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1.
Cancer Commun (Lond) ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34555274

RESUMO

BACKGROUND: Fascin is crucial for cancer cell filopodium formation and tumor metastasis, and is functionally regulated by post-translational modifications. However, whether and how Fascin is regulated by acetylation remains unclear. This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis. METHODS: Immunoprecipitation and glutathione-S-transferase pull-down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP-associated factor (PCAF), and immunofluorescence was used to investigate their colocalization. An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry. A specific antibody against acetylated Fascin was generated and used to detect the PCAF-mediated Fascin acetylation in esophageal squamous cell carcinoma (ESCC) cells using Western blotting by overexpressing and knocking down PCAF expression. An in vitro cell migration assay was performed, and a xenograft model was established to study in vivo tumor metastasis. Live-cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation. The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry. RESULTS: Fascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471 (K471) by PCAF. Using the specific anti-AcK471-Fascin antibody, Fascin was found to be acetylated in ESCC cells, and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown. Functionally, Fascin-K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis, whereas Fascin-K471 deacetylation exhibited a potent oncogenic function. Moreover, Fascin-K471 acetylation reduced filopodial length and density, and lifespan of ESCC cells, while its deacetylation produced the opposite effect. In the filipodium shaft, K471-acetylated Fascin displayed rapid dynamic exchange, suggesting that it remained in its monomeric form owing to its weakened actin-bundling activity. Clinically, high levels of AcK471-Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease-free survival of ESCC patients. CONCLUSIONS: Fascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells. Fascin-K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin-bundling activity.

2.
Cancer Lett ; 522: 171-183, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34571081

RESUMO

The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3ß (STAT3ß), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3ß contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3ß was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3ß blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3ß and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3ß sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3ß in ESCC therapy.

3.
Nucleic Acids Res ; 49(16): 9246-9263, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34370013

RESUMO

To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.

4.
Int J Biochem Cell Biol ; 139: 106056, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34390855

RESUMO

Fascin, one of actin bundling proteins, plays an important role in the cross-linking of actin filaments (F-actin). Phosphorylation of Fascin is an important posttranslational modification to affect its structure and function. For example, a phosphomimetic mutation of Fascin-S39D decrease its bundling ability with F-actin significantly. In this paper, we studied the actin-bundling activity of Fascin by using molecular dynamics (MD) simulations and biochemical methods. All single-site mutations from serine/threonine to aspartic acid were mimicked by MD simulations. For five mutants (S146D, S156D, S218D, T239D and S259D), the mutated residues in domain 2 of Fascin were found to form salt-bridge interactions with an adjacent residue, indicating that mutations of these residues could potentially reduce actin-bundling activity. Further, F-actin-bundling assays and immunofluorescence technique showed S146D and T239D to have a strong effect on Fascin bundling with F-actin. Finally, we show that single-site mutations do not change the general shape of Fascin, but local structures near the mutated residues in Fascin-S146D and T239D become unstable, thereby affecting the ability of Fascin to bind with F-actin. These findings suggest that targeting domain 2 of Fascin would be very useful for the drug design. In addition, our study indicates that MD simulation is a useful method to screening which residues on Fascin are important.

5.
Nat Commun ; 12(1): 4961, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400640

RESUMO

Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes-S1 and S2-based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.


Assuntos
Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Espectrometria de Massas/métodos , Proteômica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Estudos de Coortes , Elonguina/genética , Elonguina/metabolismo , Humanos , Prognóstico , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo
6.
Nat Commun ; 12(1): 4362, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272396

RESUMO

Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63), a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Metabolismo dos Lipídeos/genética , Neoplasias Pulmonares/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Acetilação , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sequenciamento de Cromatina por Imunoprecipitação , Cromatografia Líquida , Epigenômica , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Esofágicas/genética , Ácidos Graxos/biossíntese , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Histonas/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Pulmonares/genética , Elementos Reguladores de Transcrição , Transdução de Sinais/genética , Esfingolipídeos/biossíntese , Esfingolipídeos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Espectrometria de Massas em Tandem , Fatores de Transcrição/genética , Transcriptoma/genética , Proteínas Supressoras de Tumor/genética
7.
Amino Acids ; 53(8): 1197-1209, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34223992

RESUMO

Riboflavin is an essential micronutrient for normal cellular growth and function. Lack of dietary riboflavin is associated with an increased risk for esophageal squamous cell carcinoma (ESCC). Previous studies have identified that the human riboflavin transporter SLC52A3a isoform (encoded by SLC52A3) plays a prominent role in esophageal cancer cell riboflavin transportation. Furthermore, SLC52A3 gene single nucleotide polymorphisms rs3746804 (T>C, L267P) and rs3746803 (C >T, T278M) are associated with ESCC risk. However, whether SLC52A3a (p.L267P) and (p.T278M) act in riboflavin transportation in esophageal cancer cell remains inconclusive. Here, we constructed the full-length SLC52A3a protein fused to green fluorescent protein (GFP-SLC52A3a-WT and mutants L267P, T278M, and L267P/T278M). It was confirmed by immunofluorescence-based confocal microscopy that SLC52A3a-WT, L267P, T278M, and L267P/T278M expressed in cell membrane, as well as in a variety of intracellular punctate structures. The live cell confocal imaging showed that SLC52A3a-L267P and L267P/T278M increased the intracellular trafficking of SLC52A3a in ESCC cells. Fluorescence recovery after photobleaching of GFP-tagged SLC52A3a meant that intracellular trafficking of SLC52A3a-L267P and L267P/T278M was rapid dynamics process, leading to its stronger ability to transport riboflavin. Taken together, the above results indicated that the rs3746804 (p.L267P) polymorphism promoted intracellular trafficking of SLC52A3a and riboflavin transportation in ESCC cells.

8.
Cancers (Basel) ; 13(4)2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33670049

RESUMO

Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3ß regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic marker and a potential marker for response to adjuvant chemoradiotherapy (ACRT). We aimed to investigate the relationship between STAT3ß and CCRT. We examined the expression of STAT3α and STAT3ß in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3ß expression in the cytoplasm have a significantly better survival rate, and STAT3ß expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3ß expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3ß expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3ß enhances sensitivity to CCRT (platinum plus radiation therapy). Mechanistically, through RNA-seq analysis, we found that the TNF signaling pathway and necrotic cell death pathway were significantly upregulated in highly expressed STAT3ß cells after CCRT treatment. Overall, our study highlights that STAT3ß could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC.

9.
Eur J Nutr ; 60(2): 807-820, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32458157

RESUMO

PURPOSE: Riboflavin deficiency causes ariboflavinosis, a common nutritional deficiency disease. The purpose of this study is to investigate the effects of riboflavin deficiency on the important internal organs and its potential mechanisms. METHODS: Experiment 1, male F344 rats were randomly assigned to R6 (normal riboflavin, 6 mg/kg) and R0 (riboflavin-deficient, 0 mg/kg) groups. Experiment 2 rats were assigned to R6, R0.6 (0.6 mg/kg) and R0.06 (0.06 mg/kg) groups. Experiment 3 rats were assigned to R6 and R0 → R6 (riboflavin replenishment) groups. Bacterial communities were analyzed based on 16S rRNA gene sequencing. RESULTS: Riboflavin deficiency induced ariboflavinosis (R0.06 46.7%; R0 72%) and esophageal epithelial atrophy (R0.06 40%; R0 44%) in rats, while the R6 group did not display symptoms (P < 0.001, respectively). Esophageal epithelial atrophy occurred simultaneously (R0.06 66.7%; R0 63.6%) with ariboflavinosis or appeared alone (R0.06 33.3%; R0 36.4%). Esophagus is the most vulnerable internal organ. Riboflavin deficiency followed by replenishment (R0 → R6) was effective in treating ariboflavinosis (83.3% vs. 0%, P < 0.001) and esophageal epithelial atrophy (66.7% vs. 20%, P = 0.17). Riboflavin deficiency modulated gut microbiota composition. The several key genera (Romboutsia, Turicibacter and Clostridium sensu stricto 1) were strongly correlated with ariboflavinosis and esophageal epithelial atrophy (P < 0.01 or P < 0.05). The potential mechanism is that gut microbiota affects body's xenobiotic biodegradation and metabolism, and genomic instability. CONCLUSIONS: Riboflavin deficiency induces ariboflavinosis and esophageal epithelial atrophy by modulating the gut microbiota, and offers new Queryinsight into riboflavin deficiency and esophageal lesions.


Assuntos
Esôfago , Microbioma Gastrointestinal , Deficiência de Riboflavina , Animais , Atrofia , Esôfago/patologia , Masculino , RNA Ribossômico 16S , Ratos , Ratos Endogâmicos F344 , Riboflavina
10.
Food Funct ; 11(11): 10070-10083, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33135706

RESUMO

SCOPE: Epidemiologic evidence suggests that riboflavin (RBF) deficiency is a specific nutritional predisposition for esophageal cancer. The aim of this study is to investigate the potential roles of gut microbiota in esophageal tumorigenesis caused by the RBF deficiency. METHODS: Male F344 rats were subcutaneously injected with the chemical carcinogen N-nitrosomethylbenzylamine (NMBA, 0.35 mg kg-1). Rats were assigned to 4 groups, denoted as R6 (normal RBF, 6 mg kg-1), R6N (normal RBF combined with NMBA), R6N → R0N (normal RBF conversion to RBF-deficiency), and R0N → R6N (RBF-deficiency conversion to normal RBF). Bacterial communities were analyzed based on high-throughput 16S rRNA gene sequencing. Oxidative DNA damage and double-strand break markers were studied by immunohistochemistry. RESULTS: The R6N → R0N diet enhanced the incidence of esophageal intraepithelial neoplasia (EIN, 40 weeks 66.7% vs. 25 weeks 16.7%, P < 0.05). RBF deficiency and replenishment modulated the gut microbiota composition. The gut microbiota (e.g. Caulobacteraceae, Sphingomonas and Bradyrhizobium) affected xenobiotic biodegradation and the genomic instability of the host. Furthermore, the RBF deficiency aggravated oxidative DNA damage and DNA double-strand breaks (immunohistochemistry) in the esophageal epithelium, whereas the RBF replenishment had the opposite effect (P < 0.05, respectively). CONCLUSIONS: RBF deficiency promotes NMBA-induced esophageal tumorigenesis, which is associated with gut microbiota-associated genomic instability, and offers new insights into the role of RBF deficiency in esophageal carcinogenesis.

11.
Food Funct ; 11(12): 10979, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33210681

RESUMO

Correction for 'Dietary riboflavin deficiency induces genomic instability of esophageal squamous cells that is associated with gut microbiota dysbiosis in rats' by Feng Pan et al., Food Funct., 2020, DOI: .

12.
Biochim Biophys Acta Gene Regul Mech ; 1863(12): 194641, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33017669

RESUMO

Phase separation is the basis for the formation of membrane-less organelles in cells and is involved in many biological processes. Many biological macromolecules, such as proteins and nucleic acids, exert their biological functions by forming phase-separated condensates, and phase separation is closely related to various human diseases. Gene transcriptional regulation is an indispensable part of gene expression and normal function in cells. Its abnormal regulation often causes the occurrence of different diseases. In recent years, the occurrence of phase separation during transcriptional regulation has become an area of intense research. This review summarizes the process of phase separation involved in heterochromatin formation and chromatin remodeling, transcriptional regulation and post-transcriptional regulation. It provides a reference for understanding gene regulation during cell identity and disease development.


Assuntos
Cromatina/química , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Eucariotos/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , RNA Polimerase II/metabolismo , Splicing de RNA , Fatores de Transcrição/metabolismo
13.
Mol Cell Proteomics ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077686

RESUMO

Esophageal squamous cell cancer (ESCC) is an aggressive malignancy with poor therapeutic outcomes. However, the alterations in proteins and post-translational modifications (PTMs) leading to the pathogenesis of ESCC remains unclear. Here, we provide the comprehensive characterization of the proteome, phosphorylome, lysine acetylome and succinylome for ESCC and matched control cells using quantitative proteomic approach. We identify abnormal protein and post-translational modification (PTM) pathways, including significantly downregulated lysine succinylation sites in cancer cells. Focusing on hyposuccinylation, we reveal that this altered PTM was enriched on enzymes of metabolic pathways inextricably linked with cancer metabolism. Importantly, ESCC malignant behaviors such as cell migration are inhibited once the level of succinylation was restored in vitro or in vivo This effect was further verified by mutations to disrupt succinylation sites in candidate proteins. Meanwhile, we found that succinylation has a negative regulatory effect on histone methylation to promote cancer migration. Finally, hyposuccinylation is confirmed in primary ESCC specimens. Our findings together demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing new insights into the functional significance of PTM in cancer biology.

14.
Biochim Biophys Acta Rev Cancer ; 1874(2): 188435, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32976981

RESUMO

Lysyl oxidase-like 2 (LOXL2) is a copper and lysine tyrosyl-quinone (LTQ)-dependent amine oxidase belonging to the lysyl oxidase (LOX) family, the canonical function of which is to catalyze the crosslinking of elastin and collagen in the extracellular matrix (ECM). Many studies have revealed that the aberrant expression of LOXL2 in multiple cancers is associated with epithelial-mesenchymal transition (EMT), metastasis, poor prognosis, chemoradiotherapy resistance, and tumor progression. LOXL2 is regulated in many ways, such as transcriptional regulation, alternative splicing, microRNA regulation, posttranslational modification, and cleavage. Beyond affecting the extracellular environment, various intracellular roles, such as oxidation and deacetylation activities in the nucleus, have been reported for LOXL2. Additionally, LOXL2 contributes to tumor cell invasion by promoting cytoskeletal reorganization. Targeting LOXL2 has become a potential therapeutic strategy to combat many types of cancers. Here, we provide an overview of the regulation and downstream effectors of LOXL2 and discuss the intracellular role of LOXL2 in cancer.


Assuntos
Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Neoplasias/metabolismo , Transição Epitelial-Mesenquimal , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Neoplasias/genética , Prognóstico
15.
Cancers (Basel) ; 12(9)2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32872659

RESUMO

Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3ß is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3ß as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3ß on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer.

16.
Adv Sci (Weinh) ; 7(16): 2000925, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32832354

RESUMO

Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGFß2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGFß2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal-regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGFß2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGFß2 promoter, represses TGFß2 expression and fibroblasts-secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGFß2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis.

17.
Cancer Metastasis Rev ; 39(4): 1245-1262, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32772212

RESUMO

Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.


Assuntos
Neoplasias/enzimologia , Neoplasias/radioterapia , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Humanos , Metástase Neoplásica , Neoplasias/patologia , Tolerância a Radiação
18.
J Cancer ; 11(18): 5395-5402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742486

RESUMO

Background: Low serum L1 cell adhesion molecule (L1CAM) has been found in several malignant tumors. Here, we aimed to evaluate the diagnostic potential for serum L1CAM in patients with gastric cancers (GC) and esophagogastric junction adenocarcinoma (EJA). Methods: Enzyme-linked immunosorbent assay (ELISA) was carried out to detect L1CAM level in sera of 148 GC patients, 59 EJA patients and 148 healthy controls. Receiver operating characteristics (ROC) was employed to evaluate diagnostic accuracy. Results: The concentrations of serum L1CAM were significantly lower in GC and EJA than those in healthy controls (P<0.001). Detection of L1CAM provided a sensitivity of 83.1%, a specificity of 62.2%, and an area under the curve (AUC) of 0.769 (95% CI: 0.715-0.823) in diagnosing GC, and a sensitivity of 66.1%, a specificity of 62.2%, and an AUC of 0.672 (95% CI: 0.590-0.755) in diagnosing EJA. Similar results were observed in the diagnosis of early-stage GC (0.681 (95%CI: 0.596-0.766)) and early-stage EJA (0.674 (95%CI: 0.528-0.820)). Analysis of clinical data showed that the levels of L1CAM were significantly associated with lymph node metastasis in GC (P<0.05). Conclusions: Our study showed that serum L1CAM might be a diagnostic biomarker for GC and EJA.

19.
J Inorg Biochem ; 211: 111204, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32801097

RESUMO

Lysyl oxidase-like 2 (LOXL2) is a copper-dependent amine oxidase that catalyzes the oxidative deamination of the ε-amino group of lysines/hydroxylysines on substrate proteins (collagen and elastin) to form aldehyde groups. The generated aldehyde groups are of significance in crosslinking with the adjacent aldehyde or ε-amino group on proteins in extracellular matrix. In this paper, we have studied the reaction mechanism of LOXL2 by means of quantum mechanics (QM) and combined QM and molecular mechanics (QM/MM) methods. This study is divided into two parts, i.e. the biosynthesis of lysine tyrosylquinone (LTQ) cofactor and oxidative deamination of ε-amino group of lysine by LTQ. For the former part, the reaction is driven by a large exothermicity of about 284 kJ/mol. Dopaquinone radical (DPQr) is suggested to be an intermediate state in this reaction. In addition, His652 residue is predicted to serve as proton acceptor. The rate-determining step for the biosynthesis of LTQ is found to be hydrogen-atom abstraction from the benzene ring on substrate by Cu2+-hydroxide, which is a proton-coupled electron transfer (PCET) process with an energy barrier of 84 kJ/mol. For the latter part, the reaction is exothermic by about 145 kJ/mol, and the copper ion is proposed to play a role of redox catalyst in the last step to generate the product of aldehyde. However, the copper ion might not be indispensable for the latter part, which is consistent with the previous study.

20.
Biochem Biophys Res Commun ; 531(2): 172-179, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32788070

RESUMO

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP), in which exon open reading frame 15 (ORF15) of RPGR has been implicated to play a substantial role. We identified a novel hemizygous missense mutation E585K of RPGR from whole-exome sequencing of RP. RNA-Seq analysis and functional study were conducted to investigate the underlying pathogenic mechanism of the mutation. Our results showed that the mutation actually affected RPGR ORF15 splicing. RNA-Seq analysis of the human retina followed by validation in cells revealed a complex splicing pattern near the 3' boundary of RPGR exon 14 in the ORF15 region, resulting from a variety of alternative splicing events (ASEs). The wildtype RPGR mini-gene expressed in human 293T cells confirmed these ASEs in vitro. In contrast, without new RNA species detected, the mutant mini-gene disrupted the splicing pattern of the ORF15 region, and caused loss of RPGR transcript heterogeneity. The RNA species derived from the mutant mini-gene were predominated by a minor out-of-frame transcript that was also observed in wildtype RPGR, resulting from an upstream alternative 5' splice site in exon 14. Our findings therefore provide insights into the influence of RPGR exonic mutations on alternative splicing of the ORF15 region, and the underlying molecular mechanism of RP.


Assuntos
Proteínas do Olho/genética , Mutação de Sentido Incorreto/genética , Fases de Leitura Aberta/genética , Retinite Pigmentosa/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Proteínas do Olho/química , Hemizigoto , Humanos , Masculino , Splicing de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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