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Given that combination with multiple biomarkers may well raise the predictive value of wound age, it appears critically essential to identify new features under the limited cost. For this purpose, the present study explored whether the gene expression ratios provide unique time information as an additional indicator for wound age estimation not requiring the detection of new biomarkers and allowing full use of the available data. The expression levels of four wound-healing genes (Arid5a, Ier3, Stom, and Lcp1) were detected by real-time polymerase chain reaction, and a total of six expression ratios were calculated among these four genes. The results showed that the expression levels of four genes and six ratios of expression changed time-dependent during wound repair. The six expression ratios provided additional temporal information, distinct from the four genes analyzed separately by principal component analysis. The overall performance metrics for cross-validation and external validation of four typical prediction models were improved when six ratios of expression were added as additional input variables. Overall, expression ratios among genes provide temporal information and have excellent potential as predictive markers for wound age estimation. Combining the expression levels of genes with ratio-expression of genes may allow for more accurate estimates of the time of injury.
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Contusiones , Ratas , Animales , Humanos , Ratas Sprague-Dawley , Contusiones/genética , Contusiones/metabolismo , Músculo Esquelético/metabolismo , Cicatrización de Heridas/genética , Biomarcadores/metabolismoRESUMEN
The invasion of cancer cells into interstitial tissues in a cohesive unit is termed collective invasion, and it is important for the invasion and metastasis of salivary adenoid cystic carcinoma (SACC). However, the underlying mechanisms regulating SACC collective invasion are still poorly understood. Here, we found that SACC tissues exhibited remarkable FAT1 downregulation and YAP1 upregulation at the invasive front, which was closely associated with collective invasion and distant metastasis. Decreasing FAT1 expression significantly activated the YAP1 signaling pathway and promoted collective invasion. Moreover, miR-183-5p was identified as the candidate regulator of FAT1 by bioinformatic analysis and an online database algorithm. A dual luciferase reporter experiment further confirmed that miR-183-5p directly targeted the FAT1 3'-UTR to reduce FAT1 expression. Increasing or decreasing miR-183-5p expression promoted or attenuated collective invasion, which was reversed by YAP1 siRNA or FAT1 siRNA, respectively. In addition, knocking down miR-183-5p reduced tumor burden and attenuated collective invasion in vivo. Together, these results suggest that the miR-183-5p/FAT1/YAP1 signaling pathway is a critical driver of SACC collective invasion, revealing a novel therapeutic target.
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Carcinoma Adenoide Quístico , MicroARNs , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Invasividad Neoplásica/genética , Transducción de Señal , ARN Interferente Pequeño , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Proliferación Celular , Cadherinas/metabolismoRESUMEN
OBJECTIVE: Investigating T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), Galectin 9 (Gal-9), CD160 expression and tumor-infiltrating lymphocytes (TILs) and correlation with clinicopathological characteristics of salivary adenoid cystic carcinoma (SACC). METHODS: Sixty cases of SACC were detected by immunohistochemical staining to evaluate TIM-3, Gal-9, and CD160 expression and analyze the correlation between TIM-3, Gal-9, CD160 expression and clinicopathologic features by rank-sum test. The association of TILs with TIM-3, Gal-9, and CD160 expression in SACC stromal was done by Chi-square test. RESULTS: TIM-3 and CD160 overexpression were correlated with recurrence of SACC (p = 0.029, p = 0.007, respectively). High Gal-9 expression was correlated with pathological classification (p = 0.018). The average percentage of TILs was 18.2% in SACC and most of TILs were more likely to occur in minor salivary glands (p = 0.038). Pairwise positive correlations were observed between the expression of TIM-3, Gal-9, and CD160 in tumor cells as well as in TILs, respectively. CONCLUSION: Low density of TILs was characteristic of the SACC microenvironment, with upregulation of TIM-3, Gal-9, and CD160 all occurring. However, TIM-3, Gal-9, and CD160 expression in the stromal dependent on the number of TILs represent potential therapeutic targets in SACC.
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Talent is one of the basic and strategic supports for building a modern socialist country in all aspects. Since the 1980s, the establishment of forensic medicine major and the cultivation of innovative talents in forensic medicine have become hot topics in higher education in forensic medicine. Over the past 43 years, the forensic medicine team of Shanxi Medical University has adhered to the joint education of public security and colleges, and made collaborative innovation, forming a training mode of "One Combination, Two Highlights, Three Combinations, Four in One" for innovative talents in forensic medicine. It has carried out "5+3/X" integrated reform, and formed a relatively complete talent training innovation mode and management system in teaching, scientific research, identification, major, discipline, team, platform and cultural construction. It has made a historic contribution to China's higher forensic education, accumulated valuable experience for the construction of first-class major and first-class discipline of forensic medicine, and provided strong support for the construction of the national new forensic talent training system. The popularization of this training mode is conducive to the rapid and sustainable development of forensic science, and provides more excellent forensic talents for national building, regional social development and the discipline construction of forensic science.
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Medicina Legal , Humanos , Medicina Legal/educación , AptitudRESUMEN
BACKGROUND: Tumour vascular normalisation therapy advocates a balance between pro-angiogenic factors and anti-angiogenic factors in tumours. Artemisinin (ART), which is derived from traditional Chinese medicine, has been shown to inhibit tumour growth; however, the relationship between ART and tumour vascular normalisation in oral squamous cell carcinoma (OSCC) has not been previously reported. METHODS: Different concentrations(0 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg)of ART were used to treat the xenograft nude mice model of OSCC. The effects of ART on migration and proliferation of OSCC and human umbilical vein endothelial cells (HUVEC) cells were detected by scratch assay and CCK-8 assay. OSCC cells with macrophage migration inhibitory factor (MIF) silenced were constructed to explore the effect of MIF. RESULTS: Treatment with ART inhibited the growth and angiogenesis of OSCC xenografts in nude mice and downregulated vascular endothelial growth factor (VEGF), IL-8, and MIF expression levels. ART reduced the proliferation, migration, and tube formation of HUVEC, as well as the expression of VEGFR1 and VEGFR2. When the dose of ART was 50 mg/kg, vascular normalisation of OSCC xenografts was induced. Moreover, VEGF and IL-8 were needed in rhMIF restoring tumour growth and inhibit vascular normalisation after the addition of rhMIF to ART-treated cells. CONCLUSION: Artemisinin might induce vascular normalisation and inhibit tumour growth in OSCC through the MIF-signalling pathway.
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The activation of CXCL12/CXCR4 axis participated in the progression of multiple cancers, but potential effect in terms of perineural invasion (PNI) in SACC remained ambiguous. In this study, we identified that CXCL12 substantially expressed in nerve cells. CXCR4 strikingly expressed in tumour cells, and CXCR4 expression was closely associated with the level of EMT-associated proteins and Schwann cell hallmarks at nerve invasion frontier in SACC. Activation of CXCL12/CXCR4 axis could promote PNI and up-regulate relative genes of EMT and Schwann cell hallmarks both in vitro and in vivo, which could be inhibited by Twist silence. After overexpressing S100A4, the impaired PNI ability of SACC cells induced by Twist knockdown was significantly reversed, and pseudo foot was visualized frequently. Collectively, the results indicated that CXCL12/CXCR4 might promote PNI by provoking the tumour cell to differentiate towards Schwann-like cell through Twist/S100A4 axis in SACC.
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Carcinoma Adenoide Quístico/patología , Quimiocina CXCL12/metabolismo , Transición Epitelial-Mesenquimal , Proteínas Nucleares/metabolismo , Receptores CXCR4/metabolismo , Proteína de Unión al Calcio S100A4/metabolismo , Neoplasias de las Glándulas Salivales/patología , Células de Schwann/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Animales , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/metabolismo , Línea Celular Tumoral , Movimiento Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Células de Schwann/patología , Transducción de Señal , Tasa de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) is a critical regulator of tumor immunology among various cancers. However, the role and underlying molecular mechanism of CMTM6 in oral squamous cell carcinoma (OSCC) progression remains unclear. METHODS: The expression of CMTM6, PD-L1 and CD163 in OSCC tissues were detected by immunohistochemistry on tissue microarray. The effect of CMTM6 knockdown on OSCC cells and macrophage polarization were analyzed by CCK-8 assay, apoptotic assay, would-healing assay, transwell assay and qPCR. OSCC cell derived exosomes were obtained by ultracentrifugation and the mechanistic studies were conducted by qPCR and Western Blot. 4-Nitroquinoline N-oxide (4NQO) induced OSCC mice were used for verifying the effect of CMTM6 downregulation on M2 macrophage infiltration and tumor growth. RESULTS: In OSCC samples, higher CMTM6 expression has been obviously associated with higher pathological stage of OSCC patients, CD163 + macrophages infiltration and PD-L1 expression. CMTM6 knockdown of OSCC cells inhibited proliferative, migrative and invasive abilities of OSCC cells, as well as inhibited M2 macrophage polarization in vitro with downregulating PD-L1 expression. Importantly, exosomes from OSCC cells shuttled CMTM6 to macrophages and promoted M2-like macrophage polarization through activating ERK1/2 signaling. In addition, in 4NQO-induced OSCC mice, CMTM6 level was positively associated with CD163, CD206 and PD-L1 as well as M2-like macrophage infiltration. CONCLUSION: OSCC cell-secreted exosomal CMTM6 induces M2-like macrophages polarization to promote malignant progression via ERK1/2 signaling pathway, revealing a novel crosstalk between cancer cells and immune cells in OSCC microenvironment.
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Biomarcadores de Tumor/metabolismo , Exosomas/metabolismo , Proteínas con Dominio MARVEL/metabolismo , Activación de Macrófagos/inmunología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neoplasias de la Boca/patología , Proteínas de la Mielina/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Movimiento Celular , Proliferación Celular , Exosomas/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas con Dominio MARVEL/genética , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/metabolismo , Proteínas de la Mielina/genética , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer dormancy is defined that the residual cancer cells could enter into a state of quiescence and patients remain asymptomatic for years or even decades after anti-tumor therapies. Fibroblasts, which represent a predominant cell type in tumor microenvironment, play a pivotal role in determining the ultimate fate of tumor cells. This review recapitulates the pleiotropic roles of fibroblasts which are divided into normal, senescent, cancer-associated fibroblasts (CAFs) and circulation CAFs in tumor dormancy, relapse, metastasis and resistance to therapy to help the treatment of cancer metastasis.
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Fatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown. Here, we summarize recent findings and update the current understanding that FAO may enable lymph node metastasis formation. Afterward, it will open innovative possibilities to present a distinct therapy of targeting FAO, the metabolic rewiring of cancer to terminal cancer patients.
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Fatty acid synthase (FASN) has been shown to be selectively up-regulated in cancer cells to drive the development of cancer. However, the role and associated mechanism of FASN in regulating the malignant progression of salivary adenoid cystic carcinoma (SACC) still remains unclear. In this study, we demonstrated that FASN inhibition attenuated invasion, metastasis and EMT of SACC cells as well as the expression ofPRRX1, ZEB1, Twist, Slug and Snail, among which the level of PRRX1 changed the most obviously. Overexpression of PRRX1 restored migration and invasion in FASN knockdown cells, indicating that PRRX1 is an important downstream target of FASN signalling. Levels of cyclin D1 and c-Myc, targets of Wnt/ß-catenin pathway, were significantly decreased by FASN silencing and restored by PRRX1 overexpression. In addition, FASN expression was positively associated with metastasis and poor prognosis of SACC patients as well as with the expression of PRRX1, cyclin D1 and c-Myc in SACC tissues. Our findings revealed that FASN in SACC progression may induce EMT in a PRRX1/Wnt/ß-catenin dependent manner.
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Carcinoma Adenoide Quístico/patología , Transición Epitelial-Mesenquimal , Ácido Graso Sintasas/metabolismo , Proteínas de Homeodominio/metabolismo , Neoplasias de las Glándulas Salivales/patología , Vía de Señalización Wnt , Animales , Apoptosis/genética , Carcinoma Adenoide Quístico/genética , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Proteínas de Homeodominio/genética , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Neoplasias de las Glándulas Salivales/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer cells collectively invading as a cohesive and polarized group is termed collective invasion, which is a fundamental property of many types of cancers. In this multicellular unit, cancer cells are heterogeneous, consisting of two morphologically and functionally distinct subpopulations, leader cells and follower cells. Leader cells at the invasive front are responsible for exploring the microenvironment, paving the way, and transmitting information to follower cells. Here, in this review, we will describe the important role of leader cells in collective invasion and the emerging underlying mechanisms of leader cell formation including intrinsic properties and the support from neighboring cells. It will help us to elucidate the essence of collective invasion and provide new anticancer therapeutic clues.
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Comunicación Celular/fisiología , Movimiento Celular/fisiología , Invasividad Neoplásica/patología , Microambiente Tumoral/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , HumanosRESUMEN
Emerging evidence has shown that dynamic crosstalk among cells in the tumor microenvironment modulates the progression and chemotherapeutic responses of cancer. Extracellular vesicles comprise a crucial form of intracellular communication through horizontal transfer of bioactive molecules, including long non-coding RNA (lncRNA), to neighboring cells. Three main types of extracellular vesicles are exosomes, microvesicles and apoptotic bodies, exhibiting a wide range of sizes and different biogenesis. Over the last decade, dysregulation of extracellular vesicle lncRNA has been revealed to remodel the tumor microenvironment and induce aggressive phenotypes of tumor cells, thereby facilitating tumor growth and development. This review will focus on extracellular vesicle lncRNA-mediated crosstalk between tumor cells and recipient cells, including tumor cells as well as stromal cells in the tumor microenvironment, and overview the mechanisms by which lncRNA are selectively sorted into extracellular vesicles, which may pave the way for their clinical application in cancer diagnosis and treatment.
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Comunicación Celular/genética , Vesículas Extracelulares/metabolismo , Neoplasias/genética , ARN Largo no Codificante/metabolismo , Microambiente Tumoral/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Movimiento Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/diagnóstico , Neoplasias/patología , ARN Largo no Codificante/análisis , Células del Estroma/patologíaRESUMEN
Most recently, mounting evidence has shown that cancer cells can invade as a cohesive and multicellular group with coordinated movement, which is called collective invasion. In this cohesive cancer cell group, cancer cells at the front of collective invasion are defined as leader cell that are responsible for many aspects of collective invasion, including sensing the microenvironment, determining the invasion direction, modifying the path of invasion and transmitting information to other cells. To fulfill their dispensable roles, leader cells are required to embark on some specific phenotypes with unusual expression of some proteins and it's very important to investigate into these proteins as they may serve as potential therapeutic targets. Here, in this review we will summarize current knowledge on four emerging proteins highly expressed in leader cells including K14, ΔNp63α, Dll4 and cysteine protease cathepsin B (CTSB), with a focus on their important roles in collective invasion and special mechanisms by which they promote collective invasion.
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Movimiento Celular , Invasividad Neoplásica/patología , Adhesión Celular , Transición Epitelial-Mesenquimal , Humanos , Modelos Biológicos , Transducción de SeñalRESUMEN
Great attention has been attached to explore the association between oral bacteria and oral cancer. Recently, four common inhabitants of oral cavity, Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola and Streptococcus anginosus, have been identified as potential etiologic bacterial agents for oral carcinogenesis. They might promote the oncogenesis and progression of oral cancer by induction of chronic inflammation, enhancement of migration and invasiveness, inhibition of cell apoptosis, augment of cell proliferation, suppression of immune system and production of carcinogenic substances. Thus, this review will focus on the possible mechanisms of these oral bacteria contributing to occurrence and development of oral cancer, and the potential clinical implications of utilizing oral bacteria on the diagnosis, prevention and treatment of oral cancer will be discussed.
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Neoplasias de la Boca/inmunología , Neoplasias de la Boca/microbiología , Animales , Bacterias/inmunología , Carcinogénesis/inmunología , Proliferación Celular/fisiología , Humanos , Oncogenes/inmunologíaRESUMEN
PURPOSE: The purpose of the present study was to compare the efficacy of intra-articular injections of different agents for temporomandibular osteoarthritis (TMJOA) using a network meta-analysis. MATERIALS AND METHODS: A comprehensive search strategy was performed in multiple English and Chinese language electronic databases. Randomized controlled trials comparing the effect of intra-articular injections of different agents to treat TMJOA were included in accordance with the inclusion and exclusion criteria. The bias of risk in each study was assessed, with data extraction performed independently by 2 reviewers. The primary outcomes included pain intensity and maximal mouth opening. RESULTS: A total of 11 trials were included in the present study, and 10 different agents (ie, hyaluronic acid, dexamethasone, prednisolone, betamethasone, betamethasone plus hyaluronic acid, morphine, tramadol, platelet-derived growth factor [PDGF], placebo, arthrocentesis alone) administered using intra-articular injections were assessed. The evidence from the direct comparisons showed that arthrocentesis plus sodium hyaluronate resulted in significantly better pain relief outcomes compared with arthrocentesis alone. Also, the visual analog scale score was further reduced to 1.27 by PDGF injection after arthrocentesis (arthrocentesis plus PDGF) compared with arthrocentesis alone. Morphine and tramadol had a high probability of being the best treatment for pain control, with PDGF ranked third. When considering pain relief, arthrocentesis plus sodium hyaluronate resulted in a better outcome than arthrocentesis alone, and arthrocentesis plus PDGF was better than arthrocentesis plus placebo. PDGF injections had the greatest probability of being the best treatment for improving joint opening, followed by sodium hyaluronate. CONCLUSIONS: Tramadol, morphine, and PDGF injections after arthrocentesis were effective in the treatment of TMJOA with excellent effects in reducing pain and improving joint opening. Hyaluronic acid injections were effective for improving the maximal mouth opening of patients with TMJOA in the short-term. The combination of a corticosteroid and hyaluronic acid injection reduced the symptoms of TMJOA more than corticosteroid injections alone, but not of hyaluronic acid alone.
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Osteoartritis , Trastornos de la Articulación Temporomandibular/tratamiento farmacológico , Artrocentesis , Humanos , Ácido Hialurónico/uso terapéutico , Inyecciones Intraarticulares , Resultado del TratamientoRESUMEN
The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is an oncogene overexpressed in a variety of human cancers. Here, we found that EZH2 correlated with poor survival of oral squamous cell carcinoma (OSCC) patients using immunohistochemistry staining. EZH2 overexpression led to a significant induction in tumour glycolysis, Epithelial-mesenchymal transition (EMT), migration and invasion of OSCC cells. Conversely, silencing of EZH2 inhibited tumour glycolysis, EMT, migration and invasion in OSCC cells. Ectopic overexpression of EZH2 increased phosphorylation of STAT3 at pY705 and decreased FoxO1 expression, and FoxO1 expression was enhanced when inhibiting STAT3. In addition, EZH2 overexpression led to a significant decrease in FoxO1 mRNA levels in nude mice xenograft. These results indicated that regulation of EZH2 might have the potential to be targeted for OSCC treatment.
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Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Forkhead Box O1/metabolismo , Glucólisis , Neoplasias de la Boca/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Animales , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Análisis Multivariante , Invasividad Neoplásica , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
Macrophage migration inhibitory factor (MIF) has been shown to closely associate with the malignant progression of a variety of human carcinomas. However, the role and its underlying molecular mechanisms of MIF in the invasion and metastasis of oral squamous cell carcinoma (OSCC) still remains unclear. Here, we found that MIF silencing reduced the cell proliferation, migration, and invasion, as well as matrix metalloprotein-2 (MMP-2) and MMP-9 in OSCC cells. Overexpression of MMP-2 or MMP-9 restored the migration and invasion of MIF-knockdown cells, indicating that MMP-2 and MMP-9 are downstream targets of MIF. In the xenograft model, MIF silencing inhibited tumor growth and in lymph metastasis model, MIF silencing reduced tumor metastasis. More importantly, immunohistochemistry staining in a tissue microarray (TMA) demonstrated that MIF expression was positively correlated with clinic stage, recurrence, metastasis, and poor prognosis of patients with OSCC as well as with the levels of MMP-2 or MMP-9 in TMA. Therefore, our findings suggest that MIF may promote the invasion and metastasis of OSCC through the activation of MMP-2 and MMP-9 and prompt further investigation into the therapeutic value of MIF for OSCC treatment.
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Carcinoma de Células Escamosas/genética , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Neoplasias de la Boca/genética , Anciano , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Neoplasias de la Boca/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , PronósticoRESUMEN
Macrophage migration inhibitory factor (MIF) is a prominent orchestrator during the onset and progression of cancer. Recently, MIF was detected in salivary adenoid cystic carcinoma (SACC). However, its functional effect in perineural invasion (PNI) of SACC remained unknown. To illuminate the effect of MIF in genesis of PNI in SACC, we examined the expression of MIF, epithelial-to-mesenchymal transition (EMT)-related markers, and Schwann cell markers by immunohistochemical analysis in 158 cases of SACC samples. Meanwhile, the correlation between MIF and PNI of SACC species was analyzed. Our data indicated that MIF expression was associated with PNI of SACC significantly. In vitro, the silence and overexpression experiments of MIF were performed in SACC cell lines. The ability of migration, invasion and PNI could be inhibited significantly by siRNA-mediated MIF silence, and the occurrence of EMT and Schwann-like cell differentiation was also inhibited by MIF silence in SACC-LM cells. Overexpression of MIF in SACC-83 cells using expressive plasmid showed the opposite effects. Our findings identified that an association between PNI and MIF expression existed. MIF may promote PNI of SACC by participating in cytoskeletal reorganization and pseudo foot formation induced by EMT and the Schwann-like cell differentiation of SACC cells.
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Carcinoma Adenoide Quístico/patología , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Neoplasias de las Glándulas Salivales/patología , Células de Schwann/citología , Carcinoma Adenoide Quístico/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Invasividad Neoplásica , Neoplasias de las Glándulas Salivales/metabolismo , Células de Schwann/patologíaRESUMEN
BACKGROUND: Salivary adenoid cystic carcinoma (SACC) can recur after removal of the primary tumor and treatment, where they can keep no clinical symptoms and dormant state for 10-15 years. NR2F1 has been demonstrated to regulate the tumor cell dormancy in various malignant tumors and has a potential impact on recurrence and metastasis of carcinoma. However, the role and significance of NR2F1 in SACC dormancy still remain unknown. METHODS: A total number of 59 patients with a diagnosis of SACC were included to detected expression of NR2F1, Ki-67 by immunohistochemical (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling (TUNEL). Fisher's exact test was used to examine the NR2F1 expression and clinicopathologic parameters of SACC. In vitro, SACC cell lines were transfected NR2F1 and knockdown NR2F1 respectively. CCK-8, flow cytometry, wound healing assay and transwell invasion determined SACC cell proliferation, apoptosis, cell cycle, migration and invasion respectively. Chromatin immunoprecipitation (ChIP) assays were utilized to demonstrate the potential role of NR2F1 in SACC invasion via CXCL12/CXCR4 axis. In vivo, xenografts of nude mice via subcutaneous injection or tail vein injection were used to testify the results in vitro. RESULTS: Among the 59 patients with SACC, 23.73% (14/59) were positive to NR2F1 expression, a lower rate of expression compared with 60% (6/10) in normal salivary gland samples. NR2F1 was correlated with metastasis, relapse and dormancy of SACC. SACC cells with transfected NR2F1 remained dormant, as well as enhanced invasion and metastasis. Knockdown of NR2F1 via siRNA after NR2F1 overexpression restored the proliferation and the cell number in G2/M phases, and reduced the abilities of migration and invasion. In addition, NR2F1 promoted the expression of CXCL12 and CXCR4, and overexpression of CXCL12 at least partly rescued the proliferation, migration, and invasion activities induced by NR2F1 silencing. CONCLUSIONS: NR2F1 may be an underlying mechanism of SACC recurrence and metastasis via regulating tumor cell dormancy through CXCL12/CXCR4 pathway.
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Factor de Transcripción COUP I/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Quimiocina CXCL12/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Receptores CXCR4/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Adulto , Anciano , Animales , Apoptosis , Factor de Transcripción COUP I/genética , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Estudios de Cohortes , Femenino , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Transducción de Señal , Transfección , Adulto JovenRESUMEN
Epithelial-mesenchymal transition (EMT) has been shown to associate with cancer stem cells and radioresistance. However, it is obscure whether EMT itself or specific EMT regulators play causal roles in these properties of salivary adenoid cystic carcinoma (SACC). Here, we exhibited that overexpression of HSP27 drove the migration and invasion, induced EMT, as well as mediated TGF-ß1-induced EMT in SACC cells, accompanying the up-regulation of Snail1 and Prrx1. Conversely, HSP27 silencing reduced the migration and invasion and contributed to MET of SACC cells. HSP27 indirectly down-regulates the expression of E-cadherin through activating Snail1 and Prrx1 expressions. Overexpression of Snail1 or Prrx1 restored the migration and invasion in HSP27 knockdown cells. Enforced expression of HSP27 enhanced colony formation, CD133+ /CD44+ population and radioresistance of SACC cell lines. In addition, HSP27 expression was positively associated with radioresistance and poor prognosis of SACC patients as well as with the expression of Prrx1 or Snail1 in SACC tissues. The data confirm an important function for HSP27 in SACC progression through regulating EMT and stemness, and they imply the possible association between EMT and radioresistance of SACC.