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1.
Artigo em Inglês | MEDLINE | ID: mdl-31606425

RESUMO

OBJECTIVE: This study aimed to explore the relationship between the expression of the coxsackie-adenovirus receptor (CAR) in oral squamous cell carcinoma (OSCC) and the clinicopathologic parameters associated with the disease. The diagnostic and prognostic potential of CAR in OSCC was also investigated. STUDY DESIGN: Immunohistochemistry was performed on human tissue microarrays, containing 42 oral mucosa, 69 dysplasia, and 176 OSCC tissue sections, to reveal the expression pattern of CAR. Statistical analysis was used to determine the correlation between CAR expression and the patient survival rate as a measure of the prognostic value of CAR. RESULTS: CAR was overexpressed in human OSCC tissues (P = .002), and higher expression of CAR was associated with a lower survival rate, which was not statistically significant (P = .123). In addition, patients with OSCC in the human papillomavirus (HPV)-positive group showed significantly higher CAR expression compared with the HPV- negative group (P = .0491). CONCLUSIONS: This study indicated that CAR expression was upregulated in human OSCC and that patients with OSCC with higher expression of CAR had a lower survival rate. Moreover, CAR expression may be associated with HPV infection.

2.
Int J Biol Sci ; 15(11): 2408-2418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595158

RESUMO

Meiotic maturation of oocyte is an important process for successful fertilization, in which cytoskeletal integrality takes a significant role. The p-21 activated kinases (PAKs) belong to serine/threonine kinases that affect wide range of processes that are crucial for cell motility, survival, cell cycle, and proliferation. In this study, we used a highly selective inhibitor of PAK4, PF-3758309, to investigate the functions of PAK4 during meiotic maturation of mouse oocytes. We found that PAK4 inhibition resulted in meiotic arrest by inducing abnormal microfilament and microtubule dynamics. PAK4 inhibition impaired the microtubule stability and led to the defective kinetochore-microtubule (K-M) attachment which inevitably resulted in aneuploidy. Also, PAK4 inhibition induced abnormal acentriolar centrosome assembly during meiotic maturation. In conclusion, all these combined results suggest that PAK4 is necessary for the oocyte meiosis maturation as a regulator of cytoskeleton.

3.
Oral Oncol ; 96: 131-139, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422204

RESUMO

OBJECTIVES: Dysregulation of immune cells in the tumor microenvironment is a hallmark of head and neck squamous cell carcinoma (HNSCC). Increased infiltration of pDCs has been reported in the microenvironment of HNSCC. However, the precise immunological role of pDC and the therapeutic effects of pDC depletion in HNSCC need to be further investigated. MATERIALS AND METHODS: CD317 antibodies were applied for depleting pDCs in an immunocompetent transgenic HNSCC mouse model. Tumor volume was monitored. Flow cytometric analysis was conducted for studying the immune profile changes after pDC depletion. In addition, immunohistochemical staining was carried out in a human HNSCC tissue microarray for detecting the infiltration of pDCs. We also analyzed the survival implication of pDCs and its correlation with other immune related markers in human HNSCC. RESULTS: pDC depletion in the transgenic HNSCC mouse model significantly delayed tumor growth. After pDCs were depleted, T cells were markedly revitalized, and the proportions of regulatory T cells (Tregs) and monocytic myeloid-derived suppressor cells (MDSCs) were decreased. In human HNSCC microenvironment, pDC infiltration was upregulated and its high infiltration conferred a poor prognosis. Moreover, pDC infiltration was closely correlated with the expression of Foxp-3, PD-1, TIM-3, and LAG-3. CONCLUSION: Our findings demonstrated that pDCs play a negative immunomodulatory role in HNSCC and may present as a target for effective immunotherapy.

4.
Cancer Immunol Res ; 7(10): 1700-1713, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387897

RESUMO

Immunosuppression is common in head and neck squamous cell carcinoma (HNSCC). In previous studies, the TIGIT/CD155 pathway was identified as an immune-checkpoint signaling pathway that contributes to the "exhaustion" state of infiltrating T cells. Here, we sought to explore the clinical significance of TIGIT/CD155 signaling in HNSCC and identify the therapeutic effect of the TIGIT/CD155 pathway in a transgenic mouse model. TIGIT was overexpressed on tumor-infiltrating CD8+ and CD4+ T cells in both HNSCC patients and mouse models, and was correlated with immune-checkpoint molecules (PD-1, TIM-3, and LAG-3). TIGIT was also expressed on murine regulatory T cells (Treg) and correlated with immune suppression. Using a human HNSCC tissue microarray, we found that CD155 was expressed in tumor and tumor-infiltrating stromal cells, and also indicated poor overall survival. Multispectral IHC indicated that CD155 was coexpressed with CD11b or CD11c in tumor-infiltrating stromal cells. Anti-TIGIT treatment significantly delayed tumor growth in transgenic HNSCC mouse models and enhanced antitumor immune responses by activating CD8+ T-cell effector function and reducing the population of Tregs. In vitro coculture studies showed that anti-TIGIT treatment significantly abrogated the immunosuppressive capacity of myeloid-derived suppressor cells (MDSC), by decreasing Arg1 transcripts, and Tregs, by reducing TGFß1 secretion. In vivo depletion studies showed that the therapeutic efficacy by anti-TIGIT mainly relies on CD8+ T cells and Tregs. Blocking PD-1/PD-L1 signaling increased the expression of TIGIT on Tregs. These results present a translatable method to improve antitumor immune responses by targeting TIGIT/CD155 signaling in HNSCC.

5.
Environ Mol Mutagen ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454112

RESUMO

Ortho-phenylphenol (OPP), as an active ingredient of disinfectants, has been worldwide utilized as fungicides and antibacterial agents in hospital, agriculture, wood preservation, and veterinary products. However, little is known about the toxic effects of OPP on male reproduction, especially sperm motility, and the underlying mechanisms. In this study, we chose porcine sperms as in vitro model to investigate the effects and mechanisms of OPP exposure on sperm motility. Our results indicated that porcine sperm motility decreases significantly in a dose-dependent manner after exposed to OPP. Additionally, ATP synthesis deficiency was revealed by downregulation of ATP synthase subunit beta and adenosine 5'-monophosphate-activated protein kinase expression. Furthermore, OPP disturbed the expression of TP53 and PTEN, which contributed to AKT pathway deactivation. OPP exposure also disrupted platelet-derived growth factor receptor A expression, which further inhibited 3-phosphoinositide-dependent protein kinase 1 activation, resulting in protein kinase B and pyruvate dehydrogenase phosphatase catalytic subunit 1 deactivation. In conclusion, these observations suggest that OPP exposure decreases porcine sperm motility by disturbing the AMPK/AKT signaling pathway. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.

6.
Curr Med Sci ; 39(3): 442-448, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209817

RESUMO

The role of heat shock protein 70 (HSP70) in apoptosis of human retinal pigment epithelial cells (ARPE-19) induced by 4-hydroxy-2-nonenal (4-HNE) was explored. Different concentrations of 4-HNE were used to stimulate ARPE-19 cells, and apoptosis was measured by flow cytometry. The expression of apoptotic-related proteins, HSP70, X-linked inhibitor-of-apoptosis (XIAP), Bcl-2, and Bax were quantified by Western blotting. HSP70 and XIAP overexpression plasmids, or their corresponding siRNAs were transfected into ARPE-19 cells using Lipofectamine™ 2000. Co-immunoprecipitation and Western blotting were used to detect the effect of 4-HNE on the expression of HSP70 and the binding level between 4-HNE and HSP70. The results showed that 4-HNE induced late apoptosis in ARPE-19 cells, accompanied by elevated levels of 4-HNE-modified HSP70, but it did not affect HSP70 protein expression. 4-HNE-modified HSP70 down-regulated the expression of the apoptosis inhibitory protein XIAP. Overexpression of HSP70 or XIAP inhibited 4-HNE-induced apoptosis of ARPE-19 cells. It was suggested that 4-HNE could promote XIAP degradation by modification of HSP70 to induce late apoptosis of human retinal pigment epithelial cells.

7.
J Exp Clin Cancer Res ; 38(1): 278, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238980

RESUMO

BACKGROUND: Partial epithelial mesenchymal transition (p-EMT) was found to play a potential role in the initial stage of metastasis in human head and neck squamous cell carcinoma (HNSCC). Some long noncoding RNAs (lncRNAs) have been reported to function as promoters or inhibitors of cancer metastasis. This study aimed to identify p-EMT-related lncRNAs in HNSCC. METHODS: Differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DEGs) in HNSCC obtained from The Cancer Genome Atlas (TCGA) were screened out by using the "edgeR" package. DE-lncRNAs in the Oral squamous cell carcinoma (OSCC) lncRNA microarray dataset GSE84805 were screened out by using the "limma" package. Slug-related lncRNAs were determined by Pearson correlation analysis (|Pearson correlation coefficient| ≥ 0.4, p < 0.01) based on TCGA. Survival analysis were performed for the overlapping DE-lncRNAs by using the "Survival" package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to predict the potential functions of MYOSLID. RT-qPCR and In Site Hybridization (ISH) were used to explore the MYOSLID expression and its clinical significance in HNSCC specimens. Immunohistochemical staining, siRNA, wound healing assay, transwell assay, and western blot were used to explore the biological function and potential molecular mechanisms. RESULTS: MYOSLID was identified as a Slug-related lncRNA and with prognostic value among the 9 overlapping DE-lncRNAs. GO and KEGG analyses revealed that MYOSLID was closely related to important biological processes and pathways that regulate cancer metastasis. The results of univariate and multivariate Cox regression analysis based on TCGA and HNSCC tissue microarray data suggested MYOSLID was an independent prognostic factor. MYOSLID expression in HNSCC was closely correlated with Slug, PDPN and LAMB3. The knockdown of MYOSLID in OSCC cell line significantly inhibited cell migration and invasion compared to those in the control cells. In addition, the knockdown of MYOSLID significantly reduced Slug, PDPN and LAMB3 expression levels. However, the knockdown of MYOSLID had no effect on the expression levels of the EMT biomarkers E-cadherin and Vimentin. CONCLUSIONS: Our study revealed that MYOSLID expression was closely related to the p-EMT program in HNSCC, and it might be a new predictive biomarker for aggressive HNSCC.

8.
Dis Markers ; 2019: 5421985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089395

RESUMO

Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) and transmembrane and immunoglobulin domain containing 2 (TMIGD2) are new immune checkpoint molecules of the B7:CD28 family; however, little research has been performed on these immune checkpoint molecules. In this study, we used oral squamous cells carcinoma (OSCC) tissue microarrays and immunohistochemistry methods to investigate the expression patterns of HHLA2 and TMIGD2 in OSCC. After comparing the HHLA2 and TMIGD2 expression levels in OSCC, dysplasia, and mucosa, we found increased HHLA2 expression in OSCC and dysplasia, while the TMIGD2 expression was decreased in OSCC and dysplasia. Using the Kaplan-Meier method and log-rank test, we found that higher HHLA2 or TMIGD2 expression levels in OSCC indicate poor prognosis. Furthermore, two-tailed Pearson's statistical analysis revealed that the HHLA2 expression levels in OSCC, dysplasia, and mucosa were positively correlated with the T cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), B7 homolog 3 protein (B7-H3), B7 homolog 4 protein (B7H4), and V-domain Ig suppressor of T cell activation (VISTA) levels, while the TMIGD2 expression levels in OSCC, dysplasia, and mucosa were inversely correlated with the TIM3, LAG3, and B7H3 levels. Our current study demonstrates that HHLA2 may serve as an immune target for OSCC therapy and that the TMIGD2 expression level in OSCC could forecast patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Antígenos CD28/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Imunoglobulinas/genética , Neoplasias Bucais/genética , Biomarcadores Tumorais/metabolismo , Antígenos CD28/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imunoglobulinas/metabolismo , Masculino , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia
9.
Int J Syst Evol Microbiol ; 69(6): 1821-1825, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30994432

RESUMO

One bacterial strain, denoted as LB2P30T, was isolated from Laigu glacier located on the Tibetan Plateau, PR China. Strain LB2P30T was an aerobic, non-motile, rod-shaped, yellow-pigmented and Gram-stain-negative bacterium. The temperature range for growth was 4-20 °C (optimum, 14 °C). The phylogenetic analysis based on partial 16S rRNA gene sequences showed that strain LB2P30T belonged to the genus Flavobacterium and was most similar to Flavobacterium fluvii (98.12 %) and Flavobacterium limicola (97.91 %). The average nucleotide identity values between strain LB2P30T and its closest relatives, F. fluvii DSM 19978T and F. limicola DSM 15094T, were 76.73 % and 77.40 %, respectively. Cells of strain LB2P30T contained summed feature 3 (comprising C16:1ω7c and/or C16:1ω6c) and iso-C15 : 0 as the predominant fatty acids and menaquinone-6 as the sole menaquinone. The genomic DNA G+C content was 34.74 mol%. Based on the phenotypic, chemotaxonomic, genotypic and phylogenetic characteristics, we propose strain LB2P30T as a novel species of the genus Flavobacterium with the nomenclature of Flavobacteriumlaiguense sp. nov. The type strain is LB2P30T (=CGMCC 1.11271T=NBRC 113059T).


Assuntos
Flavobacterium/classificação , Camada de Gelo/microbiologia , Filogenia , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/química , Flavobacterium/isolamento & purificação , Pigmentação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Tibet , Vitamina K 2/análogos & derivados , Vitamina K 2/química
10.
Reproduction ; 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30884466

RESUMO

It is demonstrated that repeated superovulation has deleterious effects on mouse ovaries and cumulus cells. However, little is known about the effects of repeated superovulation on early embryos. Epigenetic reprogramming is an important event in early embryonic development, and could be easily disrupted by the environment. Thus, we speculated that multiple superovulations may have adverse effects on histone modifications in the early embryos. Female CD1 mice were randomly divided into four groups: (a) spontaneous estrus cycle (R0); (b) with once superovulation (R1); (c) with three times superovulation at a 7-day interval (R3); (d) with five times superovulation at a 7-day interval (R5). We found that repeated superovulation remarkably decreased the fertilization rate. With the increase of superovulation times, the rate of early embryo development was decreased. The expression of Oct4, Sox2, and Nanog was also affected by superovulation in blastocysts. The immunofluorescence results showed that the acetylation level of histone 4 at lysine 12 (H4K12ac) was significantly reduced by repeated superovulation in mouse early embryos (P<0.01). Acetylation level of histone 4 at lysine 16 (H4K16ac) was also significantly reduced in pronuclei and blastocyst along with the increase of superovulation times (P<0.01). H3K9me2 and H3K27me3 were significantly increased in 4-cell embryos and blastocysts. We further found that repeated superovulation treatment increased the mRNA level of histone deacetylases Hdac1, Hdac2, and histone methyltransferase G9a, but decreased the expression level of histone demethylase-encoding genes Kdm6a and Kdm6b in early embryos. In a word, multiple superovulations alter histone modifications in early embryos.

11.
Histol Histopathol ; 34(7): 803-810, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30632601

RESUMO

Glycoprotein non-metastatic protein B (GPNMB) is a transmembrane glycoprotein that is highly expressed in several malignancies compared with its expression in matched healthy tissues. The aim of this study was to investigate the clinical characteristics and prognostic value of GPNMB expression in tumor tissue derived from a cohort of patients with head and neck squamous cell carcinoma (HNSCC). GPNMB expression in human HNSCC, oral dysplasia and normal mucosal tissue was evaluated by immunohistochemistry (IHC). The correlations of GPNMB expression with the clinical characteristics of HNSCC were assessed by one-way ANOVA and t test analyses. Survival data were analyzed using Kaplan-Meier analysis and the Cox proportional hazards model. GPNMB was highly expressed in HNSCC tissue compared with dysplasia and normal mucosal tissue. Additionally, a high level of GPNMB expression in HNSCC was associated with poor prognosis (P<0.01). In the analysis of tumor-node-metastasis (TNM) staging, a high GPNMB expression level in HNSCC tissue, as well as metastatic lymph node tissue, correlated with an advanced N stage. In conclusion, GPNMB was overexpressed in human HNSCC tissue and predicted poor prognosis in human HNSCC tissue. In addition, GPNMB expression was closely correlated with N stage in patients with HNSCC.

12.
Head Neck ; 41(4): 1080-1086, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30549148

RESUMO

BACKGROUND: This study aims to investigate the characteristic role of inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) in oral squamous cell carcinoma (OSCC). METHODS: The expressions of LAIR-1 and other immune-related molecules were detected in a human OSCC tissue microarray. LAIR-1 expression difference among different clinicopathological parameters was analyzed. The correlations of LAIR-1 with several immune-related markers were assessed. RESULTS: Compared with dysplasia and oral mucosa, the expression of LAIR-1 was significantly upregulated in the stroma of OSCC, and its overexpression was correlated with advanced pathological grade. Overexpression of LAIR-1 was significantly associated with tumor-associated macrophage and myeloid-derived suppressor cell markers (CD68, CD163; CD33, CD11b), indoleamine 2,3-dioxygenase (IDO) and two immune checkpoints (B7-H3 and VISTA). CONCLUSIONS: Overexpression of LAIR-1 was associated with advanced pathological grade and correlated with immune suppressive features in OSCC. Further studies are required to identify the specific immunological role of LAIR-1.

13.
Environ Toxicol Pharmacol ; 64: 172-180, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30445373

RESUMO

Malathion is a wide spectrum organophosphorothionate insecticide that is frequently found in drinking water, food and foodstuffs. Ovarian granulosa cells modulate oogenesis by providing metabolic nutrients to oocytes. They can decide the fate of folliculogenesis and oocyte maturation by supplying regulatory cues that help in reproduction. However, little is known about the underlying mechanisms of malathion as a reproductive toxicant in porcine granulosa cells. In the present study, we found that malathion has obvious toxic effects on cultured porcine granulosa cells in a dose-dependent manner. Malathion exposure resulted in significantly increased oxidative stress levels and DNA damage response, which was measured by the mRNA expression levels of homologous recombination (HR) pathway and non-homologous end-joining (NHEJ) pathway-related genes. Subsequently, it was found that malathion exposure could induce apoptosis and autophagy by qRT-PCR and fluorescence intensity analysis. In conclusion, malathion is a reproductive toxicant by inhibiting granulosa cell proliferation by multiple pathways connected to oxidative stress, DNA damage, apoptosis and autophagy.

14.
Pest Manag Sci ; 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30152098

RESUMO

BACKGROUND: Fenoxaprop-ethyl (FE) is an active ingredient of commercially available herbicide formulations. Its overuse has caused much damage to the environment, livestock breeding, agricultural crops and humans. However, little is known about the effects of FE exposure on female reproductive health and the mechanisms underlying those effects. In this study, we investigated the toxic effects of FE on oocyte quality and their underlying mechanisms in mice fed a diet containing FE. RESULTS: Ovary weight and numbers of oocytes were reduced in FE-treated mice. Moreover, oocyte quality was seriously impaired, as shown by the reduced rate of first polar body extrusion and fertilization ability in vivo. In FE-treated mice, oocytes presented reduced actin expression and abnormal meiotic spindle morphology, which indicate that cytoskeletal integrality is disrupted. Also, FE induced mitochondrial dysfunction, reflected by the accumulation of reactive oxygen species (ROS), apoptosis and autophagy, as revealed by fluorescent staining analysis and real-time polymerase chain reaction (qPCR). Finally, FE led to changes in epigenetic modifications such as histone H3K27me3 and H3K9me2 in oocytes. CONCLUSIONS: Our results indicate that FE has adverse effects on oocyte quality as assessed by maturation and fertilization potential, due to disrupted cytoskeletal integrality, and mitochondrial dysfunction leading to ROS accumulation, apoptosis and autophagy. © 2018 Society of Chemical Industry.

15.
BMC Endocr Disord ; 18(1): 41, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29921267

RESUMO

BACKGROUND: Pheochromocytoma, especially for noncatecholamine-secreting pheochromocytoma, is an extremely rare cause of ectopic corticotrophin-releasing hormone (CRH) syndrome. CASE PRESENTATION: A 27-year-old Chinese woman was administered dexamethasone for a skin allergy, but her general condition rapidly deteriorated over a month. She was subsequently hospitalized for typical clinical features of Cushing's syndrome. Endocrinological investigation confirmed severe hypercortisolism along with elevated plasma adrenocorticotropin hormone (ACTH). However, magnetic resonance imaging (MRI) revealed no pituitary adenoma. Abdominal contrast-enhanced computed tomography (CT) revealed a 6.5 cm heterogeneous right adrenal mass with mildly contrast enhancement. The tumor was found during a routine physical check-up at a local hospital 16 months ago; however, the patient did not have any symptoms and did not seek further medical attention at that time. Laparoscopic resection of the right adrenal tumor led to a rapid remission of Cushing's syndrome. Based on pathological findings and the presence of normal catecholamine metabolites in her serum and urine, the patient was diagnosed with noncatecholamine-secreting pheochromocytoma. Immunohistochemical staining of the adrenal tumor revealed positive staining for CRH and negative staining for ACTH. CONCLUSIONS: This is an extremely rare case of ectopic CRH syndrome caused by an adrenal noncatecholamine-secreting pheochromocytoma. Both ectopic ACTH syndrome and ectopic CRH syndrome should be considered in patients presenting with ACTH-dependent Cushing's syndrome caused by extrapituitary diseases.


Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Hormônio Liberador da Corticotropina/metabolismo , Síndromes Endócrinas Paraneoplásicas/etiologia , Feocromocitoma/complicações , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Feminino , Humanos , Imuno-Histoquímica , Feocromocitoma/metabolismo , Feocromocitoma/patologia
16.
Cell Mol Life Sci ; 75(22): 4223-4234, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29955905

RESUMO

The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/terapia , Dasatinibe/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator de Transcrição STAT3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral , Quinases da Família src/antagonistas & inibidores
17.
Future Oncol ; 14(11): 1091-1100, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29714078

RESUMO

AIM: p21-activated kinase 2 (PAK2) is overexpressed in several tumors but the expression of PAK2 in oral squamous cell carcinomas (OSCCs) remains unclear. MATERIALS & METHODS: Immunohistochemistry was performed on human tissue microarrays containing 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa. RESULTS: PAK2 expression was increased in primary OSCC compared with normal mucosa and significantly increased in primary OSCC grade III compared with grade I, but independent of overall survival rate. Moreover, the expression of PAK2 was statistically correlated with Lck/Yes novel tyrosine kinase (LYN), zinc finger transcription factor Slug, tumor-associated macrophage marker CD163 and LAG3. CONCLUSION: Overexpression of PAK2 in OSCC may be associated with an advanced pathology grade.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Quinases Ativadas por p21/genética , Adulto , Idoso , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/patologia , Gradação de Tumores , Proteínas de Neoplasias/genética , Prognóstico , Receptores de Superfície Celular/genética , Análise Serial de Tecidos
18.
Am J Clin Pathol ; 150(1): 74-83, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29788173

RESUMO

Objectives: The aims of this study were to investigate the relationship between Golgi phosphoprotein 2 (GOLPH2) and oral squamous cell carcinoma (OSCC) and explore the clinical significance of GOLPH2 in OSCC. Methods: Tissue microarrays from human OSCC samples were stained for GOLPH2 expression and clinicopathologic features. Kaplan-Meier analysis was used to compare the survival of patients with high GOLPH2 expression and patients with low GOLPH2 expression. Results: We found GOLPH2 is highly expressed in OSCC tissue, and the GOLPH2 expression in metastatic lymph nodes is higher than in tumor tissue. Our data indicate that patients with higher GOLPH2 expression have poor overall survival compared with those with lower GOLPH2 expression. This study demonstrated that GOLPH2 was associated with CD44, SOX2, Slug, B7-H3, B7-H4, TIM3, and VISTA. Conclusions: These findings suggest GOLPH2 is a potential marker for estimating the patient's prognosis and may be a target for molecular-targeted therapy against OSCC.

19.
J Mol Histol ; 49(4): 389-398, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29846864

RESUMO

IQ-domain GTPase-activating protein 1 (IQGAP1) is associated with the development and progression of many human cancers. We aimed to investigate the expression and clinicopathological significances of IQGAP1 in head and neck squamous cell carcinoma (HNSCC). In this study, immunohistochemical staining of IQGAP1, co-inhibitory immune checkpoint molecules and macrophage markers were performed in human HNSCC samples to analyze the expression and correlation with clinicopathological characteristics. Immunoreactivity of IQGAP1 was also detected in immunocompetent mouse HNSCC tissue. We found that IQGAP1 expression level was significantly increased in human HNSCC compared with dysplasia and normal mucosa, and the expression of IQGAP1 in HNSCC was positively associated with advanced lymph node status. Besides, our data indicated that patients with higher IQGAP1 expression exhibited poor overall survival compared with patients with lower IQGAP1 expression. Furthermore, this study demonstrated that IQGAP1 expression was positively associated with TIM3, Galectin-9 (TIM3 ligand), B7H4, macrophage markers CD68 and CD163. In conclusion, these findings suggest that over-expression of IQGAP1 in human HNSCC may indicate poor prognosis.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Carcinoma de Células Escamosas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Linfonodos/patologia , Masculino , Camundongos Knockout , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de Sobrevida
20.
Biomark Med ; 12(7): 759-769, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29847156

RESUMO

AIM: Immunohistochemistry was used to detect the expression of Stathmin 1 and Serine 38 phospho-Stathmin 1 (p-Stathmin 1S38) in head and neck squamous cell carcinoma (HNSCC) and research its correlation with clinical parameters, survival and expression of immune checkpoint molecules. RESULTS: Stathmin 1 and p-Stathmin 1S38 overexpression in primary HNSCC is associated with poor overall survival. Stathmin 1 expression is related to tumor size, category and lymph node status. Stathmin 1 expression correlates with PD-L1, TIM3, VISTA, B7-H3, B7-H4, LAG-3 and p-STAT3 expression in HNSCC. P-Stathmin 1S38 expression correlates with PD-L1, VISTA, B7-H4, LAG-3 and p-STAT3 in HNSCC. CONCLUSION: We found expression of Stathmin 1 and p-Stathmin 1S38 indicates poor survival in HNSCC and may be associated with immune suppression.

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