RESUMEN
In brief: Genes expressed in cumulus cells might be used as markers for competent oocytes/embryos. This study identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos. Abstract: Studies on the mechanisms behind cumulus expansion and cumulus cell (CC) apoptosis are essential for understanding the mechanisms for oocyte maturation. Genes expressed in CCs might be used as markers for competent oocytes and/or embryos. In this study, both in vitro (IVT) and in vivo (IVO) mouse oocyte models with significant difference in cumulus expansion and CC apoptosis were used to identify and validate new genes regulating cumulus expansion and CC apoptosis of mouse oocytes. We first performed mRNA sequencing and bioinformatic analysis using the IVT oocyte model to identify candidate genes. We then analyzed functions of the candidate genes by RNAi or gene overexpression to select the candidate cumulus expansion and CC apoptosis-regulating genes. Finally, we validated the cumulus expansion and CC apoptosis-regulating genes using the IVO oocyte model. The results showed that while Spp1, Sdc1, Ldlr, Ezr and Mmp2 promoted, Bmp2, Angpt2, Edn1, Itgb8, Cxcl10 and Agt inhibited cumulus expansion. Furthermore, Spp1, Sdc1 and Ldlr inhibited CC apoptosis. In conclusion, by using both IVT and IVO oocyte models, we have identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos and for elucidating the molecular mechanisms behind oocyte maturation.
Asunto(s)
Apoptosis , Células del Cúmulo , Perfilación de la Expresión Génica , Oocitos , Animales , Células del Cúmulo/metabolismo , Oocitos/metabolismo , Oocitos/fisiología , Ratones , Femenino , Técnicas de Maduración In Vitro de los Oocitos , Sindecano-1/metabolismo , Sindecano-1/genética , Oogénesis/genética , OsteopontinaRESUMEN
Understanding the mechanisms for oocyte maturation and optimizing the protocols for in vitro maturation (IVM) are greatly important for improving developmental potential of IVM oocytes. The miRNAs expressed in cumulus cells (CCs) play important roles in oocyte maturation and may be used as markers for selection of competent oocytes/embryos. Although a recent study from our group identified several new CCs-expressed miRNAs that regulate cumulus expansion (CE) and CC apoptosis (CCA) in mouse oocytes, validation of these findings and further investigation of mechanisms of action in other model species was essential before wider applications. By using both in vitro and in vivo pig oocyte models with significant differences in CE, CCA and developmental potential, the present study validated that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes. We demonstrated that miR-149 and miR-31 targeted SMAD family member 6 (SMAD6) and transforming growth factor ß2 (TGFB2), respectively, in the transforming growth factor-ß (TGF-ß) signaling. Furthermore, both miR-149 and miR-31 increased CE and decreased CCA via activating SMAD family member 2 (SMAD2) and increasing the expression of SMAD2 and SMAD family member 4. In conclusion, the present results show that miR-149 and miR-31 improved CE and developmental potential while suppressing CCA of pig oocytes by activating the TGF-ß signaling, suggesting that they might be used as markers for pig oocyte quality.
Asunto(s)
Células del Cúmulo , Técnicas de Maduración In Vitro de los Oocitos , MicroARNs , Oocitos , Animales , Femenino , Células del Cúmulo/fisiología , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , Técnicas de Maduración In Vitro de los Oocitos/métodos , MicroARNs/genética , MicroARNs/metabolismo , Oocitos/fisiología , Porcinos , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Accurately predicting protein-ATP binding residues is critical for protein function annotation and drug discovery. Computational methods dedicated to the prediction of binding residues based on protein sequence information have exhibited notable advancements in predictive accuracy. Nevertheless, these methods continue to grapple with several formidable challenges, including limited means of extracting more discriminative features and inadequate algorithms for integrating protein and residue information. To address the problems, we propose ATP-Deep, a novel protein-ATP binding residues predictor. ATP-Deep harnesses the capabilities of unsupervised pre-trained language models and incorporates domain-specific evolutionary context information from homologous sequences. It further refines the embedding at the residue level through integration with corresponding protein-level information and employs a contextual-based co-attention mechanism to adeptly fuse multiple sources of features. The performance evaluation results on the benchmark datasets reveal that ATP-Deep achieves an AUC of 0.954 and 0.951, respectively, surpassing the performance of the state-of-the-art model. These findings underscore the effectiveness of assimilating protein-level information and deploying a contextual-based co-attention mechanism grounded in context to bolster the prediction performance of protein-ATP binding residues.
Asunto(s)
Algoritmos , Proteínas , Unión Proteica , Proteínas/química , Secuencia de Aminoácidos , Adenosina TrifosfatoRESUMEN
It is known that the oocyte has a limited capacity to acquire and metabolize glucose, and it must rely on cumulus cells (CCs) to take up glucose and produce pyruvate for use to produce ATP through oxidative phosphorylation. We therefore propose that miRNAs might regulate glucose metabolism (GM) in CCs and might be used as markers for oocyte quality assessment. Here, mouse CC models with impaired glycolysis or pentose phosphate pathway (PPP) were established, and miRNAs targeting the key enzymes in glycolysis/PPP were predicted using the miRNA target prediction databases. Expression of the predicted miRNAs was compared between CCs with normal and impaired glycolysis/PPP to identify candidate miRNAs. Function of the candidate miRNAs was validated by transfecting CCs or cumulus-oocyte-complexes (COCs) with miRNA inhibitors and observing effects on glucose metabolites of CCs and on competence of oocytes. The results validated that miR-23b-3p, let-7b-5p, 34b-5p and 145a-5p inhibited glycolysis, and miR-24-3p, 3078-3p,183-5p and 7001-5p inhibited PPP of CCs. Our observation using a more physiologically relevant model (intact cultured COCs) further validated the four glycolysis-targeting miRNAs we identified. Furthermore, miR-let-7b-5p, 34b-5p and 145a-5p may also inhibit PPP, as they decreased the production of glucose-6-phosphate. In conclusion, miRNAs play critical roles in GM of CCs and may be used as markers for oocyte quality assessment. Summary sentence: We identified and validated eight new miRNAs that inhibit glycolysis and/or pentose phosphate pathways in cumulus cells (CCs) suggesting that miRNAs play critical roles in glucose metabolism of CCs and may be used for oocyte quality markers.
Asunto(s)
Células del Cúmulo , Glucosa , Glucólisis , MicroARNs , Animales , Células del Cúmulo/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Ratones , Glucosa/metabolismo , Femenino , Glucólisis/fisiología , Vía de Pentosa Fosfato , Oocitos/metabolismoRESUMEN
Previous studies show that stressful events after ovulation in sows significantly impaired the embryo cleavage with a significant elevation of blood cortisol. However, the effects of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol on fertilization and embryo development remain to be specified, and whether they damage pig embryos directly or indirectly is unclear. This study demonstrated that embryo development was unaffected when pig parthenotes were cultured with different concentrations of CRH/ACTH/cortisol. However, embryo development was significantly impaired when the embryos were cocultured with pig oviductal epithelial cells (OECs) in the presence of CRH/cortisol or cultured in medium that was conditioned with CRH/cortisol-pretreated OECs (CRH/cortisol-CM). Fertilization in CRH/cortisol-CM significantly increased the rates of polyspermy. CRH and cortisol induced apoptosis of OECs through FAS and TNFα signaling. The apoptotic OECs produced less growth factors but more FASL and TNFα, which induced apoptosis in embryos. Pig embryos were not sensitive to CRH because they expressed no CRH receptor but the CRH-binding protein, and they were tolerant to cortisol because they expressed more 11-beta hydroxysteroid dehydrogenase 2 (HSD11B2) than HSD11B1. When used at a stress-induced physiological concentration, while culture with either CRH or cortisol alone showed no effect, culture with both significantly increased apoptosis in OECs. In conclusion, CRH and cortisol impair pig fertilization and preimplantation embryo development indirectly by inducing OEC apoptosis via the activation of the FAS and TNFα systems. ACTH did not show any detrimental effect on pig embryos, nor OECs.
Asunto(s)
Hormona Liberadora de Corticotropina , Oviductos , Animales , Femenino , Embarazo , Hormona Adrenocorticotrópica/farmacología , Apoptosis , Hormona Liberadora de Corticotropina/metabolismo , Desarrollo Embrionario/fisiología , Hidrocortisona/farmacología , Hidrocortisona/metabolismo , Oviductos/metabolismo , PorcinosRESUMEN
PURPOSE: To study the role of target genes with aberrant DNA methylation in HPV+ HNSCC. METHODS: A HumanMethylation450 BeadChip array (Illumina) was used to identify differentially methylated genes. CCK-8, flow cytometry, wound healing, and cell invasion assays were conducted to analyze the biological roles of PRKCZ. Western blot, qRT-PCR, immunohistochemistry, and animal studies were performed to explore the mechanisms underlying the functions of PRKCZ. RESULTS: We selected PRKCZ, which is associated with HPV infection, as our target gene. PRKCZ was hypermethylated in HPV+ HNSCC patients, and PRKCZ methylation status was negatively related to the pathological grading of HNSCC patients. Silencing PRKCZ inhibited the malignant capacity of HPV+ HNSCC cells. Mechanistically, HPV might promote DNMT1 expression via E6 to increase PRKCZ methylation. Cdc42 was required for the PRKCZ-mediated mechanism of action, contributing to the occurrence of epithelial-mesenchymal transition (EMT) in HPV+ HNSCC cells. In addition, blocking PRKCZ delayed tumor growth in HPV16-E6/E7 transgenic mice. Cdc42 expression was decreased, whereas E-cadherin levels increased. CONCLUSION: We suggest that PRKCZ hypermethylation induces EMT via Cdc42 to act as a potent tumor promoter in HPV+ HNSCC.
RESUMEN
Most studies on mechanisms by which prenatal stress affects offspring behavior were conducted during late pregnancy using in vivo models; studies on the effect of preimplantation stress are rare. In vivo models do not allow accurate specification of the roles of different hormones and cells within the complicated living organism, and cannot verify whether hormones act directly on embryos or indirectly to alter progeny behavior. Furthermore, the number of anxiety-related miRNAs identified are limited. This study showed that both mouse embryculture with corticosterone (ECC) and maternal preimplantation restraint stress (PIRS) increased anxiety-like behavior (ALB) while decreasing hippocampal expression of glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) in offspring. ECC/PIRS downregulated GR and BDNF expression by increasing miR-211-5p expression via promoter demethylation of its host gene Trpm1, and this epigenetic cell fate determination was exclusively perpetuated during development into mature hippocampus. Transfection with miR-211-5p mimic/inhibitor in cultured hippocampal cell lines confirmed that miR-211-5p downregulated Gr and Bdnf. Intrahippocampal injection of miR-211-5p agomir/antagomir validated that miR-211-5p dose-dependently increased ALB while decreasing hippocampal GR/BDNF expression. In conclusion, preimplantation exposure to glucocorticoids increased ALB by upregulating miR-211-5p via Trpm1 demethylation, and miR-211-5p may be used as therapeutic targets and biomarkers for anxiety-related diseases.
RESUMEN
Following the publication of this article, the authors have realized that they made an error during the compilation of the images shown in Fig. 6, and that this error was not corrected before the paper was sent to press. Specifically, in Fig. 6B, the data panels showing the results from the HUVEC + SACC83 siDll4 and HUVEC + SACCLM siDll4 experiments at 24 h were inadvertently repeated. The corrected version of Fig. 6, showing the correctly assembled data panels for Fig. 6B, is shown on the next page. The authors sincerely apologize for the errors that were introduced during the preparation of this Figure, thank the Editor for allowing them the opportunity to publish this Corrigendum, and regret any inconvenience that these errors may have caused. [the original article was published in Oncology Reports 45: 10111022, 2021; DOI: 10.3892/or.2021.7939].
RESUMEN
[This corrects the article DOI: 10.3389/fonc.2018.00492.].
RESUMEN
CXCR5 played critical roles in tumorigenesis and metastasis. Nevertheless, little was known about the involvement of CXCR5 in perineural invasion (PNI) of salivary adenoid cystic carcinoma (SACC). Here, we confirmed upregulation of CXCR5 in SACC specimens and cells and identified that CXCR5 exhibited a significant positive correlation with PNI. Functionally, knockdown of CXCR5 suppressed SACC cells migration, invasion and PNI ability, whereas CXCR5 overexpression displayed the opposite effects. Moreover, CXCR5 downregulated microRNA (miR)-187, which could competitively sponge S100A4. The PNI-inhibitory effect of CXCR5 knockdown or miR-187 overexpression could be reversed by elevated expression of S100A4. Conjointly, our data revealed that CXCR5 facilitated PNI through downregulating miR-187 to disinhibit S100A4 expression in SACC.
Asunto(s)
Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , MicroARNs/metabolismo , Receptores CXCR5/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Secuencia de Bases , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Diferenciación Celular/genética , Movimiento Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Modelos de Riesgos Proporcionales , Células de Schwann/metabolismo , Células de Schwann/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Patients were prone to have poor prognosis once dormant tumor cells being reactivated. However, the molecular mechanism of tumor cell dormancy remains poorly understood. This study aimed to investigate the function of DEC2 in the dormancy of salivary adenoid cystic carcinoma (SACC) in vitro and vivo. METHODS: The function of DEC2 in tumor dormancy of SACC was investigated in nude mice by establishing primary and lung metastasis model. Meanwhile, the interaction between hypoxia and SACC dormancy and the role of DEC2 were demonstrated through CoCl2 induced hypoxia-mimicking microenvironments. Furthermore, the expression of DEC2 was detected by immunohistochemical staining in primary SACC samples with and without recurrence. RESULTS: In the primary SACC, DEC2 overexpression inhibited cell proliferation, increased cell population arrested in G0/G1 phase, and participated in dormancy regulation, which limited tumor growth. Intriguingly, in the model of lung metastasis, the level of DEC2 was reduced significantly and resulted in dormancy exit and growth resumption of SACC cells. Then, we found that DEC2 may associate with hypoxia in contributing to tumor dormancy, which might provide a possible cue to explain the different roles of DEC2 in primary and metastasis lesions. And overexpression of DEC2 induced dormancy and promoted migration and invasion through activating EMT program. Finally, DEC2 positive expression was shown to be significantly correlated with recurrence and dormancy of SACC patients. CONCLUSIONS: These findings provide a novel insight into the role of DEC2 gene in tumor dormancy and metastasis.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma Adenoide Quístico/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Animales , Apoptosis/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
High expression of δlike ligand 4 (Dll4) is reportedly related to the invasion, metastasis, and clinical prognosis of various malignant tumours. Our previous study revealed that collective cell invasion was a common pattern in salivary adenoid cystic carcinoma (SACC). However, the roles of the Dll4/Notch1 signalling pathway in the collective invasion of SACC remain unclear. The present study revealed that Dll4 expression was higher at the invasive front of SACC, and that this upregulation was associated with solid tumour type, high TNM grade, and high rates of metastasis and recurrence. Furthermore, the expression levels of Notch1 and Dll4 were positively correlated at the invasive front, and a threedimensional (3D) culture model revealed that leader cells showed high expression of Dll4, while follower cells showed high expression of Notch1. Moreover, silencing of Dll4 expression using small interfering RNA reduced the migration, invasion, and collective invasion of SACC cells, and these abilities were rescued by Notch1 overexpression. Finally, SACC collective invasion was increased via the Dll4/Notch1 signalling pathway in experiments that involved a stiff 3D gel, hypoxia and coculture with human endothelial cells. These findings indicated that the Dll4/Notch1 signalling pathway may be involved in the collective invasion of SACC, which may help to provide possible targets for the treatment of SACC.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al Calcio/metabolismo , Carcinoma Adenoide Quístico/genética , Receptor Notch1/metabolismo , Neoplasias de las Glándulas Salivales/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/genética , Proteínas de Unión al Calcio/genética , Carcinoma Adenoide Quístico/patología , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Técnicas de Cocultivo , Células Endoteliales , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Transducción de Señal/genética , Hipoxia Tumoral/genética , Regulación hacia ArribaRESUMEN
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.
Asunto(s)
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 cell migration and invasion are integral components of metastatic disease, which is the major cause of death in cancer patients. Cancer cells can disseminate and migrate via several alternative mechanisms including amoeboid cell migration, mesenchymal cell migration, and collective cell migration. These diverse movement strategies display certain specific and distinct hallmarks in cell-cell junctions, actin cytoskeleton, matrix adhesion, and protease activity. During tumor progression, cells pass through complex microenvironments and adapt their migration strategies by reversible mesenchymal-amoeboid and individual-collective transitions. This plasticity in motility patterns enables cancer cells disseminate further and thus limit the efficiency of anti-metastasis therapies. In this review, we discuss the modes and mechanisms of cancer cell migration and focus on the plasticity of tumor cell movement as well as potential emerging therapeutic options for reducing cancer cell invasion.
RESUMEN
Studies have observed that restraint stress (RS) and the associated elevation in corticotrophin-releasing hormone (CRH) impair oocyte competence by triggering apoptosis of ovarian cells but the underlying mechanisms are largely unclear. Although one study demonstrated that RS and CRH elevation triggered apoptosis in ovarian cells and oocytes via activating Fas/FasL signalling, other studies suggested that RS might damage cells by activating other pathways as well as Fas signalling. The objective of this study was to test whether RS and CRH elevation impairs oocytes by activating tumour necrosis factor α (TNF-α) signalling. Our invivo experiments showed that RS applied during oocyte prematuration significantly increased expression of TNF-α and its receptor (TNFR1) while inducing apoptosis in both oocytes and mural granulosa cells (MGCs). Invitro treatment of MGCs with CRH significantly increased their apoptotic percentages and levels of TNF-α and TNFR1 expression. Invitro knockdown by interfering RNA, invivo knockout of the TNF-α gene or injection of TNF-α antagonist etanercept significantly relieved the adverse effects of RS and CRH on apoptosis of MGCs and/or the developmental potential and apoptosis of oocytes. The results suggest that RS and CRH elevation in females impair oocyte competence through activating TNF-α signalling and that a TNF-α antagonist might be adopted to ameliorate the adverse effects of psychological stress on oocytes.
Asunto(s)
Apoptosis , Hormona Liberadora de Corticotropina/metabolismo , Oocitos/metabolismo , Restricción Física , Estrés Psicológico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Técnicas de Cultivo de Embriones , Etanercept/farmacología , Femenino , Fertilización In Vitro , Ratones Endogámicos C57BL , Ratones Noqueados , Oocitos/efectos de los fármacos , Oocitos/patología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Estrés Psicológico/etiología , Estrés Psicológico/genética , Estrés Psicológico/patología , Inhibidores del Factor de Necrosis Tumoral/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Regulación hacia ArribaRESUMEN
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.
Asunto(s)
Comunicación Celular/fisiología , Movimiento Celular/fisiología , Invasividad Neoplásica/patología , Microambiente Tumoral/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , HumanosRESUMEN
BACKGROUND: Human papillomavirus (HPV)-positive oral squamous cell carcinoma (OSCC) is increasing worldwide with typically higher grade and stage, while better prognosis. microRNAs (miRNAs) has been shown to play a critical role in cancer, however, their role in HPV-positive OSCC progression remains unclear. METHODS: miRNA microarray was performed to identify differentially expressed miRNAs. qRT-PCR and FISH were performed to determine the relative expression of miR-550a-3-5p. CCK-8, Flow cytometry, Wound healing, Cell invasion assays and xenograft experiments were conducted to analyze the biological roles of miR-550a-3-5p. Tumor-associated macrophages (TAMs) generation, co-culturing of cancer cells with TAMs, Western blot, Dual-luciferase reporter gene assay, Immunohistochemistry and animal studies were performed to explore the mechanisms underlying the functions of miR-550a-3-5p. RESULTS: We identified 19 miRNAs differentially expressed in HPV-positive OSCC specimens and miR-550a-3-5p was down-regulated. The low expression of miR-550a-3-5p correlated with higher tumor size and nodal metastasis of HPV-positive OSCC patients. Then, we found that miR-550a-3-5p suppressed the migration, invasion and EMT of HPV-positive OSCC cells dependent on decreasing M2 macrophages polarization. Moreover, miR-550a-3-5p, down-regulated by E6 oncoprotein, inhibited M2 macrophages polarization by YAP/CCL2 signaling, which in turn abrogating EMT program in HPV-positive OSCC cells. In addition, in both xenografts and clinical HPV-positive OSCC samples, miR-550a-3-5p levels were inversely associated with YAP, CCL2 expressions and the number of M2 macrophages. CONCLUSIONS: E6/miR-550a-3-5p/YAP/CCL2 signaling induces M2 macrophages polarization to enhance EMT and progression, revealing a novel crosstalk between cancer cells and immune cells in HPV-positive OSCC microenvironment.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Regulación Neoplásica de la Expresión Génica , Macrófagos/patología , MicroARNs/genética , Neoplasias de la Boca/patología , Infecciones por Papillomavirus/complicaciones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Proliferación Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Macrófagos/virología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/virología , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Pronóstico , Transducción de Señal , Tasa de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAPRESUMEN
Langerhans cell histiocytosis is commonly found in cranial bones and rarely found in the mandible. This article presents a case of mandibular Langerhans cell histiocytosis and discusses its pathogeny, clinical features, diagnosis, and treatment.