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1.
Med Image Anal ; 71: 102031, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33798993

RESUMO

Fundus diseases classification is vital for the health of human beings. However, most of existing methods detect diseases by means of single angle fundus images, which lead to the lack of pathological information. To address this limitation, this paper proposes a novel deep learning method to complete different fundus diseases classification tasks using ultra-wide field scanning laser ophthalmoscopy (SLO) images, which have an ultra-wide field view of 180-200˚. The proposed deep model consists of multi-branch network, atrous spatial pyramid pooling module (ASPP), cross-attention and depth-wise attention module. Specifically, the multi-branch network employs the ResNet-34 model as the backbone to extract feature information, where the ResNet-34 model with two-branch is followed by the ASPP module to extract multi-scale spatial contextual features by setting different dilated rates. The depth-wise attention module can provide the global attention map from the multi-branch network, which enables the network to focus on the salient targets of interest. The cross-attention module adopts the cross-fusion mode to fuse the channel and spatial attention maps from the ResNet-34 model with two-branch, which can enhance the representation ability of the disease-specific features. The extensive experiments on our collected SLO images and two publicly available datasets demonstrate that the proposed method can outperform the state-of-the-art methods and achieve quite promising classification performance of the fundus diseases.

2.
Cell Death Dis ; 12(2): 202, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608512

RESUMO

Ring1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell-cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

3.
Neural Netw ; 132: 477-490, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33039786

RESUMO

The scanning laser ophthalmoscopy (SLO) has become an important tool for the determination of peripheral retinal pathology, in recent years. However, the collected SLO images are easily interfered by the eyelash and frame of the devices, which heavily affect the key feature extraction of the images. To address this, we propose a generative adversarial network called AMD-GAN based on the attention encoder (AE) and multi-branch (MB) structure for fundus disease detection from SLO images. Specifically, the designed generator consists of two parts: the AE and generation flow network, where the real SLO images are encoded by the AE module to extract features and the generation flow network to handle the random Gaussian noise by a series of residual block with up-sampling (RU) operations to generate fake images with the same size as the real ones, where the AE is also used to mine features for generator. For discriminator, a ResNet network using MB is devised by copying the stage 3 and stage 4 structures of the ResNet-34 model to extract deep features. Furthermore, the depth-wise asymmetric dilated convolution is leveraged to extract local high-level contextual features and accelerate the training process. Besides, the last layer of discriminator is modified to build the classifier to detect the diseased and normal SLO images. In addition, the prior knowledge of experts is utilized to improve the detection results. Experimental results on the two local SLO datasets demonstrate that our proposed method is promising in detecting the diseased and normal SLO images with the experts labeling.

4.
Mol Cells ; 43(9): 793-803, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32863280

RESUMO

Myeloid-derived suppressor cells (MDSCs) promote tumour progression by contributing to angiogenesis, immunosuppression, and immunotherapy resistance. Although recent studies have shown that microRNAs (miRNAs) can promote the expansion of MDSCs in the tumour environment, the mechanisms involved in this process are largely unknown. Here, we report that microRNA 449c (miR-449c) expression was upregulated in myeloid progenitor cells upon activation of C-X-C motif chemokine receptor 2 (CXCR2) under tumour conditions. MiR-449c upregulation increased the generation of monocytic MDSCs (mo-MDSCs). The increased expression of miR-449c could target STAT6 mRNA in myeloid progenitor cells to shift the differentiation balance of myeloid progenitor cells and lead to an enhancement of the mo-MDSCs population in the tumour environment. Thus, our results demonstrate that the miR-449c/STAT6 axis is involved in the expansion of mo-MDSCs from myeloid progenitor cells upon activation of CXCR2, and thus, inhibition of miR-449c/STAT6 signalling may help to attenuate tumour progression.

5.
Cell Mol Life Sci ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32789690

RESUMO

Poly(ADP-ribosyl)ation (PARylation) is an important post-translational modification mainly catalyzed by poly-ADP-ribose polymerase 1 (PARP1). In addition to having important roles in DNA damage detection and repair, it functions in gene expression regulation, especially at the posttranscriptional level. Embryonic lethal abnormal vision-like 1/human antigen R (ELAVL/HuR), a canonical 3' untranslated region AU-rich element-binding protein, is a crucial mRNA-stabilizing protein that protects target mRNAs from RNA-destabilizing protein- or microRNA-induced silencing complex (miRISC)-mediated degradation. Additionally, in some cases, HuR itself either promotes or suppresses translation. Here, we demonstrated that in response to inflammatory stimuli, the PARylation of HuR, mostly at the conserved D226 site, by PARP1 increased the formation of the HuR oligomer/multimer, and HuR oligomerization promoted the disassociation of miRISC and stabilized the pro-inflammatory gene mRNAs. The prevention of PARP1 activation or HuR oligomerization attenuated lipopolysaccharide-induced inflammatory gene expression and the airway recruitment of neutrophils in mouse lungs. The present study verified a novel mechanism of PARP1 and HuR PARylation in the RNA stability regulation, increasing our understanding of how PARP1 regulates gene expression.

6.
FASEB J ; 34(6): 7427-7441, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378256

RESUMO

8-Oxoguanine DNA glycosylase1 (OGG1)-initiated base excision repair (BER) is the primary pathway to remove the pre-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG) from DNA. Recent studies documented 8-oxoG serves as an epigenetic-like mark and OGG1 modulates gene expression in oxidatively stressed cells. For this new role of OGG1, two distinct mechanisms have been proposed: one is coupled to base excision, while the other only requires substrate binding of OGG1--both resulting in conformational adjustment in the adjacent DNA sequences providing access for transcription factors to their cis-elements. The present study aimed to examine if BER activity of OGG1 is required for pro-inflammatory gene expression. To this end, Ogg1/OGG1 knockout/depleted cells were transfected with constructs expressing wild-type (wt) and repair-deficient mutants of OGG1. OGG1's promoter enrichment, oxidative state, and gene expression were examined. Results showed that TNFα exposure increased levels of oxidatively modified cysteine(s) of wt OGG1 without impairing its association with promoter and facilitated gene expression. The excision deficient K249Q mutant was even a more potent activator of gene expression; whereas, mutant OGG1 with impaired substrate recognition/binding was not. These data suggested the interaction of OGG1 with its substrate at regulatory regions followed by conformational adjustment in the adjacent DNA is the primary mode to modulate inflammatory gene expression.

7.
Mol Med Rep ; 22(2): 612-619, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468042

RESUMO

Tyrosine phosphorylation is an essential post­translational protein modification catalyzed by tyrosine kinases. c­Abl is a crucial non­receptor tyrosine kinase, which is most commonly activated by auto­phosphorylation, DNA damage and by interacting with other protein kinases. DNA damage response (DDR) proteins stimulated by DNA lesions or chromatin alterations recruit the DNA repair and cell cycle checkpoint machinery to restore genome integrity and cellular homeostasis. The fundamental roles of activated c­Abl tyrosine kinase in cellular response pathways have been intensively and extensively investigated and in recent years, a number of c­Abl protein binding partners have been determined; however, the functional roles of these molecules remain to be determined. The present review aimed to summarize the DDR proteins phosphorylated by c­Abl tyrosine kinase that have been identified to date, in addition to the functional outcomes of these phosphotyrosine events. Notably, it has been discovered that c­Abl tyrosine kinase can bind with and phosphorylate DDR proteins at different tyrosine sites, which serve distinct roles in various cellular contexts.

8.
Cell Prolif ; 53(3): e12780, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32031738

RESUMO

OBJECTIVES: RING finger protein 8 (RNF8) is an E3 ligase that plays an essential role in DSB repair. p53 is a well-established tumour suppressor and cellular gatekeeper of genome stability. This study aimed at investigating the functional correlations between RNF8 and p53 in DSB damage repair. MATERIALS AND METHODS: In this article, wild-type, knockout and shRNA-depleted HCT116 and U2OS cells were stressed, and the roles of RNF8 and p53 were examined. RT-PCR and Western blot were utilized to investigate the expression of related genes in damaged cells. Cell proliferation, apoptosis and neutral cell comet assays were applied to determine the effects of DSB damage on differently treated cells. DR-GFP, EJ5-GFP and LacI-LacO targeting systems, flow cytometry, mass spectrometry, IP, IF, GST pull-down assay were used to explore the molecular mechanism of RNF8 and p53 in DSB damage repair. RESULTS: We found that RNF8 knockdown increased cellular sensitivity to DSB damage and decreased cell proliferation, which was correlated with high expression of the p53 gene. RNF8 improved the efficiency of DSB repair by inhibiting the pro-apoptotic function of p53. We also found that RNF8 restrains cell apoptosis by inhibiting over-activation of ATM and subsequently reducing p53 acetylation at K120 through regulating Tip60. CONCLUSIONS: Taken together, these findings suggested that RNF8 promotes efficient DSB repair by inhibiting the pro-apoptotic activity of p53 through regulating the function of Tip60.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Lisina Acetiltransferase 5/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Apoptose , Linhagem Celular Tumoral , Células HCT116 , Humanos
9.
Mol Cell Probes ; 50: 101498, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31891749

RESUMO

In cancer patients, the prevalence of myeloid-derived suppressor cells (MDSCs) is correlated with the degree of malignancy. In the present study, we investigated the role of circulating M-MDSCs in premetastatic niche formation using a mouse syngeneic tumor model and found that there was an increased frequency of M-MDSCs in the peripheral blood of tumor-bearing mice. M-MDSCs tracking and lung tissue histological analyses revealed that the malignant conditions promote the residence of circulating M-MDSCs and increased tumor cell arrest in the lungs. We further found that MMP-9 expression was increased in the circulating M-MDSCs and the administration of an MMP-9 inhibitor suppressed M-MDSCs transplantation-induced tumor cell arrest in the lung. Therefore, our findings suggest that the expansion of circulating M-MDSCs during tumor progression contributes to premetastatic niche formation by increasing MMP-9 expression.

10.
Cell Death Dis ; 10(9): 641, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488810

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

11.
Cells ; 8(9)2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500199

RESUMO

Poly(ADP-ribosyl)ation (PARylation) is an essential post-translational modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. Poly(ADP-ribose) polymerase 1 (PARP1) is a well-characterized member of the PARP family. PARP1 plays a crucial role in multiple biological processes and PARP1 activation contributes to the development of various inflammatory and malignant disorders, including lung inflammatory disorders, cardiovascular disease, ovarian cancer, breast cancer, and diabetes. In this review, we will focus on the role and molecular mechanisms of PARPs enzymes in inflammation- and metabolic-related diseases. Specifically, we discuss the molecular mechanisms and signaling pathways that PARP1 is associated with in the regulation of pathogenesis. Recently, increasing evidence suggests that PARP inhibition is a promising strategy for intervention of some diseases. Thus, our in-depth understanding of the mechanism of how PARPs are activated and how their signaling downstream effecters can provide more potential therapeutic targets for the treatment of the related diseases in the future is crucial.


Assuntos
Poli ADP Ribosilação/fisiologia , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/fisiologia , Animais , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/fisiopatologia , Poli Adenosina Difosfato Ribose/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Processamento de Proteína Pós-Traducional , Transdução de Sinais
12.
J Immunol ; 203(6): 1521-1531, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31399520

RESUMO

Poly(ADP-ribosyl)ation is a rapid and transient posttranslational protein modification mostly catalyzed by poly(ADP-ribose) polymerase-1 (PARP1). Fundamental roles of activated PARP1 in DNA damage repair and cellular response pathways are well established; however, the precise mechanisms by which PARP1 is activated independent of DNA damage, and thereby playing a role in expression of inflammatory genes, remain poorly understood. In this study, we show that, in response to LPS or TNF-α exposure, the nonreceptor tyrosine kinase c-Abl undergoes nuclear translocation and interacts with and phosphorylates PARP1 at the conserved Y829 site. Tyrosine-phosphorylated PARP1 is required for protein poly(ADP-ribosyl)ation of RelA/p65 and NF-κB-dependent expression of proinflammatory genes in murine RAW 264.7 macrophages, human monocytic THP1 cells, or mouse lungs. Furthermore, LPS-induced airway lung inflammation was reduced by inhibition of c-Abl activity. The present study elucidated a novel signaling pathway to activate PARP1 and regulate gene expression, suggesting that blocking the interaction of c-Abl with PARP1 or pharmaceutical inhibition of c-Abl may improve the outcomes of PARP1 activation-mediated inflammatory diseases.


Assuntos
Genes abl/genética , Inflamação/genética , Fosforilação/genética , Poli(ADP-Ribose) Polimerase-1/genética , Tirosina/genética , Animais , Linhagem Celular , Dano ao DNA/genética , Reparo do DNA/genética , Feminino , Expressão Gênica/genética , Humanos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Processamento de Proteína Pós-Traducional/genética , Células RAW 264.7 , Transdução de Sinais/genética , Células THP-1
13.
Cell Death Dis ; 10(8): 598, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395859

RESUMO

Myeloid-derived suppressor cells (MDSCs) comprise a critical component of the tumor environment and CXCR2 reportedly plays a key role in the pathophysiology of various inflammatory diseases. Here, CXCR2 expression on granulocyte and macrophage progenitor cells (GMPs) was found to participate in myeloid cell differentiation within the tumor environment. In CXCR2-deficient tumor-bearing mice, GMPs exhibited fewer macrophage and dendritic cell progenitor cells than wild-type tumor-bearing mice, thereby decreasing monocytic MDSCs (mo-MDSCs) expansion. CXCR2 deficiency increased SAP18 expression in tumor-bearing mice, which reduced STAT3 phosphorylation through restraining ERK1/2 activation. Our findings reveal a critical role for CXCR2 in regulating hematopoietic progenitor cell differentiation under tumor conditions, and SAP18 is a key negative regulator in this process. Thus, inhibiting CXCR2 expression may alter the tumor microenvironment and attenuate tumor progression.


Assuntos
Proteínas Correpressoras/genética , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Melanoma Experimental/genética , Proteínas de Ligação a RNA/genética , Receptores de Interleucina-8B/genética , Fator de Transcrição STAT3/genética , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Células Progenitoras de Granulócitos e Macrófagos/patologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Melanoma Experimental/patologia , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , RNA Interferente Pequeno/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Microambiente Tumoral/genética
14.
Cell Mol Life Sci ; 76(17): 3283-3299, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31055645

RESUMO

Poly(ADP-ribosyl)ation (PARylation) is an important post-translational modification in which an ADP-ribose group is transferred to the target protein by poly(ADP-riboses) polymerases (PARPs). Since the discovery of poly-ADP-ribose (PAR) 50 years ago, its roles in cellular processes have been extensively explored. Although research initially focused on the functions of PAR and PARPs in DNA damage detection and repair, our understanding of the roles of PARPs in various nuclear and cytoplasmic processes, particularly in gene expression, has increased significantly. In this review, we discuss the current advances in understanding the roles of PARylation with a particular emphasis in gene expression through RNA biogenesis and processing. In addition to updating PARP's significance in transcriptional regulation, we specifically focus on how PARPs and PARylation affect gene expression, especially inflammation-related genes, at the post-transcriptional levels by modulating RNA processing and degrading. Increasing evidence suggests that PARP inhibition is a promising treatment for inflammation-related diseases besides conventional chemotherapy for cancer.


Assuntos
Poli(ADP-Ribose) Polimerases/genética , RNA/metabolismo , Transporte Ativo do Núcleo Celular , Cromatina/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Poliadenilação , RNA/genética , Processamento de RNA , Proteínas de Ligação a RNA/metabolismo
15.
J Leukoc Biol ; 106(2): 431-446, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31075185

RESUMO

Cytoskeletal reorganization driven by Rho GTPases plays a crucial role in the migration of T cells, which are key regulators of immunity. The molecular mechanisms that control actin cytoskeleton remodeling during T cell movement have only partially been clarified as the function of many modulators has not been evaluated in these cells. Here, we report a new function of RhoGDI2 by showing that this protein positively regulates Rho GTPase activation during T cell adhesion and migration. RhoGDI2 knockdown significantly reduced T cell adhesion and migration. Furthermore, RhoGDI2 knockdown decreased the activation of Rac1 and Cdc42, 2 members of Rho GTPases, and the remodeling of the actin cytoskeleton. Upon P-selectin glycoprotein ligand-1 engagement, RhoGDI2 was phosphorylated at Y24 and Y153 by kinases related to ß2 integrin outside-in signaling, Src, c-Abl, and Syk, resulting in the accumulation of RhoGDI2 at the cell membrane. Subsequent phosphorylation of S31 induced the opening of RhoGDI2 and the release of Rho GTPases, whereas phosphorylation of Y153 might promote the activation of Rho GTPases by recruiting Vav1. Moreover, the disruption of lipid rafts with methyl-ß-cyclodextrin blocked the interaction between integrins and RhoGDI2, reducing the level of phosphorylated RhoGDI2 and the activation of downstream Rho GTPases. Based on these observations, RhoGDI2 is a target of intergrin outside-in signaling that activates Rho GTPases during T cell adhesion and migration, and RhoGDI2-mediated signal transduction is based on the lipid rafts integrity.


Assuntos
Antígenos CD18/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/metabolismo , Adesão Celular/genética , Adesão Celular/imunologia , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Microdomínios da Membrana/metabolismo , Fosforilação , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/deficiência
16.
J Cell Physiol ; 234(7): 11871-11881, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30478995

RESUMO

Acquired resistance to cytotoxic antineoplastic agents is a major clinical challenge in tumor therapy; however, the mechanisms involved are still poorly understood. In this study, we show that knockdown of CtIP, a corepressor of CtBP, promotes cell proliferation and alleviates G2/M phase arrest in etoposide (Eto)-treated HCT116 cells. Although the expression of p21 and growth arrest and DNA damage inducible α (GADD45a), which are important targets of p53, was downregulated in CtIP-deficient HCT116 cells, p53 deletion did not affect G2/M arrest after Eto treatment. In addition, the phosphorylation levels of Ser317 and Ser345 in Chk1 and of Ser216 in CDC25C were lower in CtIP-deficient HCT116 cells than in control cells after Eto treatment. Our results indicate that CtIP may enhance cell sensitivity to Eto by promoting G2/M phase arrest, mainly through the ATR-Chk1-CDC25C pathway rather than the p53-p21/GADD45a pathway. The expression of CtIP may be a useful biomarker for predicting the drug sensitivity of colorectal cancer cells.


Assuntos
Endodesoxirribonucleases/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA/efeitos dos fármacos , Etoposídeo/farmacologia , Células HCT116 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
17.
Oncol Lett ; 16(5): 6540-6546, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30405793

RESUMO

Lipid rafts, distinct liquid-ordered plasma membrane microdomains, have been shown to regulate tumor cell migration by internalizing and recycling cell-surface proteins. The present study reports that lipid rafts are a prerequisite for lamellipodia formation, which is the first step in the processes of tumor cell migration. The results from the wound-healing assay and immunostaining indicated that lipid rafts were asymmetrically distributed to the leading edge of migrating melanoma A375 cells during lamellipodia formation. When the integrity of lipids rafts was disrupted, lamellipodia formation was inhibited. The investigation of possible molecular mechanisms indicated that lipid rafts recruited ß1 and ß3 integrins, two important adhesion proteins for cell migration, to the lamellipodia. However, the different distribution characteristics of ß1 and ß3 integrins implied disparate functions in lamellipodia formation. Further immunostaining experiments showed that the actin cytoskeleton was responsible for lipid raft-mediated ß1 and ß3 integrin distribution in the lamellipodia. Together, these findings provide novel insights into the regulation of lipid rafts in lamellipodia formation, and suggest that lipid rafts may be novel and attractive targets for cancer therapy.

18.
Cancer Sci ; 109(12): 3826-3839, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30259595

RESUMO

Accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is a hallmark of tumor-associated inflammation, which is thought to be a barrier to immunosurveillance. Multiple factors secreted by tumor cells and tumor stromal cells are reported to be involved in promoting the expansion of MDSC. Herein, we showed that s.c. inoculation of tumor cells and i.v. injection of tumor-conditioned medium increased the number of MDSC. Subsequent investigation elucidated that chemokine (C-X-C motif) ligand 1 (CXCL1) and CXCL2, which were originally characterized as the chemokines of neutrophils, specifically promoted the expansion of monocytic MDSC (mo-MDSC), a subtype of MDSC, in the presence of granulocyte-macrophage colony-stimulating factor. Depletion of CXCL1 or CXCL2 in B16F10 cells or in B16F10-bearing mice noticeably decreased the generation of mo-MDSC in bone marrow. Moreover, we found that, in addition to the tumor cells, tumor-infiltrated CD11b+ myeloid cells also expressed CXCL1 and CXCL2. Furthermore, CXCL1- and CXCL2-induced increase of mo-MDSC was not correlated with chemotaxis, proliferation or apoptosis of mo-MDSC. These findings show a novel role of CXCL1 and CXCL2 in promoting mo-MDSC generation by favoring the differentiation of bone marrow cells in tumor-bearing conditions, which suggests that inhibition of CXCL1 and CXCL2 could decrease mo-MDSC generation and improve host immunosurveillance.


Assuntos
Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Melanoma Experimental/imunologia , Monócitos/citologia , Células Supressoras Mieloides/citologia , Animais , Apoptose , Antígeno CD11b/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células , Meios de Cultivo Condicionados/farmacologia , Camundongos , Monócitos/imunologia , Células Supressoras Mieloides/imunologia
19.
Biosci Biotechnol Biochem ; 82(10): 1733-1741, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29912633

RESUMO

Triple negative breast cancer (TNBC) patients cannot benefit from EGFR-targeted therapy even though the EGFR is highly expressed, because patients exhibit resistance to these drugs. Unfortunately, the molecular mechanisms remain relatively unknown. ANXA2, highly expressed in invasive breast cancer cells, is closely related with poor prognosis, and acts as a molecular switch to EGFR activation. In this study, MDA-MB-231 cells and MCF7 cells were used. Our results showed that ANXA2 expression is inversely correlated with cell sensitivity to gefitinib. Knockdown of ANXA2 expression in MDA-MB-231 cells increased the gefitinib induced cell death. When ANXA2 was overexpressed in MCF7 cells, the gefitinib induced cell death was decreased. Furthermore, we demonstrated that phosphorylation of ANXA2 at Tyr23 is negatively correlated with the sensitivity of TNBC to gefitinib. Altogether, our results suggest a new role of ANXA2 in regulating sensitivity of TNBC MDA-MB-231 cells to the EGFR inhibitor gefitinib.


Assuntos
Anexina A2/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Anexina A2/química , Anexina A2/genética , Anexina A2/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Técnicas de Silenciamento de Genes , Humanos , Fosforilação , Neoplasias de Mama Triplo Negativas/patologia , Tirosina/metabolismo
20.
Mol Med Rep ; 18(2): 1353-1360, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901076

RESUMO

Previous studies have demonstrated that lipid rafts and ß­adducin serve an important role in leukocyte rolling. In the present study the migratory ability and behavior of neutrophils was demonstrated to rely on the integrity of the lipid raft structure. ß­adducin was demonstrated to have a critical role in neutrophil migration. Knockdown of ß­adducin attenuated the migratory ability of dHL­60 cells and the distribution of ß­adducin in lipid raft structures was changed by N­formylmethionyl­leucyl­phenyl­alanine treatment. Furthermore, the findings demonstrated that the tyrosine phosphorylation of ß­adducin was required for its relocation. The results of the present study suggested that the lipid raft­associated protein ß­adducin may be a novel control point for the excessive infiltration of neutrophils during inflammation.


Assuntos
Movimento Celular , Proteínas do Citoesqueleto/metabolismo , Microdomínios da Membrana/metabolismo , Neutrófilos/metabolismo , Adulto , Feminino , Células HL-60 , Humanos , Masculino , N-Formilmetionina Leucil-Fenilalanina/análogos & derivados , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/citologia
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