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1.
Mol Carcinog ; 62(12): 1860-1876, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37589417

RESUMO

Hypoxia is characteristic of the ovarian tumor (OC) microenvironment and profoundly affects tumorigenesis and therapeutic response. Long noncoding RNAs (lncRNAs) play various roles in tumor progression; however, the characteristics of lncRNAs in pathological responses of the OC microenvironment are not entirely understood. Through high-throughput sequencing, lncRNA expression in hypoxia (1% O2 ) and normoxia (21% O2 ) SKOV3 cells was explored and analyzed. The 5'- and 3'-rapid amplification of complementary DNA ends was used to detect the full length of the novel HIF1A-AS3 transcript. Real-time quantitative polymerase chain reaction was used to assess HIF1A-AS3 expression in OC cells and tissues. In vitro and in vivo evaluations of the biological functions of hypoxic HIF1A-AS3 were conducted. To clarify the underlying mechanisms of HIF1A-AS3 in hypoxic OC, a dual-luciferase assay, chromatin immunoprecipitation, RNA pull-down, RNA immunoprecipitation, and RNA-sequencing were used. We used high-throughput sequencing to investigate a novel lncRNA, HIF1A-AS3, as a hypoxic candidate significantly elevated in OC cells/tissues. HIF1A-AS3 was predominantly localized in the nucleus and promoted in vitro and in vivo OC growth and tumorigenesis. Hypoxia-inducible factor 1α bound to hypoxia response elements in the HIF1A-AS3 promoter region and stimulated its expression in hypoxia. Under hypoxia, HIF1A-AS3 directly integrated with Y-Box binding protein 1 and inhibited its ability to bind to the promoters of p21 and AJAP1 to repress their transcriptional activity, thereby promoting hypoxic OC progression. Our results revealed the crucial role and mechanism of the novel hypoxic HIF1A-AS3 in the oncogenesis of OC. The novel HIF1A-AS3 could be a crucial biomarker and therapeutic target for future OC treatments.


Assuntos
Neoplasias Ovarianas , RNA Longo não Codificante , Humanos , Feminino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transformação Celular Neoplásica/genética , Carcinogênese/genética , Hipóxia/genética , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Proteína 1 de Ligação a Y-Box/metabolismo , Moléculas de Adesão Celular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
2.
J Clin Lab Anal ; 35(11): e24012, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34655124

RESUMO

OBJECTIVE: This investigation devoted to lncRNA FGF14 antisense RNA 2 (FGF14-AS2) in prostate carcinoma progression. METHODS: The levels of lncRNA FGF14-AS2, miR-96-5p, and Adherens junction-associated protein-1 (AJAP1) in prostate carcinoma were tested by Western blot and qRT-PCR. How these two genes interacted was confirmed by RNA immunoprecipitation and dualluciferase gene methods. The effect of FGF14-AS2/miR-96-5p/AJAP1 axis in prostate carcinoma progression was determined by MTT, Transwell, and nude mice tumor model. RESULTS: FGF14-AS2 was a downregulated lncRNA in prostate carcinoma tissue and cells. FGF14-AS2 could restrain miR-96-5p expression while miR-96-5p hampered AJAP1. FGF14-AS2 could effectively decrease the biological behaviors of prostate carcinoma cells, while knock-down of FGF14-AS2 triggered opposite results. Moreover, miR-96-5p mimic presented a cancer promoter role in prostate carcinoma cells. AJAP1 expression level could affect levels of proteins related to epithelial-mesenchymal transition. In vivo experiment suggested that overexpressing FGF14-AS2 could reverse the promotion of silenced AJAP1 on prostate carcinoma cell metastasis, thus to inhibit tumor growth. CONCLUSION: lncRNA FGF14-AS2 was a downregulated lncRNA in prostate carcinoma and influenced cell proliferation and metastasis. The influence relied on modulating miR-96-5p and its target gene AJAP1.


Assuntos
Moléculas de Adesão Celular/metabolismo , MicroRNAs/metabolismo , Neoplasias da Próstata , RNA Longo não Codificante , Animais , Moléculas de Adesão Celular/genética , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
3.
Biochem Biophys Res Commun ; 524(4): 1057-1063, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32067740

RESUMO

Adherens junction-associated protein-1 (AJAP1), also called SHREW1, was first discovered as a novel component of adherens junctions in 2004. In later studies, AJAP1 was found to suppress invasion and predict recurrence of some tumors. Apart from its function as a putative tumor suppressor, AJAP1 is still poorly understood. Schwenk et al. recently found that AJAP1 was tightly associated with the γ-Aminobutyric acid type B receptor subunit 1(GABABR1). It is well known that GABABR plays a vital role in epilepsy as an inhibitory transmitter receptor. Structurally adjacent, possibly functionally interacting, therefore, we hypothesize that AJAP1 participates in the onset and progression of epilepsy. We designed this experiment to investigate the expression and location of AJAP1 in temporal lobe epilepsy (TLE) patients and kainic acid(KA)-induced epilepsy animal models by immunofluorescence and Western blot analyses. We overexpressed and inhibited AJAP1 through lentiviruses in KA-induced models and observed the corresponding effects on epileptic animals. Double-label immunofluorescence showed that AJAP1 was expressed mainly in neurons. Western blot analysis revealed that AJAP1 expression was downregulated in the neocortex of TLE patients and the hippocampus and neocortex of epileptic animal models. The overexpression of AJAP1 can reduce the frequency of spontaneous seizures, whereas the inhibition of AJAP1 expression can increase the incidence rate. Our study demonstrated that AJAP1 may be involved in the pathogenic process of epilepsy and may represent a novel antiepileptic target.


Assuntos
Epilepsia/metabolismo , Receptores de GABA-B/metabolismo , Adolescente , Adulto , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/metabolismo , Criança , Epilepsia/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptores de GABA-B/análise , Adulto Jovem
4.
J Cell Mol Med ; 23(2): 1541-1552, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30597727

RESUMO

Our goal was to explore the function of miR-552 and its potential target AJAP1 in hepatocellular carcinoma (HCC) oncogenesis and progression. In this study, bioinformatics analysis was performed to detect abnormally expressed miRNAs. The relationship between miR-552 and AJAP1 was validated using luciferase reporter assays. RT-qPCR and Western blot assays were applied to explore the expression level of miR-552, AJAP1 and epithelial-mesenchymal transition (EMT) markers. HCC cell proliferation was examined using CCK8 assays, while migration and invasion were investigated using Transwell assays. Nude mouse tumourigenesis models were established to facilitate observation of HCC progression in vivo. Finally, prognostic analysis was performed to discover how the prognosis of HCC patients correlated with miR-552 and AJAP1 expression. MiR-552 overexpression in HCC cells promoted HCC cell migration, invasion and EMT by targeting/suppressing AJAP1. Poorer prognosis appeared in HCC patients with higher miR-552 expression or lower AJAP1 levels. Our findings suggested that miR-552 promotes HCC oncogenesis and progression by inhibiting AJAP1 expression.


Assuntos
Carcinoma Hepatocelular/genética , Moléculas de Adesão Celular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , Idoso , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Biologia Computacional/métodos , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Prognóstico , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Pathol Res Pract ; 241: 154224, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36566599

RESUMO

BACKGROUND: AJAP1 is down-regulated in multiple cancer types and plays a suppressive role in cancer progression. However, its molecular regulatory mechanism in prostate cancer has not been reported. METHODS: Bioinformatics methods were employed to analyze AJAP1 expression in prostate cancer tissues and its association with TNM staging. MSP and qRT-PCR were used to quantify promoter methylation and AJAP1 expression after 5-aza-20-deoxycytidine (5-AzaC) treatment. Scratch healing assay and Transwell method were adopted to analyze the effects of aberrant AJAP1 expression, 5-AzaC and AG490 on cell migration and invasion. The levels of AJAP1 protein, EMT-related and JAK/STAT pathway-related proteins were determined by Western blot. The effects of AJAP1 aberrant expression and AG490 treatment on the sphere forming ability of prostate cancer cells were analyzed by sphere formation assay. RESULTS: This study confirmed the significant down-regulation of AJAP1 expression in prostate cancer tissues and cells, and its negative correlation with TNM staging. 5-AzaC treatment led to a significant reduction of AJAP1 methylation level and a significant upregulation of AJAP1 expression, indicating that the methylation level of AJAP1 promoter may affect the expression of AJAP1. Cell function experiments found that overexpression or decreased methylation of AJAP1 inhibited epithelial mesenchymal transition (EMT), migration, and invasion, while silencing or increased methylation of AJAP1 had the opposite functions. JAK2/STAT3 pathway inhibiting assay found that inhibition of JAK2/STAT3 pathway significantly reduced EMT, cell migration, and stem cell sphere formation in prostate cancer. SIGNIFICANCE: Therefore, investigating the influence of aberrant AJAP1 expression on functions of prostate cancer cells is conducive to our in-depth understanding of the mechanism of prostate cancer genesis and development.


Assuntos
Janus Quinases , Neoplasias da Próstata , Masculino , Humanos , Janus Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição STAT/metabolismo , Metilação de DNA/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transição Epitelial-Mesenquimal/genética , Movimento Celular/genética , Células-Tronco/metabolismo , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/genética , Moléculas de Adesão Celular/metabolismo
6.
Gland Surg ; 12(6): 834-852, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37441023

RESUMO

Background: Salivary adenoid cystic carcinoma (SACC) is a unique malignant tumor of the salivary gland with poor prognosis, which is not effective with chemotherapy and targeted drugs. Therefore, it is important to explore the molecular mechanism underlying SACC invasion and metastasis to develop novel therapeutic strategies and targets in clinical research. Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were performed to detect the expression of Adherens Junctions Associated Protein 1 (AJAP1). Methylation-specific PCR was used to evaluate the methylation of the AJAP1 promoter. AJAP1 was overexpressed or knocked down by lentivirus-mediated transfection. Kaplan-Meier analysis was conducted to create a survival curve and the log-rank test was used to analyze the overall survival (OS). The prognostic correlation was assessed using univariate and multivariate Cox regression analyses. Co-immunoprecipitation (Co-IP) was utilized to pull down the possible binding protein of AJAP1 and laser scanning confocal microscopy was applied to detect the subcellular localization of AJAP1, E-cadherin, and ß-catenin. Cell viability, colony formation, wound healing, and Transwell invasion assays were performed to evaluate the function of AJAP1 in vitro. A subcutaneous xenograft assay in nude mice was performed to verify the function of AJAP1 in vivo. Results: AJAP1 was downregulated in SACC tumors and was closely related to SACC lymph node/distant metastasis, which was an independent risk factor for SACC prognosis. Methylation-specific PCR confirmed that high methylation of the AJAP1 promoter was the main cause of its silencing. Overexpression or knockdown of AJAP1 in SACC cells could significantly inhibit or promote the proliferation, invasion, and metastasis of SACC cells, respectively, in both the in vitro and in vivo experiments. Mechanically, we found that AJAP1 binds to E-cadherin and ß-catenin to form a complex in cytomembrane, reducing the nuclear translocation of ß-catenin and blocking the Wingless/Integrated/ß-catenin (Wnt/ß-catenin) signaling pathway to play a suppressive role in cancer. Conclusions: In conclusion, these results suggest that the downregulation of AJAP1 protein expression may play a certain role in progression and metastasis of SACC. Our study indicates that AJAP1 may be a potential prognostic molecular marker and therapeutic target for SACC.

7.
Genes (Basel) ; 13(12)2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36553518

RESUMO

Few studies have addressed how selective pressures have shaped the genetic structure of the current Native American populations, and they have mostly limited their inferences to admixed Latin American populations. Here, we searched for local adaptation signals, based on integrated haplotype scores and population branch statistics, in 325 Mexican Indigenous individuals with at least 99% Native American ancestry from five previously defined geographical regions. Although each region exhibited its own local adaptation profile, only PPARG and AJAP1, both negative regulators of the Wnt/ß catenin signaling pathway, showed significant adaptation signals in all the tested regions. Several signals were found, mainly in the genes related to the metabolic processes and immune response. A pathway enrichment analysis revealed the overrepresentation of selected genes related to several biological phenotypes/conditions, such as the immune response and metabolic pathways, in agreement with previous studies, suggesting that immunological and metabolic pressures are major drivers of human adaptation. Genes related to the gut microbiome measurements were overrepresented in all the regions, highlighting the importance of studying how humans have coevolved with the microbial communities that colonize them. Our results provide a further explanation of the human evolutionary history in response to environmental pressures in this region.


Assuntos
Adaptação Fisiológica , Indígena Americano ou Nativo do Alasca , Humanos , México , Adaptação Fisiológica/genética , Hispânico ou Latino , Grupos Raciais
8.
Front Oncol ; 12: 831507, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35311087

RESUMO

Ezrin and adherens junction-associated protein 1 (AJAP1) are structural proteins which are involved in numerous human malignancies. However, little is known about the relationship between them in breast cancer. This study was set out to investigate the relationship between them and to further explore the mechanism of AJAP1-mediating cytoskeleton in breast cancer progression. Ezrin and AJAP1 expressions were detected in 377 samples of breast cancer by immunohistochemistry, and different expression patterns between AJAP1 and Ezrin with clinicopathological parameters were analyzed. Besides, univariate and multivariate Cox models were used to evaluate their prognostic potential. Enzyme-linked immunosorbent assay, Western blot, qRT-PCR, and phalloidin staining of F-actin were used to explore the relationship and the mechanism between AJAP1 and Ezrin in cytoskeleton arrangement. 377 cases of breast cancer results showed that AJAP1 expression was negatively related with histological grade and lymph node involvement and could be an independent prognosis marker of breast cancer. AJAP1 expression tended to be higher in the Ezrin-negative expression case. Patients with AJAP1negative and Ezrinpositive expression had a worse prognosis (p < 0.0001) and shorter DFS (p = 0.015). More importantly, AJAP1 depletion increased the cell ability of F-actin formation through promoting Ezrin expression. AJAP1 depletion might mediate breast cancer malignancy potential through promoting Ezrin expression and cytoskeleton formation.

9.
Curr Top Behav Neurosci ; 52: 19-37, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-32812202

RESUMO

GABAB receptors (GBRs), the G protein-coupled receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), activate Go/i-type G proteins that regulate adenylyl cyclase, Ca2+ channels, and K+ channels. GBR signaling to enzymes and ion channels influences neuronal activity, plasticity processes, and network activity throughout the brain. GBRs are obligatory heterodimers composed of GB1a or GB1b subunits with a GB2 subunit. Heterodimeric GB1a/2 and GB1b/2 receptors represent functional units that associate in a modular fashion with regulatory, trafficking, and effector proteins to generate receptors with distinct physiological functions. This review summarizes current knowledge on the structure, organization, and functions of multi-protein GBR complexes.


Assuntos
Receptores de GABA-B , Receptores de GABA , Neurônios , Transdução de Sinais , Ácido gama-Aminobutírico
10.
Front Oncol ; 10: 667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528872

RESUMO

Ten-eleven translocation 1 (TET1) is a member of methylcytosine dioxygenase, which catalyzes 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) to promote the demethylation process. The dysregulated TET1 protein and 5 hmC level were reported to either suppress or promote carcinogenesis in a cancer type-dependent manner. Currently, the role of TET1 in the development of urinary bladder cancer (UBC) and its underlying molecular mechanisms remain unclear. Herein, we found that TET1 expression was downregulated in UBC specimens compared with normal urothelium and was inversely related to tumor stage and grade and overall survival, suggesting its negative association with UBC progression. TET1 silencing in UBC cells increased cell proliferation and invasiveness while the ectopic expression of wild-type TET1-CD, but not its enzymatic inactive mutant, reversed these effects and suppressed tumorigenicity in vivo. In addition, as a direct regulator of TET1 activity, vitamin C treatment increased 5 hmC level and inhibited the anchorage-independent growth and tumorigenicity of UBC cells. Furthermore, we found that TET1 maintained the hypomethylation in the promoter of the AJAP1 gene, which codes for adherens junction-associated protein 1. The downregulation of AJAP1 reversed TET1-CD-induced nuclear translocation of ß-catenin, thus inhibiting the expression of its downstream genes. In human UBC specimens, AJAP1 is frequently downregulated and positively associated with TET1. Notably, low expression levels of both TET1 and AJAP1 predict poor prognosis in UBC patients. In conclusion, we found that the frequently downregulated TET1 level reduces the hydroxymethylation of AJAP1 promoter and subsequently activates ß-catenin signaling to promote UBC development. The downregulation of both TET1 and AJAP1 might be a promising prognostic biomarker for UBC patients.

11.
J Exp Clin Cancer Res ; 38(1): 238, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171012

RESUMO

BACKGROUND: Adherent junction associated protein 1 (AJAP1), a typical molecule of adherent junctions, has been found to be a tumor suppressor in many cancer types. Aberrant activation of ß-catenin has been demonstrated to be associated with malignant biological properties of tumors including breast cancer. This study aimed to investigate the function and mechanism of AJAP1-mediated ß-catenin activity of breast cancer lines in vitro and in breast cancer patients. METHODS: AJAP1 and ß-catenin expressions in breast cancer tissues and cell lines were detected by immunohistochemistry, western blotting and qRT-PCR. The EGF/EGFR axis-mediated AJAP1 attenuated ß-catenin nuclear location was measured by western blotting, immunofluorescence assay, co-immunoprecipitation, luciferase assay and ubiquitination assays. Furthermore, the function of AJAP1 and ß-catenin regulated breast cancer progression was explored both in vivo and in vitro. RESULTS: It was found that AJAP1 had a high negative correlation with ß-catenin nuclear expression and was a novel tumor suppressor in breast cancer. AJAP1 loss can mediate ß-catenin accumulated in cytoplasm and then transferred it to the nucleus, activating ß-catenin transcriptional activity and downstream genes. Additionally, ß-catenin can reverse the invasion, proliferation ability and tumorigenicity of the depletion of AJAP1 caused both in vivo and in vitro. Besides, EGF/EGFR also involved in the process of AJAP1-depiction induced ß-catenin transactivation to the nucleus. More importantly, EGFR depletion/AJAP1 knocked down promoted the progression of breast cancer by regulating the activity of ß-catenin nuclear transactivation. CONCLUSION: This study demonstrated that AJAP1 acted as a putative tumor suppressor while ß-catenin nuclear localization positively fed back on EGF/EGFR-attenuated AJAP1 expression in breast cancer, which might be beneficial to develop new therapeutic targets for decreasing nuclear ß-catenin-mediated malignancy in breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/genética , Fator de Crescimento Epidérmico/metabolismo , Regulação Neoplásica da Expressão Gênica , beta Catenina/metabolismo , Adulto , Idoso , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Xenoenxertos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Ligação Proteica
12.
Cancer Lett ; 403: 119-127, 2017 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-28634045

RESUMO

EGFR amplification and mutations are the most common oncogenic events in GBM. EGFR overexpression correlates with GBM invasion, but the underlying mechanisms are poorly understood. In a previous study, we showed that AJAP1 is involved in regulating F-actin to inhibit the invasive ability of GBM. In addition, in a GBM cell line, the AJAP1 promoter was highly bound by H3K27me3 and, through bioinformatics analysis, we found that AJAP1 expression was negatively correlated with EGFR. In this study, we found that the pathway downstream of EGFR had a higher activation level in GBM cell lines, which led to excessive tumor suppressor silencing. Therefore, we deduced that in glioma cells, the pathway downstream of EGFR remodels the cytoskeleton via AJAP1 epigenetic silencing to enhance invasion. Furthermore, MK2206 reversed AJAP1 downregulation by inhibiting the EGFR pathway. In vivo, MK2206 also inhibited the proliferation and local invasion of 87-EGFRvIII. These data suggest that activation of the EGFR signal transduction pathway genetically silences anti-oncogenes to enhance GBM malignancy. MK2206 might be a promising therapeutic for EGFR/EGFRvIII-positive GBMs.


Assuntos
Citoesqueleto de Actina/metabolismo , Neoplasias Encefálicas/metabolismo , Moléculas de Adesão Celular/metabolismo , Movimento Celular , Metilação de DNA , Epigênese Genética , Receptores ErbB/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Bases de Dados Genéticas , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Receptores ErbB/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fosfatidilinositol 3-Quinase/metabolismo , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Biol Open ; 6(6): 723-731, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28483980

RESUMO

The adherens junction associated protein 1 (AJAP1, aka shrew-1) is presumably a type-I transmembrane protein localizing and interacting with the E-cadherin-catenin complex. In various tumors, AJAP1 expression is reduced or lost, including hepatocellular and esophageal squamous cell carcinoma, and glial-derived tumors. The aberrant expression of AJAP1 is associated with alterations in cell migration, invasion, increased tumor growth, and tumor vascularization, suggesting AJAP1 as a putative tumor suppressor. We show that AJAP1 attenuates sprouting angiogenesis by reducing endothelial migration and invasion capacities. Further, we show for the first time that endogenous AJAP1 is associated with the microtubule cytoskeleton. This linkage is independent from cell confluency and stable during angiogenic sprouting in vitro Our work suggests that AJAP1 is a putative negative regulator of angiogenesis, reducing cell migration and invasion by interfering with the microtubule network. Based on our results and those of other authors, we suggest AJAP1 as a novel tumor suppressor and diagnostic marker.

14.
Biol Open ; 5(11): 1607-1619, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27870635

RESUMO

Shrew-1, also called AJAP1, is a transmembrane protein associated with E-cadherin-mediated adherence junctions and a putative tumor suppressor. Apart from its interaction with ß-catenin and involvement in E-cadherin internalization, little structure or function information exists. Here we explored shrew-1 expression during postnatal differentiation of mammary gland as a model system. Immunohistological analyses with antibodies against either the extracellular or the cytoplasmic domains of shrew-1 consistently revealed the expression of full-length shrew-1 in myoepithelial cells, but only part of it in luminal cells. While shrew-1 localization remained unaltered in myoepithelial cells, nuclear localization occurred in luminal cells during lactation. Based on these observations, we identified two unknown shrew-1 transcript variants encoding N-terminally truncated proteins. The smallest shrew-1 protein lacks the extracellular domain and is most likely the only variant present in luminal cells. RNA analyses of human tissues confirmed that the novel transcript variants of shrew-1 exist in vivo and exhibit a differential tissue expression profile. We conclude that our findings are essential for the understanding and interpretation of future functional and interactome analyses of shrew-1 variants.

15.
CNS Neurosci Ther ; 20(5): 429-37, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24483339

RESUMO

AIMS: Down-regulation of AJAP1 in glioblastoma multiforme (GBM) has been reported. However, the expression profiles of AJAP1 in gliomas and the underlying mechanisms of AJAP1 function on invasion are still poorly understood. METHODS: The gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 overexpression in GBM cell lines, cellular polarity, cytoskeleton distribution, and antitumor effect were investigated in vitro and in vivo. RESULTS: AJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low-grade gliomas and AJAP1-overexpressing GBM cells, but difficult to assess in high-grade gliomas due to its absence. AJAP1 overexpression altered the cytoskeleton and cellular polarity in vitro and inhibited the tumor growth in vivo. CONCLUSIONS: AJAP1 is dysregulated at an early stage of gliomagenesis and may suppress glioma cell invasion and proliferation, which suggests that AJAP1 may be a potential diagnostic and prognostic marker for gliomas.


Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Moléculas de Adesão Celular/metabolismo , Citoesqueleto/metabolismo , Glioma/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Estudos de Coortes , Citoesqueleto/ultraestrutura , Progressão da Doença , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Camundongos Nus , Microscopia Confocal , Estadiamento de Neoplasias , Transplante de Neoplasias
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