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1.
Nucleic Acids Res ; 48(10): 5572-5590, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32365187

RESUMO

RNA decay is a key element of mitochondrial RNA metabolism. To date, the only well-documented machinery that plays a role in mtRNA decay in humans is the complex of polynucleotide phosphorylase (PNPase) and SUV3 helicase, forming the degradosome. REXO2, a homolog of prokaryotic oligoribonucleases present in humans both in mitochondria and the cytoplasm, was earlier shown to be crucial for maintaining mitochondrial homeostasis, but its function in mitochondria has not been fully elucidated. In the present study, we created a cellular model that enables the clear dissection of mitochondrial and non-mitochondrial functions of human REXO2. We identified a novel mitochondrial short RNA, referred to as ncH2, that massively accumulated upon REXO2 silencing. ncH2 degradation occurred independently of the mitochondrial degradosome, strongly supporting the hypothesis that ncH2 is a primary substrate of REXO2. We also investigated the global impact of REXO2 depletion on mtRNA, revealing the importance of the protein for maintaining low steady-state levels of mitochondrial antisense transcripts and double-stranded RNA. Our detailed biochemical and structural studies provide evidence of sequence specificity of the REXO2 oligoribonuclease. We postulate that REXO2 plays dual roles in human mitochondria, 'scavenging' nanoRNAs that are produced by the degradosome and clearing short RNAs that are generated by RNA processing.


Assuntos
Proteínas 14-3-3/metabolismo , Biomarcadores Tumorais/metabolismo , Exorribonucleases/metabolismo , Processamento Pós-Transcricional do RNA , Estabilidade de RNA , RNA de Cadeia Dupla/metabolismo , RNA Mitocondrial/metabolismo , Proteínas 14-3-3/química , Proteínas 14-3-3/fisiologia , Biomarcadores Tumorais/química , Biomarcadores Tumorais/fisiologia , Exorribonucleases/química , Exorribonucleases/fisiologia , Células HeLa , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Multimerização Proteica , Especificidade por Substrato
2.
PLoS One ; 15(5): e0232029, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374732

RESUMO

BACKGROUND: Translationally controlled tumor protein (TCTP) is a conserved, multifunctional protein involved in numerous cellular processes in eukaryotes. Although the functions of TCTP have been investigated sporadically in animals, invertebrates, and plants, few lineage-specific activities of this molecule, have been reported. An exception is in Arabidopsis thaliana, in which TCTP (AtTCTP1) functions in stomatal closuer by regulating microtubule stability. Further, although the development of next-generation sequencing technologies has facilitated the analysis of many eukaryotic genomes in public databases, inter-kingdom comparative analyses using available genome information are comparatively scarce. METHODOLOGY: To carry out inter-kingdom comparative analysis of TCTP, TCTP genes were identified from 377 species. Then phylogenetic analysis, prediction of protein structure, molecular docking simulation and molecular dynamics analysis were performed to investigate the evolution of TCTP genes and their binding proteins. RESULTS: A total of 533 TCTP genes were identified from 377 eukaryotic species, including protozoa, fungi, invertebrates, vertebrates, and plants. Phylogenetic and secondary structure analyses reveal lineage-specific evolution of TCTP, and inter-kingdom comparisons highlight the lineage-specific emergence of, or changes in, secondary structure elements in TCTP proteins from different kingdoms. Furthermore, secondary structure comparisons between TCTP proteins within each kingdom, combined with measurements of the degree of sequence conservation, suggest that TCTP genes have evolved to conserve protein secondary structures in a lineage-specific manner. Additional tertiary structure analysis of TCTP-binding proteins and their interacting partners and docking simulations between these proteins further imply that TCTP gene variation may influence the tertiary structures of TCTP-binding proteins in a lineage-specific manner. CONCLUSIONS: Our analysis suggests that TCTP has undergone lineage-specific evolution and that structural changes in TCTP proteins may correlate with the tertiary structure of TCTP-binding proteins and their binding partners in a lineage-specific manner.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/fisiologia , Evolução Molecular , Especiação Genética , Sequência de Aminoácidos , Animais , Biomarcadores Tumorais/química , Sequência Conservada , Células Eucarióticas/classificação , Células Eucarióticas/metabolismo , Fungos/classificação , Fungos/genética , Humanos , Invertebrados/classificação , Invertebrados/genética , Mamíferos/classificação , Mamíferos/genética , Simulação de Acoplamento Molecular , Filogenia , Células Vegetais/classificação , Células Vegetais/metabolismo , Células Procarióticas/classificação , Células Procarióticas/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína , Especificidade da Espécie
3.
J Neurooncol ; 147(1): 49-58, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31953611

RESUMO

INTRODUCTION: Progression-free survival (PFS) in glioma patients varies widely, even when stratifying for known predictors (i.e. age, molecular tumor subtype, presence of epilepsy, tumor grade and Karnofsky performance status). Neuronal activity has been shown to accelerate tumor growth in an animal model, suggesting that brain activity may be valuable as a PFS predictor. We investigated whether postoperative oscillatory brain activity, assessed by resting-state magnetoencephalography is of additional value when predicting PFS in glioma patients. METHODS: We included 27 patients with grade II-IV gliomas. Each patient's oscillatory brain activity was estimated by calculating broadband power (0.5-48 Hz) in 56 epochs of 3.27 s and averaged over 78 cortical regions of the Automated Anatomical Labeling atlas. Cox proportional hazard analysis was performed to test the predictive value of broadband power towards PFS, adjusting for known predictors by backward elimination. RESULTS: Higher broadband power predicted shorter PFS after adjusting for known prognostic factors (n = 27; HR 2.56 (95% confidence interval (CI) 1.15-5.70); p = 0.022). Post-hoc univariate analysis showed that higher broadband power also predicted shorter overall survival (OS; n = 38; HR 1.88 (95% CI 1.00-3.54); p = 0.038). CONCLUSIONS: Our findings suggest that postoperative broadband power is of additional value in predicting PFS beyond already known predictors.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirurgia , Ondas Encefálicas , Glioma/diagnóstico , Glioma/cirurgia , Adulto , Biomarcadores Tumorais/fisiologia , Neoplasias Encefálicas/fisiopatologia , Proteínas Correpressoras , Feminino , Glioma/fisiopatologia , Humanos , Magnetoencefalografia , Masculino , Período Pós-Operatório , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
4.
Expert Rev Gastroenterol Hepatol ; 14(2): 85-92, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31922886

RESUMO

Introduction: In recent years, circular RNAs (circRNAs) have emerged in the field of RNA research and their biological functions are now being gradually identified. circRNAs are divided into three categories: exonic circular RNAs (ecircRNAs), exon-intron circular RNAs (EIciRNAs), and intronic circular RNAs (ciRNAs). The circular structure of circRNAs confers unique biological characteristics upon them, such as enhanced stability over linear RNAs.Areas covered: circRNAs function to competitively bind with microRNAs (miRNAs) and proteins, participate in protein coding, regulate transcription, and form pseudogenes after reverse transcription. In gastric cancer, the circRNA-miRNA-mRNA axis is the most studied mechanisms underlying gastric cancer occurrence and development. Some specific and sensitive circRNAs, such as hsa_circ_102958, hsa_circ_0000520, and hsa_circ_0001017 may have potential diagnostic potential in early-stage gastric cancer. Abnormal expression of some circRNAs, including circ-LMTK2, circ-PSMC3, and circ-DLST are associated with the development of gastric cancer. Other circRNAs, such as hsa_circ_0001368, circ-ZFR, and circ-ERBB2, may also play important roles in gastric cancer treatment.Expert opinion: Exploring the roles of circRNAs in gastric cancer occurrence and development will help us to elucidate the functions of circRNAs and develop potential tools for early diagnosis and effective treatment of gastric cancer.


Assuntos
RNA Circular/fisiologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/classificação , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/fisiologia , Humanos , Terapia de Alvo Molecular , RNA Circular/análise , RNA Circular/classificação , RNA Circular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/fisiopatologia
5.
Am J Physiol Cell Physiol ; 318(3): C542-C554, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913695

RESUMO

Chemokines are a family of soluble cytokines that act as chemoattractants to guide the migration of cells, in particular of immune cells. However, chemokines are also involved in cell proliferation, differentiation, and survival. Chemokines are associated with a variety of human diseases including chronic inflammation, immune dysfunction, cancer, and metastasis. This review discusses the expression of CC and CXC chemokines in the tumor microenvironment and their supportive and inhibitory roles in tumor progression, angiogenesis, metastasis, and tumor immunity. We also specially focus on the diverse roles of CXC chemokines (CXCL9-11, CXCL4 and its variant CXCL4L1) and their two chemokine receptor CXCR3 isoforms, CXCR3-A and CXCR3-B. These two distinct isoforms have divergent roles in tumors, either promoting (CXCR3-A) or inhibiting (CXCR3-B) tumor progression. Their effects are mediated not only directly in tumor cells but also indirectly via the regulation of angiogenesis and tumor immunity. A full comprehension of their mechanisms of action is critical to further validate these chemokines and their receptors as biomarkers or therapeutic targets in cancer.


Assuntos
Biomarcadores Tumorais/fisiologia , Quimiocina CXCL9/fisiologia , Fator Plaquetário 4/fisiologia , Receptores CXCR3/fisiologia , Microambiente Tumoral/fisiologia , Animais , Progressão da Doença , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia
6.
Exp Cell Res ; 389(1): 111861, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31981592

RESUMO

SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family. Although it was reported that SETD5 gene mutations are associated with the several types of human cancer, its functional role in esophageal squamous cell carcinoma (ESCC) progression has not been fully elucidated. In the present study, we used tissue samples from 147 patients with ESCC and ESCC cell lines to determine the clinicopathological significance of SETD5 in ESCC and its effects on ESCC stemness. We performed immunohistochemical staining, immunofluorescence imaging, and tumor sphere formation, colony formation, flow cytometry, wound healing, Transwell, and western blotting assays. SETD5 expression was upregulated in ESCC tissue and associated with primary tumor (pT) stage, clinical stage, lymph node metastasis, shorter overall survival rate, and disease-free survival rate. Cox regression analyses indicated that SETD5 is an independent poor prognostic factor of ESCC. In addition, SETD5 expression was correlated with cancer stemness-related protein, hypoxia-inducible factor-1α (HIF-1α), and CD68 expression. Moreover, immunofluorescence analysis revealed that SETD5 was co-localized with CD44 and SOX2 in TE10 and TE11 cells and that exposing cells to cobalt chloride increased HIF-1α, SETD5, and stemness-related protein expression in a time-dependent manner. Furthermore, SETD5 expression was significantly correlated with the expression of cell cycle-related genes and PI3K/Akt signaling pathway-related proteins. Finally, knocking down SETD5 downregulated the expression of stemness-related and PI3K/Akt signaling pathway proteins, while inhibiting tumor spheroid formation, cell proliferation, migration, and invasion in ESCC cells. These results indicate that SETD5 expression is associated with cancer stemness and that SETD5 is a potential prognostic biomarker and therapeutic target for ESCC.


Assuntos
Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/patologia , Metiltransferases/fisiologia , Células-Tronco Neoplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/fisiologia , Progressão da Doença , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Prognóstico , RNA Interferente Pequeno/farmacologia , Células Tumorais Cultivadas
7.
Biochimie ; 167: 42-48, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31509760

RESUMO

Gastrokine1 (GKN1), important for maintaining the physiological function of the gastric mucosa, is highly expressed in the stomach of healthy individuals but is down-regulated or absent in gastric tumor tissues and derived cell lines. The mechanisms underlying GKN1 gene inactivation are still unknown. We previously showed that GKN1 downregulation in gastric tumors is likely associated with an epigenetic transcriptional complex that negatively regulates GKN1 expression. In addition, TSA-mediated inhibition of HDACs leads to GKN1 restoration at the transcriptional level, but no at the translational level. These findings led to hypothesize the activation of a second regulatory mechanism microRNAs-mediated, thus resulting in translational repression and gene silencing. Bioinformatic analyses performed with 5 different algorithms highlighted that 4 miRNAs contained a seed sequence for the 3'UTR of GKN1 mRNA. Among these, only two miRNAs, hsa-miR-544a and miR-1245b-3p directly target the GKN1-3'UTR as evaluated by luciferase reporter assays. TaqMan miRNA assay performed on gastric cancer cell lines after TSA treatment showed a stronger increase of miR-544a expression than that of miR-1245b-3p. Finally, co-transfection of AGS cells with GKN1-3'UTR and premiR-544a showed compared to controls, a strong reduction of GKN1 expression both at translational and transcriptional levels. The up-regulation of miR-544a could be crucially involved in the GKN1 translational repression, thus suggesting its potential role as a biomarker and therapeutic target in GC patients. These findings indicate that epigenetic mechanisms leading to the inactivation of GKN1 play a key role in the multi-step process of gastric carcinogenesis and would provide an essential starting point for the development of new therapeutic strategies based on epigenetic targets for alternatives gene.


Assuntos
Carcinogênese/metabolismo , MicroRNAs/fisiologia , Hormônios Peptídicos/metabolismo , Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/fisiologia , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação para Baixo , Mucosa Gástrica/metabolismo , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células HEK293 , Humanos , Hormônios Peptídicos/genética , Neoplasias Gástricas/genética
8.
Breast Cancer Res ; 21(1): 105, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511085

RESUMO

BACKGROUND: In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYßB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYßB2 pseudogene, CRYßB2P1, and not CRYßB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYßB2 and CRYßB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYßB2 and CRYßB2P1 to racial disparities. METHODS: Custom scripts for CRYßB2 or CRYßB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. RESULTS: We provide evidence that CRYßB2P1 is expressed at higher levels in breast tumors compared to CRYßB2, but only CRYßB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYßB2, CRYßB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYßB2P1 may function as a non-coding RNA to regulate CRYßB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYßB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYßB2 and CRYßB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. CONCLUSIONS: Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYßB2 and CRYßB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Pseudogenes/fisiologia , Cadeia B de beta-Cristalina/fisiologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/fisiologia , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Grupos Étnicos/genética , Feminino , Expressão Gênica , Estudos de Associação Genética , Humanos , Interleucina-6/metabolismo , Neoplasias Mamárias Experimentais , Camundongos , Camundongos Nus , Pseudogenes/genética , Neoplasias de Mama Triplo Negativas/etnologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Cadeia B de beta-Cristalina/genética , Cadeia B de beta-Cristalina/metabolismo
9.
Acta Biochim Biophys Sin (Shanghai) ; 51(9): 953-959, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31435668

RESUMO

LncRNA MIR4435-2HG is characterized as an oncogene in lung cancer. However, its role in ovarian carcinoma (OC) is unclear. In this study, we aimed to investigate the role of MIR4435-2HG in OC. We found that both MIR4435-2HG and transforming growth factor beta 1 (TGF-ß1) were upregulated in OC. MIR4435-2HG is associated with tumor metastasis but not with tumor size. Upregulation of MIR4435-2HG distinguished early stage (Stage I and II) OC patients from healthy controls. Correlation analysis showed that plasma levels of MIR4435-2HG and TGF-ß1 were positively correlated only in OC patients. qPCR and western blot analysis results showed that MIR4435-2HG overexpression led to upregulation of TGF-ß1 in OC cells, while TGF-ß1 treatment did not significantly affect MIR4435-2HG expression. Transwell invasion and migration assays showed that MIR4435-2HG and TGF-ß1 promoted the invasion and migration of OC cells while TGF-ß inhibitor suppressed the invasion and migration of these cells. Further analysis of the Transwell invasion and migration assay results showed that TGF-ß inhibitor reduced the effects of MIR4435-2HG overexpression. Therefore, our results suggested that lncRNA MIR4435-2HG may promote OC by upregulating TGF-ß1. Further characterization of the functions of MIR4435-2HG in OC may provide novel targets for cancer therapies.


Assuntos
Biomarcadores Tumorais/fisiologia , Carcinoma/diagnóstico , MicroRNAs/fisiologia , Neoplasias Ovarianas/diagnóstico , RNA Longo não Codificante/fisiologia , Adulto , Idoso , Biomarcadores Tumorais/sangue , Carcinoma/sangue , Linhagem Celular Tumoral , Feminino , Humanos , MicroRNAs/sangue , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , RNA Longo não Codificante/sangue , Fator de Crescimento Transformador beta1/sangue
10.
PLoS Pathog ; 15(8): e1008002, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31404116

RESUMO

The galectin 3 binding protein (LGALS3BP, also known as 90K) is a ubiquitous multifunctional secreted glycoprotein originally identified in cancer progression. It remains unclear how 90K functions in innate immunity during viral infections. In this study, we found that viral infections resulted in elevated levels of 90K. Further studies demonstrated that 90K expression suppressed virus replication by inducing IFN and pro-inflammatory cytokine production. Upon investigating the mechanisms behind this event, we found that 90K functions as a scaffold/adaptor protein to interact with TRAF6, TRAF3, TAK1 and TBK1. Furthermore, 90K enhanced TRAF6 and TRAF3 ubiquitination and served as a specific ubiquitination substrate of TRAF6, leading to transcription factor NF-κB, IRF3 and IRF7 translocation from the cytoplasm to the nucleus. Conclusions: 90K is a virus-induced protein capable of binding with the TRAF6 and TRAF3 complex, leading to IFN and pro-inflammatory production.


Assuntos
Antígenos de Neoplasias/fisiologia , Biomarcadores Tumorais/fisiologia , Glicoproteínas/fisiologia , Fator 3 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Viroses/imunologia , Replicação Viral , Vírus/imunologia , Animais , Células Cultivadas , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Viroses/metabolismo , Viroses/virologia
11.
Biochimie ; 166: 223-232, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31362036

RESUMO

The 72-kDa type IV collagenase or gelatinase A is the second member of the matrix metalloproteinase family, MMP-2. Since the discovery of its first two substrates within components of the extracellular matrix, denatured interstitial type I collagen and native type IV collagen, the roles and various levels of regulation of MMP-2 have been intensively studied, mainly in vitro. Its (over)expression in most if not all tumors was considered a hallmark of cancer aggressiveness and boosted investigations aiming at its inhibition. Unfortunately, the enthusiasm subsided like a soufflé after clinical trial failures, mostly because of insufficient knowledge of in vivo MMP-2 activities and detrimental side effects of broad-spectrum MMP inhibition. Nowadays, MMP-2 remains a major topic of interest in research, the second in the MMP family after MMP-9. This review presents a broad overview of the major features of this protease. This knowledge is crucial to identify diagnostic or therapeutic strategies focusing on MMP-2. In this sense, recent publications and clinical trials underline the potential value of measuring circulating or tissular MMP-2 levels as diagnostic or prognostic tools, or as a useful secondary outcome for therapies against other primary targets. Direct MMP-2 inhibition has benefited from substantial progress in the design of more specific inhibitors but their in vivo application remains challenging but certainly worth the efforts it receives.


Assuntos
Metaloproteinase 2 da Matriz , Inibidores de Metaloproteinases de Matriz/farmacologia , Neoplasias/enzimologia , Biomarcadores Tumorais/química , Biomarcadores Tumorais/fisiologia , Colágeno Tipo I/metabolismo , Colágeno Tipo IV/metabolismo , Humanos , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/fisiologia , Células Tumorais Cultivadas
12.
Cell Signal ; 63: 109377, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31362044

RESUMO

The prominent role of CD44 in tumor cell signaling together with its establishment as a cancer stem cell (CSC) marker for various tumor entities imply a key role for CD44 in CSC functional properties. Hyaluronan, the main ligand of CD44, is a major constituent of CSC niche and, therefore, the hyaluronan-CD44 signaling axis is of functional importance in this special microenvironment. This review aims to provide recent advances in the importance of hyaluronan-CD44 interactions in the acquisition and maintenance of a CSC phenotype. Hyaluronan-CD44 axis has a substantial impact on stemness properties of CSCs and drug resistance through induction of EMT program, oxidative stress resistance, secretion of extracellular vesicles/exosomes and epigenetic control. Potential therapeutic approaches targeting CSCs based on the hyaluronan-CD44 axis are also presented.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores de Hialuronatos/fisiologia , Ácido Hialurônico/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Biomarcadores Tumorais/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos
13.
Cell Mol Life Sci ; 76(21): 4203-4219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300868

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular/métodos , RNA Neoplásico/metabolismo , RNA não Traduzido/metabolismo
15.
Oncogene ; 38(35): 6301-6318, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31312022

RESUMO

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.


Assuntos
Fator 4 Ativador da Transcrição/fisiologia , Biomarcadores Tumorais/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/metabolismo , Resposta a Proteínas não Dobradas/genética , Animais , Proliferação de Células/genética , Estresse do Retículo Endoplasmático/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/genética , Células Tumorais Cultivadas
16.
J Transl Med ; 17(1): 192, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174544

RESUMO

BACKGROUND: Gastric cancer (GC) remains a refractory cancer worldwide. Currently, exploring the differences of the immune status in GC patients with different subgroups might provide promising immunotherapeutic approaches for the treatment of GC. METHODS: In this study, a total of 598 surgically resected FFPE primary gastric cancer samples were assessed for FOXP3, CD163, CD3, CD8, and PD-L1 markers. The correlations between the immune markers expression and clinicopathological features and prognosis were investigated retrospectively. RESULTS: In general, PD-L1, CD3, and CD8 could be regarded as favorable prognostic factors. Our data demonstrated that high infiltration of FOXP3+ Treg indicates better prognosis in stage I-II patients, while the converse outcome was noted in stage III-IV patients. Our data also confirmed different prognostic value in different pathological classifications, chemotherapy strategies, and locations, with or without lymph node metastasis. Also, M2 macrophages indicated poor prognosis in general. However, high M2 macrophage infiltration suggests a favorable prognosis in signet ring cell carcinoma and mucinous adenocarcinoma. Moreover, the prognostic value of the two indices when they are combined is reported. CONCLUSIONS: These results suggested that different immune statuses are exhibited in different subgroups of GC, which may direct further understanding of the immune status of GC as well as provide a further theoretical basis and potential targets for GC immunotherapy.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/fisiologia , Macrófagos/fisiologia , Neoplasias Gástricas/diagnóstico , Linfócitos T Reguladores/fisiologia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Linfócitos do Interstício Tumoral/patologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/patologia , Microambiente Tumoral/imunologia
17.
Cells ; 8(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083325

RESUMO

The partner of activated epidermal growth factor receptor (EGFR), growth factor receptor bound protein-7 (Grb7), a functionally multidomain adaptor protein, has been demonstrated to be a pivotal regulator for varied physiological and pathological processes by interacting with phospho-tyrosine-related signaling molecules to affect the transmission through a number of signaling pathways. In particular, critical roles of Grb7 in erythroblastic leukemia viral oncogene homolog (ERBB) family-mediated cancer development and malignancy have been intensively evaluated. The overexpression of Grb7 or the coamplification/cooverexpression of Grb7 and members of the ERBB family play essential roles in advanced human cancers and are associated with decreased survival and recurrence of cancers, emphasizing Grb7's value as a prognostic marker and a therapeutic target. Peptide inhibitors of Grb7 are being tested in preclinical trials for their possible therapeutic effects. Here, we review the molecular, functional, and clinical aspects of Grb7 in ERBB family-mediated cancer development and malignancy with the aim to reveal alternative and effective therapeutic strategies.


Assuntos
Biomarcadores Tumorais , Proteína Adaptadora GRB7 , Neoplasias/metabolismo , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/fisiologia , Receptores ErbB/metabolismo , Proteína Adaptadora GRB7/química , Proteína Adaptadora GRB7/metabolismo , Proteína Adaptadora GRB7/fisiologia , Humanos , Neoplasias/terapia , Transdução de Sinais
18.
Gene ; 704: 91-96, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30965130

RESUMO

LncRNA CASC11 is a recently identified oncogenic lncRNA in colorectal cancer. This study aimed to investigate the role of lncRNA CASC11 in small cell lung cancer (SCLC). In the present study, expression levels of CASC11 and TGF-ß1 were found to be positively and significantly correlated with the percentage of CDD133+ cells of SCLC cell lines. Plasma CASC11 and TGF-ß1 were upregulated and positively correlated in SCLC patients, but not in healthy controls. Upregulation of plasma CASC11 and TGF-ß1 predicted poor survival of SCLC patients. Overexpression of CASC11 and TGF-ß1 also resulted in the increased percentage of CDD133+ cells of SCLC cell lines, while TGF-ß inhibitor attenuated the effects of CASC11 overexpression. CASC11 overexpression mediated the upregulation of TGF-ß1 in SCLC cells, while treatment with exogenous TGF-ß1 showed no significant effect on CASC11. Therefore, lncRNA CASC11 promotes TGF-ß1, increases cancer cell stemness and predicts postoperative survival in SCLC.


Assuntos
Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Células-Tronco Neoplásicas/fisiologia , RNA Longo não Codificante/fisiologia , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/cirurgia , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Biomarcadores Tumorais/fisiologia , Estudos de Casos e Controles , Proliferação de Células/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Período Pós-Operatório , Prognóstico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Análise de Sobrevida , Resultado do Tratamento , Regulação para Cima/genética
19.
Neural Dev ; 14(1): 6, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30867000

RESUMO

BACKGROUND: Purkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology. METHODS: To resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development. RESULTS: Our results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists. CONCLUSIONS: Our data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.


Assuntos
Ataxia/fisiopatologia , Biomarcadores Tumorais/fisiologia , Proliferação de Células/fisiologia , Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Homeostase/fisiologia , Transtornos dos Movimentos/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Células de Purkinje/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Biomarcadores Tumorais/deficiência , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência
20.
Oncogene ; 38(25): 4990-5006, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30858545

RESUMO

Cancer cells associated with radioresistance are likely to give rise to local recurrence and distant metastatic relapse. However, it remains unclear whether specific miRNAs have direct roles in radioresistance and/or prognosis. In this study, we find that miR-339-5p promotes radiosensitivity, and is downregulated in radioresistant subpopulations of esophageal cancer cells. Notably, miR-339-5p was selectively secreted into blood via exosomes, and that higher serum miR-339-5p levels were positively associated with radiotherapy sensitivity and good survival. Moreover, miR-339-5p expression was downregulated in the T3/T4 stage compared with T1/T2 stage in esophageal squamous cell carcinoma (ESCC) patients (P = 0.04), and low miR-339-5p expression in tissue was significantly associated with poor overall survival (P = 0.036) and disease-free survival (P = 0.037). Overexpression of miR-339-5p enhanced radiosensitivity in vitro and in vivo. Mechanistically, miR-339-5p enhances radiosensitivity by targeting Cdc25A, and is transcriptionally regulated by Runx3. Correlations were observed between miR-339-5p levels and Cdc25A/Runx3 levels in tissue samples. Intriguingly, combined analysis of miR-339-5p expression with Runx3 increased the separation of the survival curves obtained for either gene alone in the TCGA datasets (P = 0.009). Overall, exosome-derived miR-339-5p mediates radiosensitivity through downregulation of Cdc25A, and predicts pathological response to preoperative radiotherapy in locally advanced ESCC, suggesting it could be a promising non-invasive biomarker for facilitating personalized treatments.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs/fisiologia , Tolerância a Radiação/genética , Fosfatases cdc25/genética , Animais , Biomarcadores Tumorais/fisiologia , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Prognóstico
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