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1.
BMJ Case Rep ; 14(9)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34511423

RESUMO

We report a case of a frail 68-year-old woman with stage 4 pancreatic carcinoma harbouring a fibroblastic growth factor receptor 2 (FGFR2) fusion who achieved a durable complete response after treatment with erdafitinib a pan-FGFR inhibitor. The FGFR2-TACC2 fusion was detected on comprehensive tumour somatic mutation profiling. There is ongoing complete response at 10 months after initiation of erdafitinib. Transient central serous retinopathy, grade 2 hyperphosphataemia and diarrhoea were the adverse events encountered.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Idoso , Proteínas de Transporte , Feminino , Humanos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Pirazóis , Quinoxalinas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas Supressoras de Tumor
2.
Nat Commun ; 12(1): 5232, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475402

RESUMO

Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes.


Assuntos
Neoplasias da Mama/patologia , Fator I de Transcrição COUP/genética , Neoplasias Pulmonares/secundário , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Regiões 5' não Traduzidas , Animais , Neoplasias da Mama/genética , Fator I de Transcrição COUP/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Sítios Internos de Entrada Ribossomal , Pulmão/patologia , Neoplasias Pulmonares/genética , Camundongos , Invasividade Neoplásica , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
3.
Nat Immunol ; 22(9): 1152-1162, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34385712

RESUMO

The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.


Assuntos
Neoplasias do Colo/patologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/imunologia , Animais , Proliferação de Células/fisiologia , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Fator 1-alfa Nuclear de Hepatócito/genética , Memória Imunológica/imunologia , Inflamação/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Transcrição Genética/genética , Proteínas Supressoras de Tumor/metabolismo
4.
J Int Med Res ; 49(8): 3000605211035895, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34433328

RESUMO

OBJECTIVE: Tuberous sclerosis (TSC) is an autosomal dominant disorder, often detected during childhood. We present the results of genetic testing in a newborn with suspected TSC. METHODS: A newborn with no specific clinical manifestations of TSC showed evidence of TSC on magnetic resonance imaging and echocardiography. Next-generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA) of the TSC1 and TSC2 gene exons were carried out to confirm the diagnosis. RESULTS: The results of MLPA were negative, but NGS showed a heterozygous mutation in the TSC1 gene comprising insertion of a T residue at c.2165 (exon 17) to c.2166 (exon 17), indicating a loss of function mutation. These results were verified by Sanger sequencing. This genetic change was present in the newborn but the parental genotypes were wild-type, indicating a de novo mutation. CONCLUSIONS: In this case, a case of TSC caused by a heterozygous mutation in the TSC1 gene was confirmed by NGS sequencing. This indicates the suitability of genetic testing for the early diagnosis of clinically rare and difficult-to-diagnose diseases, to guide clinical treatment.


Assuntos
Proteína 1 do Complexo Esclerose Tuberosa , Esclerose Tuberosa , Análise Mutacional de DNA , Diagnóstico Precoce , Humanos , Recém-Nascido , Mutação , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética
5.
Zhonghua Bing Li Xue Za Zhi ; 50(8): 904-909, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34344074

RESUMO

Objective: To study the expression of GATA3 and bcl-11b in peripheral T-cell lymphoma (PTCL) and their correlation with clinicopathological features. Methods: The Oncomine and GEO databases were used for analyzing the expression levels of GATA3 and bcl-11b mRNA in PTCL. Immunohistochemistry was used to detect the expression of GATA3 and bcl-11b proteins in 127 cases of PTCL diagnosed at Shanxi Provincial Cancer Hospital from January 2010 to June 2020, as well as 40 cases of lymph node with reactive hyperplasia. Results: The data in Oncomine and GEO databases showed that the expression of GATA3 and bcl-11b mRNA in PTCL was lower than that in normal tissues (P<0.05). Immunohistochemistry showed that the positive rates of GATA3 in PTCL and lymph nodes with reactive hyperplasia were 60.6% (77/127) and 85.0% (34/40, P<0.05), respectively. The expression rates of bcl-11b in PTCL and lymph nodes with reactive hyperplasia were 55.1% (70/127) and 75.0% (30/40, P<0.05), respectively. The expression of GATA3 was related to the pathological classification of the patients with PTCL, and was inversely related to the Ann Arbor stage of the patient, while the expression of bcl-11b was inversely correlated with the IPI score of the patient (P<0.05). The expression of GATA3 and bcl-11b was related to the patients' age, gender, LDH level, and B symptoms. Other clinicopathological characteristics were irrelevant. Spearman correlation analysis shows that the expression of GATA3 protein was associated with that of bcl-11b protein in PTCL. Conclusion: GATA3 and bcl-11b are closely related to the prognosis of PTCL, and may be important factors involved in the occurrence and development of PTCL.


Assuntos
Linfoma de Células T Periférico , Fator de Transcrição GATA3/genética , Humanos , Imuno-Histoquímica , Linfonodos , Linfoma de Células T Periférico/genética , Prognóstico , Proteínas Repressoras , Proteínas Supressoras de Tumor
6.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360855

RESUMO

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Pirimidinas/uso terapêutico , Fator de Transcrição STAT5/antagonistas & inibidores , Tiofenos/uso terapêutico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Proteínas Proto-Oncogênicas/genética , Tirosina Quinase 3 Semelhante a fms/genética
7.
Nat Commun ; 12(1): 5016, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408138

RESUMO

DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168- and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.


Assuntos
Proteína BRCA1/metabolismo , Dano ao DNA , Proteína do Grupo de Complementação N da Anemia de Fanconi/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteína BRCA1/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , DNA/genética , DNA/metabolismo , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Ligação Proteica , Transporte Proteico , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Reparo de DNA por Recombinação , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
8.
Nat Commun ; 12(1): 4928, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389720

RESUMO

Diabetes results from a decline in functional pancreatic ß-cells, but the molecular mechanisms underlying the pathological ß-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces ß-cell apoptosis and impaired function. LATS2 deficiency in ß-cells and primary isolated human islets as well as ß-cell specific LATS2 ablation in mice improves ß-cell viability, insulin secretion and ß-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in ß-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates ß-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating ß-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic ß-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic ß-cell survival and function in diabetes.


Assuntos
Autofagia , Diabetes Mellitus/metabolismo , Células Secretoras de Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Células Cultivadas , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Humanos , Células Secretoras de Insulina/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Ratos , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética
9.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445578

RESUMO

The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic RasV12 and the loss of the tumor suppressor scribble in flies, this and other tumor models have provided new concepts and findings in cancer biology that has remarkable parallels and relevance to human cancer. Here we review findings using the RasV12; scrib-/- tumor model and how it has contributed to our understanding of how these initial simple genetic insults cooperate within the tumor cell to set in motion the malignant transformation program leading to tumor growth through cell growth, cell survival and proliferation, dismantling of cell-cell interactions, degradation of basement membrane and spreading to other organs. Recent findings have demonstrated that cooperativity goes beyond cell intrinsic mechanisms as the tumor interacts with the immediate cells of the microenvironment, the immune system and systemic organs to eventually facilitate malignant progression.


Assuntos
Carcinogênese , Proteínas de Membrana/metabolismo , Mutação , Neoplasias/patologia , Microambiente Tumoral , Proteínas Supressoras de Tumor/metabolismo , Proteínas ras/metabolismo , Animais , Humanos , Proteínas de Membrana/genética , Neoplasias/etiologia , Neoplasias/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Proteínas ras/genética
10.
Clin Lab ; 67(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383404

RESUMO

BACKGROUND: Abnormal expression of miR 20a is reported in various types of malignancy neoplasms. However, its function is not consistent in different tumors. This study aims to explore the potential functions of miR 20a and its underlying mechanisms in bladder cancer. METHODS: Ninety-six patients diagnosed with bladder cancer were recruited into the study. The expression levels of miR-20a in bladder cancer samples and adjacent non-tumor samples were investigated by qRT-PCR. Wound healing, CCK8, and transwell migration assays were carried out for determining the functions of miR20a. Bioinformatics analysis was used for predicting the downstream gene of miR-20a. Western blot, qRT-PCR, and fluorescent reporter assays were used to verify the target gene. RESULTS: MiR-20a was significantly increased in bladder cancer tissues, and its rising level was closely correlated with histological grade, clinical stage, recurrence and metastasis in bladder cancer. Exogenous upregulation of miR-20a expression obviously enhanced the aggressive biological functions of bladder cancer in vitro. LASS2 was verified to be a target gene of miR-20a. Moreover, miR-20a can negatively regulate LASS2 at protein and mRNA levels. CONCLUSIONS: Increasing miR-20a is closely related to aggressive clinicopathological features. MiR 20a plays an oncogenic role in bladder cancer, which contributes to target LASS2 directly.


Assuntos
Proteínas de Membrana/genética , MicroRNAs , Esfingosina N-Aciltransferase/genética , Proteínas Supressoras de Tumor/genética , Neoplasias da Bexiga Urinária , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Invasividade Neoplásica , Recidiva Local de Neoplasia , Esfingosina N-Aciltransferase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Bexiga Urinária/genética
11.
BMC Genomics ; 22(1): 613, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384362

RESUMO

BACKGROUND: Hypertrophic scar (HTS) is a fibroproliferative skin disorder characterized by excessive cell proliferation, migration, and extracellular matrix (ECM) deposition. The CUB and Sushi multiple domains 1 (CSMD1) has previously been identified as the key regulatory gene of hypertrophic scar by a large sample GWAS study. However, further research has not yet been conducted to verify this finding in other HTS patients and to determine the underlying mechanism. RESULTS: In this study, we verified that CSMD1 was downregulated in both HTS tissue and HTS-derived fibroblasts. The knockdown of CSMD1 resulted in enhanced migration and fibronectin1 (FN1) secretion in fibroblasts in vitro. In addition, the upstream and downstream regulatory mechanisms of CSMD1 were also investigated through microRNA (miRNA) databases screening and RNA-sequencing (RNA-seq) respectively. The screening of four common microRNA (miRNA) databases suggested that miR-190a-3p binds to the CSMD1 and may regulate its expression. We confirmed that miR-190a-3p directly targeted the CSMD1-3'-UTR using luciferase reporter assays. Furthermore, the overexpression of miR-190a-3p showed promotion of migratory activity and FN1 secretion in fibroblasts, resembling the effect of CSMD1 knockdown; whereas the knockdown of miR-190a-3p exerted the opposite effect. Finally, transcriptomic analysis showed activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway in the CSMD1 knockdown fibroblasts. CONCLUSIONS: This study has validated the conclusions of the previous GWAS study conducted in Chinese population. In vitro experiments have provided further evidence on the function of CSMD1 in the development of HTS, and have also revealed the underlying upstream and downstream regulating mechanisms. Additionally, the JAK/STAT signaling pathway identified using RNA-seq might provide a potential treatment approach, especially for HTS.


Assuntos
Cicatriz Hipertrófica , MicroRNAs/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/patologia , Fibroblastos , Humanos , Proteínas de Membrana , MicroRNAs/genética , Proteínas Supressoras de Tumor
12.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445673

RESUMO

The transcription factor p63, one of the p53 family members, plays an essential role in regulating maternal reproduction and genomic integrity as well as epidermal development. TP63 (human)/Trp63 (mouse) produces multiple isoforms: TAp63 and ΔNp63, which possess a different N-terminus depending on two different promoters, and p63a, p63b, p63g, p63δ, and p63ε as products of alternative splicing at the C-terminus. TAp63 expression turns on in the nuclei of primordial germ cells in females and is maintained mainly in the oocyte nuclei of immature follicles. It has been established that TAp63 is the genomic guardian in oocytes of the female ovaries and plays a central role in determining the oocyte fate upon oocyte damage. Lately, there is increasing evidence that TP63 mutations are connected with female infertility, including isolated premature ovarian insufficiency (POI) and syndromic POI. Here, we review the biological functions of p63 in females and discuss the consequences of p63 mutations, which result in infertility in human patients.


Assuntos
Fertilidade/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Processamento Alternativo/genética , Animais , Núcleo Celular/metabolismo , Feminino , Genes p53/genética , Humanos , Camundongos , Mutação/genética , Oócitos/metabolismo , Ovário/metabolismo , Insuficiência Ovariana Primária/metabolismo , Isoformas de Proteínas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
13.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360911

RESUMO

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s).


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Pirimetamina/farmacologia , Apoptose/genética , Autofagia/genética , Proteína 7 Relacionada à Autofagia/deficiência , Proteína 7 Relacionada à Autofagia/genética , Proteína Beclina-1/deficiência , Proteína Beclina-1/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT5/deficiência , Fator de Transcrição STAT5/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células THP-1 , Transfecção , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética
14.
Afr Health Sci ; 21(1): 41-46, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34394279

RESUMO

Background: In spite of the strong evidence demonstrating the role of overexpression of Ki-67 and Cyclin D1 markers in breast carcinomas, clinical and pathological data remain to be discussed. This can be explained partly by intratumor heterogeneity. Objectives: To define the prevalence and clinical significance of Ki-67 and Cyclin D1 overexpression in primary breast tumors ER positive, while highlighting the existence of intratumor heterogeneity in this type of cancer. Materials and methods: 51 ER positive breast cancer tumors were used to evaluate the intratumoral distribution of Ki-67 and Cyclin D1 expression. Image acquisition and visualization of the markers were performed by optical microscopy and stereology sampling method. Results: The mean Ki-67 labeling index was distributed heterogeneously in the same tumor, from 20.67±6.87 to 45.10±10.65. The coefficient of variation (COV) revealed dispersion values between 13.4% and 42.9%. Associated with positive ER status, all the tumors presented a Cyclin D1 expression with a COV varying between 19% and 28.5% and a mean labeling index fluctuating between 19.40±4.42 and 41.64±10.08 within the same patient showing important intratumor heterogeneous distribution. Conclusion: In this study, we have adopted a strictly quantitative approach to evaluate and demonstrate intratumor heterogeneity. This establishes one of the main factors for poor response to cancer therapy. To achieve this, intratumor heterogeneity should be usually definable and quantifiable but this domain awaits future progress and methods need to move towards a better understanding of molecular and cellular mechanisms that initiate and maintain this tumor heterogeneity.


Assuntos
Neoplasias da Mama/genética , Ciclina D1/metabolismo , Antígeno Ki-67/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Proteínas de Neoplasias/análise , Proteínas Supressoras de Tumor
15.
Klin Monbl Augenheilkd ; 238(7): 773-780, 2021 Jul.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-34376007

RESUMO

Over the last ten years, much has been learnt about the genetic characteristics and genetic evolution of uveal melanoma. It has been shown that uveal melanoma differs fundamentally from non-uveal melanoma and is an independent genetic subtype. Compared to other tumours, uveal melanoma has a low mutational burden. There are recurring chromosomal aberrations with losses of 1p, 6q, 8p and 16q, gains of 6p and 8q, and the presence of monosomy 3. GNAQ, GNA11, PLCB4, CYSLTR2, MAPKAPK5, as well as mutations in BAP1, SF3B1, SRSF2 and EIF1AX, the latter being linked to a higher risk of metastasis, have been identified as significantly mutated genes. In rare cases, a BAP1 germline mutation may also be present. In addition to higher risk of uveal melanoma, this variant is also linked with other tumours. In this case, additional work-up, genetic counselling and screening of family members should be offered. While the knowledge about the genetic characteristics of uveal melanoma is already routinely used for diagnostic and prognostic purposes, targeted genotype-dependent therapy of uveal melanoma is currently still missing.


Assuntos
Melanoma , Ubiquitina Tiolesterase , Neoplasias Uveais , Análise Mutacional de DNA , Humanos , Melanoma/diagnóstico , Melanoma/genética , Mutação , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética
16.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
17.
Nat Commun ; 12(1): 4245, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253722

RESUMO

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). Transcription factor EB (TFEB), a master regulator of lysosome biogenesis, is negatively regulated by mTORC1 through a RAG GTPase-dependent phosphorylation. Here we show that lysosomal biogenesis is increased in TSC-associated renal tumors, pulmonary lymphangioleiomyomatosis, kidneys from Tsc2+/- mice, and TSC1/2-deficient cells via a TFEB-dependent mechanism. Interestingly, in TSC1/2-deficient cells, TFEB is hypo-phosphorylated at mTORC1-dependent sites, indicating that mTORC1 is unable to phosphorylate TFEB in the absence of the TSC1/2 complex. Importantly, overexpression of folliculin (FLCN), a GTPase activating protein for RAGC, increases TFEB phosphorylation at the mTORC1 sites in TSC2-deficient cells. Overexpression of constitutively active RAGC is sufficient to relocalize TFEB to the cytoplasm. These findings establish the TSC proteins as critical regulators of lysosomal biogenesis via TFEB and RAGC and identify TFEB as a driver of the proliferation of TSC2-deficient cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Lisossomos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Biogênese de Organelas , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/patologia , Núcleo Celular/metabolismo , Proliferação de Células , Feminino , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Neoplasias Renais/patologia , Lisossomos/ultraestrutura , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação , Fosfosserina/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas/metabolismo , Transcrição Genética , Proteína 2 do Complexo Esclerose Tuberosa/deficiência , Proteínas Supressoras de Tumor/metabolismo
18.
Hum Genet ; 140(9): 1395-1401, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34313816

RESUMO

The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in ZNF668 comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name ZNF668-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery.


Assuntos
Anormalidades Múltiplas/genética , Dano ao DNA , Genes Recessivos , Homozigoto , Proteínas Supressoras de Tumor/deficiência , Anormalidades Múltiplas/patologia , Criança , Humanos , Masculino
19.
Cancer Treat Rev ; 99: 102261, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34332293

RESUMO

BACKGROUND: Temozolomide (TEM) is an active treatment in metastatic neuroendocrine tumors (NETs). Patients affected by glioblastoma multiforme or advanced melanoma treated with TEM who have deficiency of O6-methylguanine DNA methyltransferase (MGMT) have a better responses and survival. However, the predictive role of MGMT in patients with NETs treated with TEM is still debated. METHODS: We conducted a systematic review of the literature and meta-analysis, based on PRISMA methodology, searching in the main databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library and clinical trial.gov) and the proceedings of the main international congresses, until April 26, 2021. RESULTS: Twelve out of 616 articles were selected for our analysis, regarding a total of 858 NET patients treated with TEM-based chemotherapy. The status of MGMT had been tested in 513 (60%) patients, using various methods. The pooled overall response rate (ORR) was higher in MGMT-deficient compared with MGMT-proficient NETs, with a risk difference of 0.31 (95% confidence interval, CI: 0.13-0.50; p < 0.001; I2: 73%) and risk ratio of 2.29 (95% CI: 1.34-3.91; p < 0.001; I2: 55%). The pooled progression free survival (PFS) (hazard ratio, HR = 0.56; 95% CI: 0.43-0.74; p < 0.001) and overall survival (OS) (HR = 0.41; 95% CI: 0.20-0.62; p = 0.011) were longer in MGMT-deficient versus MGMT-proficient NETs. CONCLUSIONS: Our meta-analysis suggested that MGMT status may be predictive of TEM efficacy. However, due to the high heterogeneity of the evaluated studies the risk of biases should be considered. On this hypothesis future homogeneous prospective studies are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metilases de Modificação do DNA/deficiência , Enzimas Reparadoras do DNA/deficiência , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/enzimologia , Proteínas Supressoras de Tumor/deficiência , Ensaios Clínicos Fase II como Assunto , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Humanos , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Temozolomida/administração & dosagem , Proteínas Supressoras de Tumor/metabolismo
20.
Molecules ; 26(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34299435

RESUMO

KRIBB11, an HSF1 inhibitor, was shown to sensitize various types of cancer cells to treatment with several anticancer drugs. However, the exclusive effects of KRIBB11 in preventing the growth of glioblastoma cells and the related mechanisms have not been elucidated yet. Herein, we aimed to examine the potential of KRIBB11 as an anticancer agent for glioblastoma. Using MTT and colony formation assays and Western blotting for c-PARP, we demonstrated that KRIBB11 substantially inhibits the growth of A172 glioma cells by inducing apoptosis. At the molecular level, KRIBB11 decreased anti-apoptotic protein MCL-1 levels, which was attributable to the increase in MULE ubiquitin ligase levels. However, the constitutive activity of HSF1 in A172 cells was not influenced by the exclusive treatment with KRIBB11. Additionally, based on cycloheximide chase assay, we found that KRIBB11 markedly retarded the degradation of MULE. In conclusion, stabilization of MULE upon KRIBB11 treatment is apparently an essential step for degradation of MCL-1 and the subsequent induction of apoptosis in A172 cells. Our results have expanded the knowledge on molecular pathways controlled by KRIBB11 and could be potentially effective for developing an inhibitory therapeutic strategy for glioblastoma.


Assuntos
Aminopiridinas/farmacologia , Glioblastoma/tratamento farmacológico , Indazóis/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Aminopiridinas/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Indazóis/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Supressoras de Tumor/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
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