. This inhibition triggers morphological transformation in a murine two-stage Balb/c 3T3 cell assay, suggesting that this small RNA acts as an initiator of the carcinogenesis process.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Metais Pesados/farmacologia , MicroRNAs/metabolismo , Rad51 Recombinase/metabolismo , Animais , Antagomirs/metabolismo , Arsênico/química , Células 3T3 BALB , Cádmio/química , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Chumbo/química , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Rad51 Recombinase/genética
17.
No Shinkei Geka ; 47(11): 1173-1178, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31761779

RESUMO

Intracranial epidermoid cysts are benign cystic lesions that typically exhibit slow growth. Their malignant transformation into squamous cell carcinoma is rare. We report a 77-year-old woman who was admitted to our hospital because of a near-drowning incident due to a seizure sustained in her bathtub. Magnetic resonance imaging(MRI)revealed an extra-axial tumor occupying the right cerebellopontine angle. The lesion appeared hyperintense in diffusion-weighted images and exhibited contrast enhancement after gadolinium injection. Cerebrospinal fluid examination revealed noninfectious meningitis, presumably due to the ruptured epidermoid cyst. Tumor resection was performed and histopathological examination revealed squamous cell carcinoma, which was indicative of malignant transformation of the cyst. The patient underwent adjuvant radiotherapy and has no signs of recurrence 9 months postsurgery. Rapid neurological deterioration and contrast enhancement on MRI are key signs of malignant transformation of epidermoid cysts.


Assuntos
Ângulo Cerebelopontino/cirurgia , Cisto Epidérmico , Idoso , Transformação Celular Neoplásica , Neoplasias Cerebelares , Cisto Epidérmico/cirurgia , Feminino , Humanos , Imagem por Ressonância Magnética , Recidiva Local de Neoplasia
18.
Georgian Med News ; (294): 123-128, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31687963

RESUMO

Microenvironment plays central role in the development of cervical precancerous and cancerous lesions. Cervical intraepithelial neoplasia (CIN) represents a group of precancerous lesions, divided into three degrees. We investigated the distribution of intraepithelial lymphocytes and macrophages in different grades of CIN. We analysed lymphocyte marker CD103, macrophage marker CD68 and proliferation marker Ki67 using standard immunohistochemistry. In addition, we investigated the distribution of lymphocytes using standard haematoxylin and eosin method. The results of our study indicated thatgrade I CIN which subsequently progressed into grade II CIN was characterised with low lymphocytic infiltration, low lympho-epithelial index and low lymphocyte proliferation index. Similar results were seen in cases of CINII which were later progressed into CINIII or in carcinoma. Therefore, we would like to recommend the analysis of microenvironment alterations in CIN lesions, in order to assess their progression potential.


Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/análise , Transformação Celular Neoplásica/patologia , Neoplasia Intraepitelial Cervical/patologia , Linfócitos Intraepiteliais/patologia , Antígeno Ki-67/metabolismo , Macrófagos/patologia , Microambiente Tumoral , Neoplasias do Colo do Útero/patologia , Antígenos CD/análise , Neoplasia Intraepitelial Cervical/metabolismo , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/análise , Gradação de Tumores , Neoplasias do Colo do Útero/metabolismo
19.
Anticancer Res ; 39(11): 6299-6305, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704860

RESUMO

BACKGROUND/AIM: A minority of grade I meningiomas (MG1s) recur after surgical resection and their progression is associated with high grade transformation (HGT). This study aimed to characterize the clinicoradiological features of recurrent MGs (RMG) with HGT. PATIENTS AND METHODS: We identified 17 patients diagnosed with MG1 who then underwent surgery for RMG. Patients were categorized into HGT group vs. non-HGT (nHGT) group based on RMG histological grade and clinicoradiological features were comparatively analyzed. RESULTS: HGT was observed in 41.4% of RMGs. Original tumor size was larger in the HGT group and recurrence time interval was shorter. Following recurrence, 57.1% in the HGT group experienced further disease progression, compared to 22.2% in the nHGT group. CONCLUSION: A considerable HGT rate in RMGs developed after MG1 was observed. Although HGT was not distinguished from nHGT by radiological features, HGT in RMG was associated with larger initial tumor size and shorter recurrence time interval.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/diagnóstico por imagem , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
20.
Genes Dev ; 33(23-24): 1718-1738, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727771

RESUMO

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A +/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.


Assuntos
Diferenciação Celular/genética , Células Neuroendócrinas/citologia , Receptores Notch/fisiologia , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Transdução de Sinais/genética , Carcinoma de Pequenas Células do Pulmão/enzimologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linhagem Celular , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Histona Desmetilases/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Células Neuroendócrinas/patologia , Carcinoma de Pequenas Células do Pulmão/fisiopatologia
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