RESUMEN

We aimed to investigate potential roles of LRRC75A-AS1 delivered by M2 macrophage exosomes in inducing cervical cancer progression. We demonstrated LRRC75A-AS1 was highly expressed in exosomes from M2 macrophages which could be absorbed by Hela cells. M2 macrophage-derived exosomes promoted Hela cell proliferation, migration, invasion, and EMT process by delivering LRRC75A-AS1. LRRC75A-AS1 directly targeted and suppressed miR-429 in Hela cells. The regulation of cell functions by exosomes from LRRC75A-AS1-overexpressing M2 macrophages was abrogated by miR-429 mimics. miR-429 directly targeted and repressed SIX1 expression. SIX1 overexpression alleviated the modulation of cellular functions and STAT3/MMP-9 signaling by miR-429 mimics. Also, miR-429 overexpression or SIX1 silence repressed tumor formation and metastasis in nude mice, which was mitigated by exosomes from LRRC75A-AS1-overexpressing M2 macrophages. In conclusion, LRRC75A-AS1 delivered by M2 macrophage exosomes repressed miR-429 to elevate SIX1 expression and promote cervical cancer progression through activating the STAT3/MMP-9 axis.

Asunto(s)

Exosomas , MicroARNs , ARN Largo no Codificante , Neoplasias del Cuello Uterino , Humanos , Ratones , Animales , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias del Cuello Uterino/patología , Células HeLa , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Exosomas/metabolismo , Ratones Desnudos , Macrófagos/metabolismo , Proliferación Celular/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Proteínas de Homeodominio/metabolismo

RESUMEN

BACKGROUND: The incidence, risk factors, and pathogenesis of early neurological deterioration (END) in posterior circulation stroke are still unclear. In this study, we aimed to determine the risk factors and prognosis of END in patients with acute posterior circulation cerebral infarction. METHODS: Acute posterior circulation ischemic stroke patients who had completed neuroimaging within 72 h of onset were selected from a prospective registry study Demographic characteristics, physiological data, medical history, laboratory data, in-hospital evaluation, neurological severity and TOAST classification, treatment, and the modified Rankin Scale (mRS) score of patients were assessed. Early neurological deterioration was defined as an increase of 2 points in the National Institutes of Health Stroke Scale score between the baseline and 72 h evaluation. Favorable and poor outcomes were defined as mRSs of 02 and≥ 3, respectively, at 3 months. The incidence and risk factors were evaluated by univariate and multivariate regression analysis (step-back method). RESULTS: The analysis included 455 subjects with an acute posterior circulation non-cardiac ischemic stroke, 330 (72.53 %) of them male, with an average age of 63.12 ( ± 10.14) years and with 47 (10.33 %) having END. The results of univariate and multivariate logistic regression analysis showed that BATMAN scores ≥ 5 (OR: 0.1, 95 % CI: 0.02-0.53, P < 0.01), large artery atherosclerosis (OR: 11.55, 95 % CI: 4.18-31.93, P < 0.01), vascular stenosis > 50 % (OR: 2.44, 95 % CI: 1.1-5.42, P = 0.029), reperfusion therapy (OR: 4.21, 95 % CI: 1.66-10.64, P < 0.01), and the distribution of pontine lesions (OR: 5.66, 95 % CI: 2.39-13.44, P < 0.01) were significantly associated with END. Patients with END had a lower rate of favorable outcomes at discharge and long-term follow-up (P < 0.001), regardless of whether they received reperfusion therapy. CONCLUSION: The lesion distribution of the pons, the progression of temporo-occipital lobe lesions, and large arterial atherosclerosis are independent risk factors of END that might predict a poor short- and long-term prognosis.

Asunto(s)

Aterosclerosis , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Masculino , Persona de Mediana Edad , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/epidemiología , Infarto Cerebral/terapia , Pronóstico , Accidente Cerebrovascular/terapia , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/terapia , Isquemia Encefálica/complicaciones , Factores de Riesgo , Aterosclerosis/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Resultado del Tratamiento

RESUMEN

Chronic inflammation induced by persistent microbial infection plays an essential role in tumor progression. Although it is well documented that Epstein-Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC), how EBV-induced inflammation promotes NPC progression remains largely unknown. Here, we report that tumor infiltration of tumor-associated macrophages (TAM) and expression of CCL18, the cytokine preferentially secreted by TAM, closely correlate with serum EBV infection titers and tumor progression in two cohorts of NPC patients. In vitro, compared with EBV- NPC cell lines, EBV+ NPC cell lines exhibited superior capacity to attract monocytes and skew them to differentiate to a TAM-like phenotype. Cytokine profiling analysis revealed that NPC cells with active EBV replications recruited monocytes by VEGF and induced TAM by GM-CSF in an NF-κB-dependent manner. Reciprocally, TAM induced epithelial-mesenchymal transition and furthered NF-κB activation of tumor cells by CCL18. In humanized mice, NPC cells with active EBV replications exhibited increased metastasis, and neutralization of CCL18, GM-CSF, and VEGF significantly reduced metastasis. Collectively, our work defines a feed-forward loop between tumor cells and macrophages in NPC, which shows how metastatic potential can evolve concurrently with virus-induced chronic inflammation. Cancer Res; 77(13); 3591-604. ©2017 AACR.

Asunto(s)

Carcinoma/virología , Infecciones por Virus de Epstein-Barr/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Macrófagos/inmunología , Neoplasias Nasofaríngeas/virología , Factor A de Crecimiento Endotelial Vascular/inmunología , Animales , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Xenoinjertos , Humanos , Activación de Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Macrófagos/virología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Metástasis de la Neoplasia , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/biosíntesis

RESUMEN

Pyk2 and Src phosphorylation is initiated by CCL18, which promotes breast cancer metastasis via its functional G protein-coupled receptor PITPNM3. However, the function of Pyk2 and Src in CCL18-induced breast cancer metastasis is poorly understood. Quantitative reverse-transcription polymerase chain reactions (qRT-PCRs), Western blot, boyden chamber assay, and adherence assay were performed to delineate the consequences of Pyk2/Src in CCL18-induced breast cancer cells. Co-immunoprecipitation and immunofluorescence were performed to analyze the interaction of proteins. Upon the binding of CCL18 to PITPNM3, Pyk2 translocates from the cytoplasm to the plasma membrane to form a stable complex with PITPNM3, subsequently activating Src kinase. Moreover, upon stimulation with CCL18, Pyk2 and Src become essential for integrin alpha5/beta1 clustering-dependent adherence, migration, and invasion. Pyk2 and Src are important in CCL18-induced breast cancer metastasis.

Asunto(s)

Neoplasias de la Mama/genética , Quimiocinas CC/genética , Quinasa 2 de Adhesión Focal/metabolismo , Familia-src Quinasas/metabolismo , Neoplasias de la Mama/patología , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Femenino , Quinasa 2 de Adhesión Focal/genética , Humanos , Proteínas de la Membrana/metabolismo , Metástasis de la Neoplasia , Familia-src Quinasas/genética

RESUMEN

OBJECTIVE: To analyze the difference in microRNAs expression between MCF-7 and MCF-7/ADR cells and explore the association between microRNA and drug resistance of breast cancer. METHODS: The drug resistance of MCF-7/ADR cells was evaluated using MTT assay and flow cytometry. Microarray technique and RT-PCR were used to analyze the differential expressions of the microRNA between MCF-7 and MCF-7/ADR cells. RESULTS: The drug resistance index of MCF-7/ADR cells relative to the parental MCF-7 cells was 33.2. The percentages of the side population in MCF-7/ADR and MCF-7 cells were (9.50-/+0.9)% and (0.85-/+0.2)%, respectively. Microarray analysis of MCF-7 to MCF-7/ADR cells identified 36 differentially expressed genes, including 16 up-regulated and 20 down-regulated genes in MCF-7/ADR cells. RT-PCR identified 14 microRNAs that were differentially expressed between MCF-7 and MCF-7/ADR cells, including 7 up-regulated and 7 down-regulated ones in MCF-7/ADR cells. Of these differentially expressed microRNAs, mir-221, mir222, mir-130a, and mir-155 showed significantly increased expression, and mir200a, mir-200b, mir-200c, and mir-421 showed significantly lowered expression in MCF-7/ADR cells as indicated by the results of microarray analysis and RT-PCR. CONCLUSION: MCF-7/ADR cells show a different microRNA expression profile from its parental MCF-7 cells, suggesting the involvement of microRNAs in tumor cell drug resistance. This finding provides a experimental basis for further study of mechanism underlying the drug resistance of breast cancer.

Asunto(s)

Neoplasias de la Mama/genética , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Femenino , Humanos , Células Tumorales Cultivadas