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1.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34935059

RESUMO

Although gemcitabine (GEM) has been used to treat bladder cancer (BC) for a number of years, severe adverse events or drug resistance frequently develops. A series of drugs have been proved to sensitize patients to GEM and reduce the side effects. The aim of the present study was to evaluate the potential effects of berberine (BER) on GEM­induced cytotoxicity in BC and to explore the possible underlying mechanisms. T24 and 5637 human BC cell lines were treated with GEM and/or BER before cell proliferation, apoptosis and migration were studied. Oncomine databases and Gene Expression Profiling Interactive Analysis (GEPIA) were used to retrieve RAD51 recombinase (Rad51) mRNA expression. Overexpression plasmid or specific Rad51 small interfering RNA were used to examine the role of Rad51 in drug­treated BC cells. BC model mice were administered with GEM and/or BER before changes in tumor volume, size and Ki67 expression were assessed. BER enhanced GEM­induced cytotoxicity, apoptosis and inhibition of migration, whilst attenuating the GEM­induced upregulation of phosphorylated Akt and Rad51 expression. According to Oncomine and GEPIA analyses, Rad51 was found to be significantly upregulated in BC tissues compared with that in normal tissues, where there was a weak positive correlation between Rad51 and Akt1 expression. Knockdown of Rad51 enhanced GEM­induced cytotoxicity, whilst overexpression of Rad51 reversed the suppressed cell viability induced by BER and GEM. Inactivation of the PI3K/Akt pathway by LY294002 or BER enhanced GEM­induced cytotoxicity and downregulated Rad51 expression, whilst overexpression of constitutively active Akt restored Rad51 expression and cell viability that was previously decreased by BER and GEM. BER additively inhibited tumor growth and Ki67 expression when combined with GEM in vivo. These results suggest that BER can enhance GEM­induced cytotoxicity in BC by downregulating Rad51 expression through inactivating the PI3K/Akt pathway, which may represent a novel therapeutic target for BC treatment.


Assuntos
Berberina/farmacologia , Desoxicitidina/análogos & derivados , Sinergismo Farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rad51 Recombinase/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Transporte , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Regulação para Cima , Neoplasias da Bexiga Urinária/genética
3.
Cancer Lett ; 527: 150-163, 2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-34942305

RESUMO

Recently, epigenetic modifications, including DNA methylation, histone modification and noncoding RNA (ncRNA)-associated gene silencing, have received increasing attention from the scientific community. Many studies have demonstrated that epigenetic regulation can render dynamic alterations in the transcriptional potential of a cell, which then affects the cell's biological function. The initiation and development of clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell cancer (RCC), is also closely related to genomic alterations by epigenetic modification. For ccRCC, lipid accumulation is one of the most typical characteristics. In other words, dysregulation of lipid uptake and synthesis occurs in ccRCC, which inversely promotes cancer proliferation and progression. However, the link among epigenetic alterations, lipid biosynthesis and renal cancer progression remains unclear. SETD8 is a histone methyltransferase and plays pivotal roles in cell cycle regulation and oncogenesis of various cancers, but its role in RCC is not well understood. In this study, we discovered that SETD8 was significantly overexpressed in RCC tumors, which was positively related to lipid storage and correlated with advanced tumor grade and stage and poor patient prognosis. Depletion of SETD8 by siRNAs or inhibitor UNC0379 diminished fatty acid (FA) de novo synthesis, cell proliferation and metastasis in ccRCC cells. Mechanistically, SETD8, which was posttranslationally stabilized by USP17, could transcriptionally modulate sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in fatty acid biosynthesis and lipogenesis, by monomethylating the 20th lysine of the H4 histone, elevating lipid biosynthesis and accumulation in RCC and further promoting cancer progression and metastasis. Taken together, the USP17/SETD8/SREBP1 signaling pathway plays a pivotal role in promoting RCC progression. SETD8 might be a novel biomarker and potential therapeutic target for treating RCC.

4.
J Proteome Res ; 20(12): 5329-5339, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34748338

RESUMO

With the steadfast development of proteomic technology, the number of missing proteins (MPs) has been continuously shrinking, with approximately 1470 MPs that have not been explored yet. Due to this phenomenon, the discovery of MPs has been increasingly more difficult and elusive. In order to face this challenge, we have hypothesized that a stable aneuploid cell line with increased chromosomes serves as a useful material for assisting MP exploration. Ker-CT cell line with trisomy at chromosome 5 and 20 was selected for this purpose. With a combination strategy of RNA-Seq and LC-MS/MS, a total of 22 178 transcripts and 8846 proteins were identified in Ker-CT. Although the transcripts corresponding to 15 and 15 MP genes located at chromosome 5 and 20 were detected, none of the MPs were found in Ker-CT. Surprisingly, 3 MPs containing at least two unique non-nest peptides of length ≥9 amino acids were identified in Ker-CT, whose genes are located on chromosome 3 and 10, respectively. Furthermore, the 3 MPs were verified using the method of parallel reaction monitoring (PRM). These results suggest that the abnormal status of chromosomes may not only impact the expression of the corresponding genes in trisomy chromosomes, but also influence that of other chromosomes, which benefits MP discovery. The data obtained in this study are available via ProteomeXchange (PXD028647) and PeptideAtlas (PASS01700), respectively.

6.
Cell Death Discov ; 7(1): 329, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725345

RESUMO

The aberrant expression of fat mass and obesity-associated protein (FTO) has been confirmed to be associated with a variety of cancers and participates in the regulation of multiple biological behaviours. FTO plays an oncogenic role in bladder cancer, but few studies have focused on how FTO promotes bladder cancer progression by regulating miRNA synthesis. Here, we confirmed that FTO expression was significantly increased in bladder cancer and was associated with a poor prognosis. FTO overexpression promoted bladder cancer cell proliferation, whereas FTO knockdown inhibited bladder cancer cell proliferation. We also demonstrated that FTO promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathways. Taken together, our work revealed that FTO plays a critical role in bladder cancer and could be a potential diagnostic or prognostic biomarker for this disease.

7.
BMC Biol ; 19(1): 200, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503495

RESUMO

BACKGROUND: Although oocyte quality is the dominant factor determining embryo quality, few studies have been conducted to evaluate embryo quality based on the metabolites related to the oocyte. With quantification of the follicular fluid (FF) metabolites, in assisted reproductive technology (ART), this study sought to evaluate the embryo or oocyte quality through an informative approach. RESULTS: An evaluation model consisting of 17 features was generated to distinguish the embryo quality on day 3 post-fertilization, and phosphatidylcholines (PCs) were the key contributors to the evaluation. The model was extended to the patients under different ages and hyperstimulations, and the features were further enriched to facilitate the evaluation of the embryo quality. The metabolites were clustered through pathway analysis, leading to a hypothesis that accumulation of arachidonic acid induced by PCs might weaken embryo quality on day 3 post-fertilization. CONCLUSIONS: A discriminating model with metabolic features elicited from follicular fluid was established, which enabled the evaluation of the embryo or oocyte quality even under certain clinical conditions, and the increase of PCs in follicular fluid implies the attenuation of embryo quality on day 3 post-fertilization.

8.
Appl Environ Microbiol ; 87(20): e0098621, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34319792

RESUMO

The twilight zone (from the base of the euphotic zone to the depth of 1,000 m) is the major area of particulate organic carbon (POC) remineralization in the ocean, and heterotrophic microbes contribute to more than 70% of the estimated remineralization. However, little is known about the microbial community and metabolic activity directly associated with POC remineralization in this chronically understudied realm. Here, we characterized the microbial community proteomes of POC samples collected from the twilight zone of three contrasting sites in the Northwest Pacific Ocean using a metaproteomic approach. The particle-attached bacteria from Alteromonadales, Rhodobacterales, and Enterobacterales were the primary POC remineralizers. Hydrolytic enzymes, including proteases and hydrolases, that degrade proteinaceous components and polysaccharides, the main constituents of POC, were abundant and taxonomically associated with these bacterial groups. Furthermore, identification of diverse species-specific transporters and metabolic enzymes implied niche specialization for nutrient acquisition among these bacterial groups. Temperature was the main environmental factor driving the active bacterial groups and metabolic processes, and Enterobacterales replaced Alteromonadales as the predominant group under low temperature. This study provides insight into the key bacteria and metabolic processes involved in POC remineralization, and niche complementarity and species substitution among bacterial groups are critical for efficient POC remineralization in the twilight zone. IMPORTANCE The ocean's twilight zone is a critical zone where more than 70% of the sinking particulate organic carbon (POC) is remineralized. Therefore, the twilight zone determines the size of biological carbon storage in the ocean and regulates the global climate. Prokaryotes are major players that govern remineralization of POC in this region. However, knowledge of microbial community structure and metabolic activity is still lacking. This study unveiled microbial communities and metabolic activities of POC samples collected from the twilight zone of three contrasting environments in the Northwest Pacific Ocean using a metaproteomic approach. Alteromonadales, Rhodobacterales, and Enterobacterales were the major remineralizers of POC. They excreted diverse species-specific hydrolytic enzymes to split POC into solubilized POC or dissolved organic carbon. Temperature played a crucial role in regulating the community composition and metabolism. Furthermore, niche complementarity or species substitution among bacterial groups guaranteed the efficient remineralization of POC in the twilight zone.


Assuntos
Carbono/metabolismo , Microbiota , Água do Mar/microbiologia , Bactérias/isolamento & purificação , Proteínas de Bactérias/análise , Oceano Pacífico , Material Particulado , Proteoma
9.
Front Microbiol ; 12: 629802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841356

RESUMO

Solubilized particulate organic matter (POM) rather than dissolved organic matter (DOM) has been speculated to be the major carbon and energy sources for heterotrophic prokaryotes in the ocean. However, the direct evidence is still lack. Here we characterized microbial transport proteins of POM collected from both euphotic (75 m, deep chlorophyll maximum DCM, and 100 m) and upper-twilight (200 m and 500 m) zones in three contrasting environments in the northwest Pacific Ocean using a metaproteomic approach. The proportion of transport proteins was relatively high at the bottom of the euphotic zone (200 m), indicating that this layer was the most active area of microbe-driven POM remineralization in the water column. In the upper-twilight zone, the predicted substrates of the identified transporters indicated that amino acids, carbohydrates, taurine, inorganic nutrients, urea, biopolymers, and cobalamin were essential substrates for the microbial community. SAR11, Rhodobacterales, Alteromonadales, and Enterobacteriales were the key contributors with the highest expression of transporters. Interestingly, both the taxonomy and function of the microbial communities varied among water layers and sites with different environments; however, the distribution of transporter types and their relevant organic substrates were similar among samples, suggesting that microbial communities took up similar compounds and were functionally redundant in organic matter utilization throughout the water column. The similar vertical distribution of transport proteins from the euphotic zone to the upper twilight zone among the contrasting environments indicated that solubilized POM rather than DOM was the preferable carbon and energy sources for the microbial communities.

10.
Front Oncol ; 11: 615568, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708629

RESUMO

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

11.
Int J Med Sci ; 18(4): 953-963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33456353

RESUMO

RNA binding protein (RBPs) dysregulation has been reported in various malignant tumors and plays a pivotal role in tumor carcinogenesis and progression. However, the underlying mechanisms in renal cell carcinoma (RCC) are still unknown. In the present study, we performed a bioinformatics analysis using data from TCGA database to explore the expression and prognostic value of RBPs. We identified 125 differently expressed RBPs between tumor and normal tissue in RCC patients, including 87 upregulated and 38 downregulated RBPs. Eight RBPs (RPL22L1, RNASE2, RNASE3, EZH2, DDX25, DQX1, EXOSC5, DDX47) were selected as prognosis-related RBPs and used to construct a risk score model. In the risk score model, the high-risk subgroup had a poorer overall survival (OS) than the low-risk subgroup, and we divided the 539 RCC patients into two groups and conducted a time-dependent receiver operating characteristic (ROC) analysis to further test the prognostic ability of the eight hub RBPs. The area under the curve (AUC) of the ROC curve was 0.728 in train-group and 0.688 in test-group, indicating a good prognostic model. More importantly, we established a nomogram based on the selected eight RBPs. The eight selected RBPS have predictive value for RCC patients, with potential applications in clinical decision-making and individualized treatment.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Nomogramas , Proteínas de Ligação a RNA/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Tomada de Decisão Clínica/métodos , Conjuntos de Dados como Assunto , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/terapia , Masculino , Modelos Genéticos , Medicina de Precisão/métodos , Valor Preditivo dos Testes , RNA-Seq , Curva ROC , Medição de Risco/métodos
12.
Sci Total Environ ; 768: 144515, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33453542

RESUMO

Dinoflagellate blooming periods are paradoxically characterized by high biomass growth rate and low ambient dissolved CO2 and inorganic nutrients, however, the underlying mechanisms linking cell growth and nutrient acquisition are poorly understood. Here, we compared metaproteomes of non-bloom, mid-blooming and late-blooming cells of a marine dinoflagellate Prorocentrum donghaiense. Cell division, metabolism of carbon, nitrogen, phosphorus, lipid, porphyrin and chlorophyll were more active in blooming cells than in non-bloom cells. Up-regulation of carbonic anhydrase, ribulose-1,5-bisphosphate carboxylase/oxygenase II, and C4-cycle proteins enhanced CO2 assimilation of P. donghaiense. Proteins participating in external organic nutrient acquisition and conversion, such as transporters for fatty acids, peptides and amino acids, external- and internal-phosphomonoester hydrolase, and diverse peptidases and amino acid transaminases, exhibited higher expression in blooming cells relative to non-bloom cells. Interestingly, dissolved organic nitrogen (DON) such as urea and aspartate significantly down-regulated expression and activity of carbon assimilation proteins except for RuBisCO form II, suggesting that DON provided sufficient carbon source which reduced the need to concentrate internal CO2. This study demonstrates that coupling of efficient CO2 assimilation with DON utilization are essential for bloom maintenance of P. donghaiense, and future efforts should be devoted to dissolved organic nutrients for prevention and management of dinoflagelllate blooms.


Assuntos
Dinoflagelados , Dióxido de Carbono , Proliferação Nociva de Algas , Nutrientes , Fósforo
13.
Rapid Commun Mass Spectrom ; 34(19): e8869, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32562559

RESUMO

RATIONALE: Whether catabolic abnormalities of fatty acids exist in the skeletal muscle of type 2 diabetes mellitus (T2DM) has not been determined. In this study, we postulated that a systematic evaluation of the protein abundance and metabolic activity related to fatty acids in the skeletal muscle tissues of a T2DM mouse model was feasible to address this question. METHODS: Mitochondria were extracted from wild-type (WT) and db/db mice followed by quantitative analysis of the proteins involved in mitochondrial fatty acid oxidation (mFAO). The pathway activity of mFAO in skeletal muscle tissues was monitored in vitro using mass spectrometry, and tissue lipidomic analysis was conducted in profiling and target mode to distinguish the levels of long-chain acylcarnitines between WT and db/db mice. RESULTS: Two proteins related to the mFAO pathway were significantly downregulated in the skeletal muscle mitochondria of db/db mice. The measurement of mFAO pathway activity in vitro revealed that the abundance of long-chain acylcarnitines (C14 to C18) in db/db mice was lower than that in WT mice, and the determination of acylcarnitines in skeletal muscle tissues in vivo revealed that most long-chain acylcarnitines were decreased in db/db mice. CONCLUSIONS: The findings of lower abundance of ACAD9 and CPT1B, reduced activity of the mFAO pathway in vitro and decreased acylcarnitines in vivo firmly support that the mFAO pathway in the skeletal muscle of diabetic mice is attenuated, possibly resulting in cell/tissue dysfunction in diabetes.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/citologia , Animais , Diabetes Mellitus Experimental , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Lipidômica , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Espectrometria de Massas em Tandem
14.
Mamm Genome ; 31(7-8): 197-204, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32556998

RESUMO

Prostate cancer, the second most common cancer among male adults, affects millions globally. We sought to investigate the expression and contribution of Eukaryotic translation initiation factor 3 subunit b (EIF3B) in prostate cancer. Expression of EIF3B was analyzed in both human prostate patient tissues and prostate cancer cell lines. Small interfering RNA (siRNA) knockdown of EIF3B was introduced into prostate cancer cell line PC-3 and LNCaP, followed by examination of cell viability, proliferation and apoptosis using the MTT, cell counting and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, respectively. An in vivo xenograft tumor mouse model was employed to address the role of EIF3B in tumorigenesis as well. Finally, a gene microarray analysis was performed to search for differentially expressed genes upon EIF3B knockdown. EIF3B was upregulated in prostate tumor tissues and prostate cancer cell lines. EIF3B knockdown inhibited viability and proliferation of prostate cancer cells, as well as promoted cell apoptosis. In the in vivo mouse model, inoculation of EIF3B knockdown PC-3 cells displayed inhibited growth of xenograft tumors. In addition, potential signaling pathways that might be involved in EIF3B action in prostate cancer were identified by the gene microarray. EIF3B is a novel oncogenic factor in prostate cancer both in vitro and in vivo, which could be employed as a novel therapeutic target in the treatment against prostate cancer.


Assuntos
Fator de Iniciação 3 em Eucariotos/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Neoplasias da Próstata/etiologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais
15.
Aging (Albany NY) ; 12(10): 8880-8892, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32428870

RESUMO

lncRNA can interact with miRNA as a ceRNA to participate in the regulation of target gene expression, thus playing an important role in the development of malignant tumors. In this research, we found that OGFRP1 was up-regulated in prostate cancer (PCa) clinical samples and cell lines. Additionally, OGFRP1 is significantly associated with TNM stages III and IV and perineural invasion. Knockdown of OGFRP1 inhibited the growth of PCa cells, suggesting a promotional effect of OGFRP1 in tumor progression. Interestingly, OGFRP1 primarily localized in the cytoplasm, while miR-124-3p was found to bind to OGFRP1. Therefore, we further analyzed the downstream target of miR-124-3p using TargetScan. The result of the luciferase reporter gene assay displayed that SARM1 was a downstream target of miR-124-3p in two PCa cell lines. The overexpression of SARM1 promoted growth and metastasis in PCa cells. Knockdown of OGFRP1 and overexpression of miR-124-3p markedly restored the promotion of SARM1 to PCa cells. In conclusion, lncRNA OGFRP1 completely bound to miR-124-3p and relieved their inhibition on SARM1, thus promoting the growth of PCa cells. This report extended our understanding of the underlying molecular mechanisms of lncRNAs in PCa, which could help us find novel diagnostic and therapeutic targets.


Assuntos
Proteínas do Domínio Armadillo , Proteínas do Citoesqueleto , MicroRNAs , Neoplasias da Próstata , RNA Longo não Codificante , Proteínas do Domínio Armadillo/genética , Proteínas do Domínio Armadillo/metabolismo , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
16.
Cell Biochem Funct ; 38(5): 574-581, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32032976

RESUMO

Renal cell carcinoma (RCC) is the seventh most common site for malignant tumours worldwide leading to a high risk of death. NKAP is a conserved nuclear protein that has critical roles in the development, maturation, and functional acquisition of T cells, iNKT cells, and cancers. But the function and underlying mechanism of NKAP in RCC is still unknown. Knockdown of NKAP by siRNA interference (siNKAP) was used to explore the roles of NAKP in human RCC cells. Here, we found that siNKAP strongly inhibited the proliferation and motility of Ketr-3 and 786-0 cells and induced cell apoptosis. Furthermore, the expression of anti-apoptotic protein Bcl2 in the siNKAP group was strongly decreased, while the expression of pro-apoptotic proteins Bax, cleaved Caspase-3, and cleaved Caspase-9 was significantly increased. Finally, to identify the potential mechanisms, we detected related proteins of the AKT/mTOR signalling pathway by western blot assay. We found that siNKAP significantly inhibited the expression of cyclin D1 and the phosphorylation of AKT and mTOR. The findings for the first time reveal that the AKT/mTOR signalling pathway is involved in the oncogenic role of NKAP in RCC, which provides an important basis for exploring the molecular regulation mechanism of RCC. SIGNIFICANCE OF THE STUDY: There is an urgent need to study the molecular mechanisms involved in RCC to promote the development of early diagnosis and more effective treatment options. This research provides an important basis for exploring the accurate regulatory mechanism of NKAP in RCC and a novel perspective to find the potential utility of NKAP inhibitors for RCC therapy.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Apoptose , Carcinoma de Células Renais/patologia , Proliferação de Células , Humanos , Neoplasias Renais/patologia , Transdução de Sinais , Células Tumorais Cultivadas
17.
J Cell Mol Med ; 23(2): 1396-1405, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30467945

RESUMO

Exosomes are small membrane vesicles released by many cells. These vesicles can mediate cellular communications by transmitting active molecules including long non-coding RNAs (lncRNAs). In this study, our aim was to identify a panel of lncRNAs in serum exosomes for the diagnosis and recurrence prediction of bladder cancer (BC). The expressions of 11 candidate lncRNAs in exosome were investigated in training set (n = 200) and an independent validation set (n = 320) via quantitative real-time PCR. A three-lncRNA panel (PCAT-1, UBC1 and SNHG16) was finally identified by multivariate logistic regression model to provide high diagnostic accuracy for BC with an area under the receiver-operating characteristic curve (AUC) of 0.857 and 0.826 in training set and validation set, respectively, which was significantly higher than that of urine cytology. The corresponding AUCs of this panel for patients with Ta, T1 and T2-T4 were 0.760, 0.827 and 0.878, respectively. In addition, Kaplan-Meier analysis showed that non-muscle-invasive BC (NMIBC) patients with high UBC1 expression had significantly lower recurrence-free survival (P = 0.01). Multivariate Cox analysis demonstrated that UBC1 was independently associated with tumour recurrence of NMIBC (P = 0.018). Our study suggested that lncRNAs in serum exosomes may serve as considerable diagnostic and prognostic biomarkers of BC.


Assuntos
Biomarcadores Tumorais/genética , Exossomos/genética , Recidiva Local de Neoplasia/diagnóstico , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/diagnóstico , Estudos de Casos e Controles , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Curva ROC , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/cirurgia
18.
Mol Cancer ; 17(1): 142, 2018 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-30268126

RESUMO

Recently, expression signatures of exosomal long non-coding RNAs (lncRNAs) have been proposed as potential non-invasive biomarkers for cancer detection. In this study, we aimed to develop a urinary exosome (UE)-derived lncRNA panel for diagnosis and recurrence prediction of bladder cancer (BC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to screen and evaluate the expressions of eight candidate lncRNAs in a training set (208 urine samples) and a validation set (160 urine samples). A panel consisting of three differently expressed lncRNAs (MALAT1, PCAT-1 and SPRY4-IT1) was established for BC diagnosis in the training set, showing an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.854. Subsequently, the performance of the panel was further verified with an AUC of 0.813 in the validation set, which was significantly higher than that of urine cytology (0.619). In addition, Kaplan-Meier analysis suggested that the up-regulation of PCAT-1 and MALAT1 was associated with poor recurrence-free survival (RFS) of non-muscle-invasive BC (NMIBC) (p < 0.001 and p = 0.002, respectively), and multivariate Cox proportional hazards regression analysis revealed that exosomal PCAT-1 overexpression was an independent prognostic factor for the RFS of NMIBC (p = 0.018). Collectively, our findings indicated that UE-derived lncRNAs possessed considerable clinical value in the diagnosis and prognosis of BC.


Assuntos
Biomarcadores Tumorais , Ácidos Nucleicos Livres , Exossomos , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Exossomos/metabolismo , Exossomos/ultraestrutura , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Biópsia Líquida , Recidiva Local de Neoplasia , Prognóstico , Estabilidade de RNA , RNA Longo não Codificante/urina , Curva ROC , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/urina
19.
J Cell Mol Med ; 22(5): 2838-2845, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29516641

RESUMO

Cell-free long non-coding RNAs (lncRNAs) are stably present in urine and can serve as non-invasive biomarkers for cancer. We aimed to identify signatures of lncRNAs in urine for diagnosis and prognosis of bladder cancer (BC). Screening of lncRNAs by microarray analysis was performed using urine samples of 10 BC patients and 10 controls. Expressions of candidate lncRNAs were evaluated in the training and validation set including 230 BC patients and 230 controls by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A two-lncRNA panel (uc004cox.4 and GAS5) was constructed and provided high diagnostic accuracy of BC with an area under the curve (AUC) of 0.885 (95% CI, 0.836-0.924). The AUCs of the lncRNA panel for Ta, T1 and T2-T4 were 0.843, 0.867 and 0.923, respectively, significantly higher than those of urine cytology (all P < .05). Kaplan-Meier analysis revealed that higher level of uc004cox.4 was associated with poor recurrence-free survival (RFS) of non-muscle invasive BC (NMIBC) (P = .008). Additionally, Cox regression analysis indicated that uc004cox.4 was an independent prognostic factor for RFS of NMIBC (P = .018). Taken together, our findings indicated that urinary lncRNA signatures possessed potential clinical value for BC diagnosis. Moreover, uc004cox.4 could provide prognostic information for NMIBC.


Assuntos
Biomarcadores Tumorais/urina , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Sistema Livre de Células , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Neoplasias da Bexiga Urinária/urina
20.
Oncotarget ; 8(25): 40832-40842, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28388561

RESUMO

Urinary microRNAs (miRNAs) are potential biomarkers for the noninvasive diagnosis of bladder cancer (BC). In this study, we aimed to develop a urinary miRNAs panel for diagnosing and predicting recurrence of BC. Genome-wide miRNAs analysis by deep sequencing followed by two phases of quantitative real-time PCR assays were performed on urine supernatant of 276 BC patients and 276 controls. We identified a seven-miRNA panel (miR-7-5p, miR-22-3p, miR-29a-3p, miR-126-5p, miR-200a-3p, miR-375, and miR-423-5p) that provided high diagnostic accuracy of BC with an AUC of 0.923 and 0.916 in training and validation set, respectively. The corresponding AUCs of this panel for Ta, T1 and T2-T4 were 0.864, 0.930 and 0.978, significantly higher than those of urine cytology, which were 0.531, 0.628 and 0.724, respectively (all p < 0.05). Moreover, Kaplan-Meier analysis showed that nonmuscle-invasive BC (NMIBC) patients with high miR-22-3p and low miR-200a-3p level had worse recurrence-free survival (RFS) (p = 0.002 and 0.040, respectively). Multivariate Cox regression analysis revealed that miR-22-3p and miR-200a-3p were independently associated with RFS of NMIBC (p = 0.024 and 0.008, respectively). In conclusion, our results suggested that urinary miRNAs may have considerable clinical value in diagnosis and recurrence prediction of BC.


Assuntos
Biomarcadores Tumorais/urina , MicroRNA Circulante/urina , Neoplasias da Bexiga Urinária/urina , Idoso , Biomarcadores Tumorais/genética , Sistema Livre de Células , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/urina , Prognóstico , Neoplasias da Bexiga Urinária/genética
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