Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.616
Filtrar
1.
Life Sci ; 248: 117469, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32109485

RESUMEN

AIMS: Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms. MAIN METHODS: MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. KEY FINDINGS: Our results demonstrated that SB939 at 0.5-1 µmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. SIGNIFICANCE: Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Vimentina/genética , Vimentina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Ann Hematol ; 99(2): 215-221, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31900500

RESUMEN

Many studies have confirmed that overexpressed WT1 exists in leukemic cells, especially in AML. However, the immunophenotypic features of this sort of leukemic cells remain to be unclarified. We retrospectively analyzed the immunophenotype of 283 newly diagnosed AML patients with intermediated and poor cytogenetic risk to evaluate the correlation between phenotype and WT1 overexpression. EVI1 transcripts, KMT2A-PTD, FLT3-ITD, and NPM1 mutations were simultaneously assessed. Our results revealed that overexpressed WT1 was significantly associated with the expression of CD117, CD13, and CD123. Besides, leukemic cells with WT1 overexpression also lacked lymphoid and myeloid differentiation-related markers. FAB subtype M2 patients had higher WT1 levels, compared with other FAB subtype. Multivariate analysis was proved that NPM1 mutation, M2 subtype, and the expression of CD123 were independently associated with WT1 overexpression. These indicated that AML with overexpressed WT1 was proliferated and blocked in the early stage of AML development. It presumably provided some clues to detect overexpressed WT1 cells via multiparameter flow cytometry. CD123-targeted drugs might become one of the alternative treatments for patients with WT1 overexpression.


Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/metabolismo , Proteínas WT1/biosíntesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos de Diferenciación/biosíntesis , Antígenos de Diferenciación/genética , Femenino , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Factores de Riesgo , Proteínas WT1/genética
3.
Cancer Sci ; 111(1): 47-58, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31710162

RESUMEN

Breast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrine-resistant breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Quimiocina CCL2/genética , Resistencia a Antineoplásicos/genética , Macrófagos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Células MCF-7 , Supervivencia sin Progresión , Receptores de Superficie Celular/genética , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Tamoxifeno/farmacología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
4.
Toxicol Lett ; 320: 37-45, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31778776

RESUMEN

As a major toxicant which is abundant in tobacco smoking, benzo(a)pyrene (BaP) is considered as a strong carcinogen of lung cancer. In spite of the intensive research, the role that BaP plays in lung cancer still lacks a comprehensive and precise understanding. Recently, a long non-coding RNA, linc00673, has emerged as a central player in different kinds of malignancies, including non-small cell lung cancer (NSCLC). In the present study, we found that BaP with the concentration of no more than 8 µM did not affect cell proliferation in the NSCLC cell line A549, while it significantly enhanced A549 cell migration and invasion. Further results revealed that BaP promoted mesenchymal biomarkers expression and inhibited the major epithelial biomarker E-cadherin in a time and dose dependent manner, which indicated epithelial-mesenchymal transition (EMT) was induced by BaP in A549 cells. Through quantitative real-time PCR, we observed that BaP significantly elevated the expression level of linc00673. While after the knockdown of aryl hydrocarbon receptor (AHR), the up-regulating effect of BaP on linc00673 was reversed. Furthermore, silencing linc00673 significantly suppressed the BaP-induced migration, invasion, and EMT in A549 cells. In summary, our study demonstrates that BaP promotes A549 cell migration, invasion and EMT through up-regulating the expression of linc00673 in an AHR-dependent manner.


Asunto(s)
Benzo(a)pireno/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , ARN Largo no Codificante/metabolismo , Células A549 , Antígenos CD/genética , Antígenos CD/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Invasividad Neoplásica , ARN Largo no Codificante/genética , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Factores de Tiempo , Regulación hacia Arriba
5.
J Biochem Mol Toxicol ; 34(2): e22422, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31729780

RESUMEN

M1 macrophages serve one edge as proinflammatory and M2 macrophages serve the other edge as an anti-inflammatory macrophage. It appears that a related "switch" in macrophage morphology may also happen in the course of atherosclerosis, which has not yet been elucidated. An atherogenic diet (AD) was given to rats, and induction of macrophage differentiation and the nuclear localization of nuclear factor-kappa B (NFκB) were investigated by Western blot and immunofluorescence. Chemokines were analyzed using an antibody array with 32 target proteins. M2 macrophage transformation was confirmed in diosgenin-treated aorta by immunofluorescence and was validated in vitro using THP-1 cells. MAC387 (macrophage marker) and NFκBp65 (inflammatory hub) were upregulated in oxidatively-modified low-density lipoprotein (OxyLDL) and AD-induced condition. Macrophage differentiation, which induced the formation of inflammatory mediators, was not significantly suppressed by the inhibition of NFκB using dexamethasone. M1 macrophage polarization was identified in OxyLDL-induced monocytes, which are proinflammatory in nature, whereas M2 macrophage polarization was noticed in diosgenin-treated monocytes, which exhibit anti-inflammatory properties. M1-and M2-specific chemokines were analyzed using chemokine antibody array. Furthermore, the expression of proinflammatory macrophage (M1) was noticed in AD-induced aorta and anti-inflammatory macrophage (M2) was observed in diosgenin-treated aorta. This is the first report where, unifying the mechanism of diosgenin as aan nti-atherosclerotic and the expression of M1 and M2 specific chemokines is shown by downregulating NFκB and not by preventing the differentiation of monocyte into a macrophage, but by allowing macrophage to differentiate into M2, which aids in preventing the atherosclerotic progression.


Asunto(s)
Aorta/metabolismo , Aterosclerosis/metabolismo , Polaridad Celular , Citocinas/metabolismo , Diosgenina/farmacología , Macrófagos/metabolismo , Extractos Vegetales/farmacología , Factor de Transcripción ReIA/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diferenciación Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dexametasona/farmacología , Dieta Aterogénica/efectos adversos , Dioscorea/química , Diosgenina/uso terapéutico , Humanos , Lipoproteínas LDL/farmacología , Masculino , Monocitos/metabolismo , Extractos Vegetales/uso terapéutico , Ratas , Transducción de Señal/efectos de los fármacos , Células THP-1 , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/genética
6.
Cancer Immunol Immunother ; 69(1): 103-114, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31811336

RESUMEN

We previously reported that CD200 overexpression in the host decreases progression and metastasis of the highly aggressive metastatic 4THM breast carcinoma. We have explored a possible synergistic interaction between the CD200 mimetic PEG-M49 and pegylated liposomal doxorubicin (Peg-Dox) in wild-type CD200 knockout (CD200-/-) and CD200 Receptor 1 knockout (CD200R1-/-) mice for the first time. A 4THM breast carcinoma model and three groups of BALB/c mice (wild type, CD200-/- and CD200R1-/-) were used. Five days after injection of tumor cells, mice were injected with Peg-Dox (ip, once a week) and PEG-M49 or a control aptamer (iv, every 3 days). Necropsies were performed either 12 (mid-point) or 24 (endpoint) days after injection and the extent of tumor growth, visceral metastasis and changes in the tumor-directed immune response were evaluated. PEG-M49 and Peg-Dox co-treatment induced complete tumor regression and loss of macroscopic lung metastasis in four out of seven WT mice. This synergistic anti-tumoral effect is thought to be due to Peg-M49-induced inhibition of Gr1 + CD11b + cells and Peg-Dox-induced increases in tumor-infiltrating CD8 + and CD8CD4 double-positive cells. Similar changes were observed in CD200R1-/- mice indicating that the primary effects of Peg-M49 are mediated by non-CD200R1 receptors. We also demonstrated for the first time that tumor growth, metastasis, and tumor infiltrating GR1 + CD11b + cells were markedly increased in CD200R1-/- mice, indicating an anti-inflammatory and protective role of CD200. CD200 mimetics might be a safe and effective immunomodulatory treatment in conjunction with classical chemotherapeutics for therapy of aggressive metastatic breast carcinoma.


Asunto(s)
Antígenos CD/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Aptámeros de Nucleótidos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Animales , Antígenos CD/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aptámeros de Nucleótidos/uso terapéutico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de Orexina/genética , Receptores de Orexina/inmunología , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico
7.
Int J Cancer ; 146(2): 475-486, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31107971

RESUMEN

Long noncoding RNAs (lncRNAs) promote cell proliferation, migration, invasion and castration resistance in prostate cancer (PCa). Understanding the inherited molecular mechanisms by which lncRNAs contribute to the progression of PCa to a lethal disease could have an important impact on cancer detection, diagnosis and prognosis. In our study, PCa-associated lncRNA transcripts from RNA-seq data were identified and screened via bioinformatics analysis, NCBI annotations and literature review. We identified a novel lncRNA, lncAPP (lncRNA activated in PCa progression), which activates in PCa progression and is expressed in primary tumor tissues and urine samples of patients with localized or advanced PCa. Urinary-based lncAPP is a promising biomarker for predicting PCa progression. In vitro and in vivo studies demonstrated that lncAPP enhanced cell proliferation and promoted migration and invasion. The underlying mechanism of lncRNA was investigated by RNA immunoprecipitation, dual-luciferase reporter system assay, etc. Upregulation of lncAPP promoted cell migration and invasion via competitively binding miR218 to facilitate ZEB2/CDH2 expression. In addition, in vivo subcutaneous tumor xenograft models and tail intravenously injection metastatic models were constructed to evaluate lncRNA function. Targeting lncAPP/miR218 axis in cell lines and tumor xenografts restrained tumor progression properties both in vitro and in vivo. These results establish that lncAPP/miR218 axis plays a critical role in PCa progression, and they also suggest new strategies to prevent tumor progression for therapeutic purposes.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias de la Próstata/genética , ARN Largo no Codificante/metabolismo , Animales , Antígenos CD/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/orina , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , MicroARNs/metabolismo , Clasificación del Tumor , Invasividad Neoplásica/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Próstata/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/orina , ARN Largo no Codificante/genética , ARN Largo no Codificante/orina , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética
8.
J Assoc Physicians India ; 67(11): 36-39, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31793267

RESUMEN

Background: Transferrin receptor (TfR) is a carrier protein for transferrin. It is regulated in response to intracellular iron concentration and plays a role for the import of iron into the cell. The transferring receptor 2 (TFR2) gene showed homology to transferrin receptor 1 (TFR1) gene and encodes a transmembrane protein with a large extracellular domain, which is able to bind transferrin. Mutations in transferrin receptors (TfR2 and TfR1) may alter the pathophysiology of iron deficiency anemia. Alteration in genes encoding transferring receptor cause change in iron homeostatsis and provides a tool for investigating the excess iron absorption and abnormal iron distribution in iron related disorders. However the clinical significance of the interaction of transferring mutations with iron deficiency anemia remains unclear. Thus, the objective of my study was to investigate the effect of TFR1 and TFR2 genotypes on pathophysiology of iron deficiency anemia. Study Design: Study subjects were 460 iron deficiency anemia patients and 500 age and sex-matched healthy controls. Transferrin receptor, ferritin and CRP analysis was done by ELISA method while ESR analysis was done according to Wintrobes's method. CBC analysis was done by auto-analyzer. TFR1-rs3817672 SNP and TFR2 (Y250X) mutation was analyzed by using PCR RFLP method. Results: Amongst the iron deficiency anemia patients, 13 were heterozygous and five were homozygous for rs3817672 SNP. TFR2 (Y250X) mutation was detected in 6 patients with heterozygous conditions. None of the patients were presenting homozygous condition while four controls were presenting heterozygous and one with homozygous condition. Controls were presenting 3% and 0.6% of TFR1 rs3817672 SNP heterozygosity respectively. Conclusion: TfR2 -Y250X and TfR1-rs3817672 SNP showed clinical association with iron deficiency anemia and screening for mutations of TFR2 is a new diagnostic tool that can be offered to patients who do not have HFE mutations or who have incomplete HFE genotypes. This results may have practical implications for the molecular diagnosis of hemochromatosis. Genotyping the TFR gene should be included in the disease diagnostic protocols.


Asunto(s)
Anemia Ferropénica , Antígenos CD , Hemocromatosis , Receptores de Transferrina , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/genética , Antígenos CD/genética , Humanos , Polimorfismo de Nucleótido Simple , Receptores de Transferrina/genética , Transferrina
9.
Presse Med ; 48(10): 1092-1100, 2019 Oct.
Artículo en Francés | MEDLINE | ID: mdl-31706893

RESUMEN

In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Mutación , Factores de Edad , Antígenos CD/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Neoplasias de la Mama Masculina/genética , Cadherinas/genética , Salud de la Familia , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Femenino , Francia , Genes BRCA1 , Genes BRCA2 , Genes p53 , Pruebas Genéticas , Síndrome de Hamartoma Múltiple/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Embarazo , Mastectomía Profiláctica , Factores de Riesgo , Nanomedicina Teranóstica , Neoplasias de la Mama Triple Negativas/genética
10.
BMC Infect Dis ; 19(1): 999, 2019 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-31775660

RESUMEN

BACKGROUND: Recent studies have shown that CD103 is an important marker for tissue-resident memory T cells (TRM) which plays an important role in anti-infection. However, the role of CD103+ TRM was not elucidated in the progress of S. japonicum infection induced disease. METHODS: 6-8 weeks old C57BL/6 mice were infected by S. japonicum. Mice were sacrificed and the lungs were removed 5-6 weeks after infection. Immunofluorescent staining and Q-PCR were performed to identify the expression of CD103 molecule. Single cellular populations were made, percentages of CD103 on both CD4+ and CD8+ T lymphocytes were dynamical observed by flow cytometry (FCM). Moreover, the expression of memory T cells related molecules CD69 and CD62L, T cell function associated molecules CD107a, IFN-γ, IL-4, IL-9, and IL-10 were compared between CD103+ CD4+ and CD8+ T cells by FCM. RESULTS: CD103+ cells were emerged in the lung of both naive and S. japonicum infected mice. Both the percentage and the absolute numbers of pulmonary CD4+ and CD8+ cells were increased after S. japonicum infection (P < 0.05). The percentage of CD103+ cells in CD8+ T cells decreased significantly at the early stage of S. japonicum infection (P < 0.05). Increased CD69, decreased CD62L and CD107a expressions were detected on both CD4+ and CD8+ CD103+ T cells in the lungs of infected mice (P < 0.05). Compared to CD8+ CD103+ T cells, CD4+ CD103+ T cells from infected mice expressed higher level of CD69 and lower level CD62L molecules (P < 0.05). Moreover, higher percentage of IL-4+, IL-9+ and IL-10+ cells on CD4+ CD103+ pulmonary T cells was found in infected mice (P < 0.05). Significantly increased IL-4 and IL-9, and decreased IFN-γ expressing cells were detected in CD8+CD103+ cells of infected mice (P < 0.05). CONCLUSIONS: CD103-expressing pulmonary CD4+ and CD8+ T cells play important roles in mediating S. japonicum infection induced granulomatous inflammation in the lung.


Asunto(s)
Antígenos CD/genética , Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Cadenas alfa de Integrinas/genética , Cadenas alfa de Integrinas/metabolismo , Schistosoma japonicum , Esquistosomiasis Japónica/metabolismo , Animales , Biomarcadores/metabolismo , Citocinas/metabolismo , Femenino , Expresión Génica/inmunología , Memoria Inmunológica , Pulmón/metabolismo , Pulmón/parasitología , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Esquistosomiasis Japónica/microbiología
11.
Bioengineered ; 10(1): 679-688, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31679450

RESUMEN

MiR-25 is a well-documented oncogenic miRNA implicated in esophageal squamous cell carcinoma (ESCC) development, progression and metastasis. However, whether and how miR-25 is involved in the development and metastasis of ESCC remain un-addressed. By using qRT-PCR analysis to compare levels of miR-25 in ESCC tissues with or without lymph node metastasis (LNM), it showed that ESCC tissues with LNM had increased levels of miR-25, which was correlated with tumor metastasis and poor prognosis. Gain- and loss-of-function assays indicated that targeting miR-25 could reverse EMT, and reduce in vitro cell migration and invasion, but not apoptosis and proliferation of ESCC. Furthermore, targeting miR-25 inhibited in vivo lung metastasis, and vice versa. And E-cadherin was a direct target of miR-25 through which affected EMT process and metastasis of ESCC. It is therefore indicated that miR-25 promotes metastasis of ESCC through E-cadherin and EMT events, thus may serves as a negative prognostic factor and possible target for treatment of ESCC patients.


Asunto(s)
Antígenos CD/genética , Cadherinas/genética , Transición Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/secundario , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Análisis de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto
12.
PLoS Genet ; 15(10): e1008451, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31658259

RESUMEN

E-cadherin complexes with the actin cytoskeleton via cytoplasmic catenins and maintains the functional characteristics and integrity of the epithelia in normal epithelial tissues. Lost expression of E-cadherin disrupts this complex resulting in loss of cell polarity, epithelial denudation and increased epithelial permeability in a variety of tissues. Decreased expression of E-cadherin has also been observed in invasive and metastatic human tumors. In this study, we investigated the effect of E-cadherin loss in prostatic epithelium using newly developed genetically engineered mouse models. Deletion of E-cadherin in prostatic luminal epithelial cells with modified probasin promoter driven Cre (PB-Cre4) induced the development of mouse prostatic intraepithelial neoplasia (PIN). An increase in levels of cytoplasmic and nuclear ß-catenin appeared in E-cadherin deleted atypical cells within PIN lesions. Using various experimental approaches, we further demonstrated that the knockdown of E-cadherin expression elevated free cytoplasmic and nuclear ß-catenin and enhanced androgen-induced transcription and cell growth. Intriguingly, pathological changes representing prostatic epithelial cell denudation and increased apoptosis accompanied the above PIN lesions. The essential role of E-cadherin in maintaining prostatic epithelial integrity and organization was further demonstrated using organoid culture approaches. To directly assess the role of loss of E-cadherin in prostate tumor progression, we generated a new mouse model with bigenic Cdh1 and Pten deletion in prostate epithelium. Early onset, aggressive tumor phenotypes presented in the compound mice. Strikingly, goblet cell metaplasia was observed, intermixed within prostatic tumor lesions of the compound mice. This study provides multiple lines of novel evidence demonstrating a comprehensive role of E-cadherin in maintaining epithelial integrity during the course of prostate oncogenic transformation, tumor initiation and progression.


Asunto(s)
Antígenos CD/metabolismo , Cadherinas/metabolismo , Transformación Celular Neoplásica/patología , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/patología , Animales , Antígenos CD/genética , Cadherinas/genética , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Epiteliales , Epitelio , Células HEK293 , Humanos , Masculino , Ratones , Ratones Transgénicos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Cultivo Primario de Células , Próstata/citología , Próstata/patología , Neoplasia Intraepitelial Prostática/genética , Neoplasias de la Próstata/genética , ARN Interferente Pequeño , beta Catenina/genética , beta Catenina/metabolismo
13.
J Ovarian Res ; 12(1): 93, 2019 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-31610800

RESUMEN

BACKGROUND: The ST6Gal-I glycosyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. RESULTS: Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including ~ 25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2-6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2-6 sialylation. CONCLUSIONS: These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.


Asunto(s)
Antígenos CD/genética , Proliferación Celular/genética , Neoplasias Ováricas/genética , Factores de Transcripción SOXB1/genética , Sialiltransferasas/genética , Apoptosis/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Glicosiltransferasas/genética , Humanos , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/patología , Unión Proteica , Transducción de Señal/genética
14.
Toxicol Lett ; 317: 102-109, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31574306

RESUMEN

BACKGROUND: Cigarette smoke is considered a risk factor for lung and colorectal cancer. A convincing link between epithelial-to-mesenchymal transition (EMT) with colorectal cancer progression and therapeutic resistance has emerged. Deregulated expression of E-Cadherin and Claudin-1 and increased miR-21 expression and invasiveness represent hallmarks of EMT. The effects of cigarette smoke exposure on EMT in colorectal adenocarcinoma cells are largely unknown. AIM: The aim of the study is to evaluate the effect of cigarette smoke extract (CSE) on miR-21, Claudin-1 and E-Cadherin, molecules associated to EMT in colorectal cancer cells. METHODS: A human colorectal adenocarcinoma cell line (Caco-2) was treated with CSE at different concentration (5% and 10%) and for different time points (3 h and 24 h). Metabolic activity (by MTS assay), cell necrosis/cell apoptosis (evaluating Propidium Iodide/Annexin V expression by flow cytometry), miR-21, Claudin-1 and E-Cadherin gene expression were evaluated by Real time PCR. Cell permeability, actin polymerization and cancer cell migration was assessed by Trans-Epitelial Electrical Resistance (TEER), Phalloidin expression and matrigel system, respectively. RESULTS: CSE at all the tested concentrations and at all time points reduced cell necrosis. CSE at 10% increased miR-21 and reduced the metabolic activity, cell necrosis, Claudin-1 and E-cadherin mRNA at 3 h. Cell permeability, actin polymerization and cancer cell migration were all increased upon CSE exposure. CONCLUSION: These results showed that CSE increasing miR-21, Claudin-1 and E-Cadherin and enhancing the aggressiveness of cancer cells, may concur to colorectal cancer progression.


Asunto(s)
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Cadherinas/metabolismo , Movimiento Celular , Fumar Cigarrillos/efectos adversos , Claudina-1/metabolismo , Neoplasias Colorrectales/metabolismo , MicroARNs/metabolismo , Humo/efectos adversos , Adenocarcinoma/genética , Adenocarcinoma/patología , Antígenos CD/genética , Células CACO-2 , Cadherinas/genética , Claudina-1/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Invasividad Neoplásica , Transducción de Señal
15.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-31600923

RESUMEN

Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband's sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.


Asunto(s)
Alelos , Antígenos CD/genética , Cadherinas/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Gástricas/genética , Adulto , Femenino , Gastrectomía/métodos , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/prevención & control , Linaje , Procedimientos Quirúrgicos Profilácticos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/prevención & control , Adulto Joven
16.
Nat Biotechnol ; 37(11): 1302-1313, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31548728

RESUMEN

Targeting membrane proteins could improve the efficacy of T cell-based immunotherapies. To facilitate the identification of T cell targets, we developed a hybrid genetic screening system where the Sleeping Beauty (SB) transposon and single guide RNA cassette are nested in an adeno-associated virus (AAV). SB-mediated genomic integration of the single guide RNA cassette enables efficient gene editing in primary murine T cells as well as a screen readout. We performed in vivo AAV-SB-CRISPR screens for membrane protein targets in CD8+ T cells in mouse models of glioblastoma (GBM). We validated screen hits by demonstrating that adoptive transfer of CD8+ T cells with Pdia3, Mgat5, Emp1 or Lag3 gene editing enhances the survival of GBM-bearing mice in both syngeneic and T-cell receptor transgenic models. Transcriptome profiling, single cell sequencing, cytokine assays and T cell signaling analysis showed that Pdia3 editing in T cells enhances effector functions. Engineered PDIA3 mutant EGFRvIII chimeric antigen T cells are more potent in antigen-specific killing of human GBM cells.


Asunto(s)
Linfocitos T CD8-positivos/trasplante , Edición Génica/métodos , Glioblastoma/terapia , Proteínas de la Membrana/genética , Transposasas/genética , Animales , Antígenos CD/genética , Linfocitos T CD8-positivos/metabolismo , Sistemas CRISPR-Cas , Línea Celular Tumoral , Dependovirus/genética , Femenino , Glioblastoma/genética , Glioblastoma/inmunología , Humanos , Inmunoterapia Adoptiva , Masculino , Ratones , N-Acetilglucosaminiltransferasas/genética , Proteínas de Neoplasias/genética , Proteína Disulfuro Isomerasas/genética , ARN Guia/genética , Receptores de Superficie Celular/genética , Transposasas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
17.
DNA Cell Biol ; 38(11): 1170-1177, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31502877

RESUMEN

Host response to viral infection is a highly regulated process involving engagement of various host factors, cytokines, chemokines, and stimulatory signals that pave the way for an antiviral immune response. The response is manifested in terms of viral sequestration, phagocytosis, and inhibition of genome replication, and, finally, if required, lymphocyte-mediated clearance of virally infected cells. During this process, cross-talk between viral and host factors can shape disease outcomes and immunopathology. Bone marrow stromal antigen 2 (BST-2), also know as tetherin, is induced by type I interferon produced in response to viral infections, as well as in certain cancers. BST-2 has been shown to be a host restriction factor of virus multiplication through its ability to physically tether budding virions and restrict viral spread. However, BST-2 has other roles in the host antiviral response. This review focuses on the diverse functions of BST-2 and its downstream signaling pathways in regulating host immune responses.


Asunto(s)
Antígenos CD/fisiología , Inmunomodulación/genética , Virión/inmunología , Virión/metabolismo , Inmunidad Adaptativa/genética , Animales , Antígenos CD/genética , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/fisiología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunomodulación/inmunología , Virosis/genética , Virosis/inmunología
18.
BMC Cancer ; 19(1): 926, 2019 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-31533668

RESUMEN

BACKGROUND: Reproductive characteristics are well-established risk factors for breast cancer, but the underlying mechanisms are not fully resolved. We hypothesized that altered DNA methylation, measured in tumor tissue, could act in concert with reproductive factors to impact breast carcinogenesis. METHODS: Among a population-based sample of women newly diagnosed with first primary breast cancer, reproductive history was assessed using a life-course calendar approach in an interviewer-administered questionnaire. Methylation-specific polymerase chain reaction and Methyl Light assays were used to assess gene promotor methylation status (methylated vs. unmethylated) for 13 breast cancer-related genes in archived breast tumor tissue. We used case-case unconditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations with age at menarche and parity (among 855 women), and age at first birth and lactation (among a subset of 736 parous women) in association with methylation status. RESULTS: Age at first birth > 27 years, compared with < 23 years, was associated with lower odds of methylation of CDH1 (OR = 0.44, 95% CI = 0.20-0.99) and TWIST1 (OR = 0.48, 95% CI = 0.28-0.82), and higher odds of methylation of BRCA1 (OR = 1.63, 95% CI = 1.14-2.35). Any vs. no lactation was associated with higher odds of methylation of the PGR gene promoter (OR = 1.59, 95% CI = 1.01-2.49). No associations were noted for parity and methylation in any of the genes assayed. CONCLUSIONS: Our findings indicate that age at first birth, lactation and, perhaps age at menarche, are associated with gene promoter methylation in breast cancer, and should be confirmed in larger studies with robust gene coverage.


Asunto(s)
Neoplasias de la Mama/genética , Metilación de ADN , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Proteína BRCA1/genética , Biomarcadores de Tumor , Neoplasias de la Mama/patología , Neoplasias de la Mama/fisiopatología , Cadherinas/genética , ADN de Neoplasias/metabolismo , Femenino , Humanos , Lactancia/genética , Menarquia/genética , Persona de Mediana Edad , Proteínas Nucleares/genética , Paridad/genética , Embarazo , Regiones Promotoras Genéticas , Receptores de Progesterona/genética , Reproducción/genética , Factores de Riesgo , Proteína 1 Relacionada con Twist/genética , Adulto Joven
19.
Nat Commun ; 10(1): 3928, 2019 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-31477692

RESUMEN

Tumor-associated macrophages (TAMs), one of the most abundant immune components in gastric cancer (GC), are difficult to characterize due to their heterogeneity. Multiple approaches have been used to elucidate the issue, however, due to the tissue-destructive nature of most of these methods, the spatial distribution of TAMs in situ remains unclear. Here we probe the relationship between tumor context and TAM heterogeneity by multiplex immunohistochemistry of 56 human GC cases. Using distinct expression marker profiles on TAMs, we report seven predominant populations distributed between tumor and non-tumor tissue. TAM population-associated gene signatures reflect their heterogeneity and polarization in situ. Increased density of CD163+ (CD206-) TAMs with concurrent high CD68 expression is associated with upregulated immune-signaling and improved patient survival by univariate, but not multivariate analysis. CD68-only and CD206+ TAMs are correlated with high PDL1 expression.


Asunto(s)
Inmunohistoquímica/métodos , Macrófagos/metabolismo , Neoplasias Gástricas/metabolismo , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
20.
BMC Cancer ; 19(1): 894, 2019 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-31492158

RESUMEN

BACKGROUNDS: Heterogeneous ribonucleoproteins (hnRNPs) are involved in the metastasis-related network. Our previous study demonstrated that hnRNP K is associated with epithelial-to-mesenchymal transition (EMT) in A549 cells. However, the precise molecular mechanism of hnRNP K involved in TGF-ß1-induced EMT remains unclear. This study aimed to investigate the function and mechanism of hnRNP K interacted with microtubule-associated protein 1B light chain (MAP 1B-LC1) in TGF-ß1-induced EMT. METHODS: Immunohistochemistry was used to detect the expression of hnRNP K in non-small-cell lung cancer (NSCLC). GST-pull down and immunofluorescence were performed to demonstrate the association between MAP 1B-LC1 and hnRNP K. Immunofluorescence, transwell assay and western blot was used to study the function and mechanism of the interaction of MAP 1B-LC1 with hnRNP K during TGF-ß1-induced EMT in A549 cells. RESULTS: hnRNP K were highly expressed in NSCLC, and NSCLC with higher expression of hnRNP K were more frequently rated as high-grade tumors with poor outcome. MAP 1B-LC1 was identified and validated as one of the proteins interacting with hnRNP K. Knockdown of MAP 1B-LC1 repressed E-cadherin downregulation, vimentin upregulation and actin filament remodeling, decreased cell migration and invasion during TGF-ß1-induced EMT in A549 cells. hnRNP K increased microtubule stability via interacting with MAP 1B-LC1 and was associated with acetylated ɑ-tubulin during EMT. CONCLUSION: hnRNP K can promote the EMT process of lung cancer cells induced by TGF-ß1 through interacting with MAP 1B-LC1. The interaction of MAP 1B/LC1 with hnRNP K may improve our understanding on the mechanism of TGF-ß1-induced EMT in lung cancer.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Células A549 , Acetilación , Antígenos CD/genética , Cadherinas/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas Asociadas a Microtúbulos/genética , Microtúbulos/fisiología , Persona de Mediana Edad , Unión Proteica , Tubulina (Proteína)/metabolismo , Vimentina/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA