RESUMEN
NLRP1, the first identified inflammasome-forming sensor, is thought to be involved in cancer, yet its definite function in lung adenocarcinoma (LUAD) remains unclear. Herein, we explored the expression and function of NLRP1 in LUAD. Decreased NLRP1 expression was identified in LUAD, which was associated with a poor prognosis. Overexpression of NLRP1 inhibited tumor growth in vitro and in vivo. Mechanically, this effect was observed regardless of inflammasome activation. Further studies revealed that overexpression of NLRP1 downregulated the phosphorylation of DRP1 and promoted mitochondrial fusion, which was mediated by inhibition of NF-κB activity. NF-κB agonist could neutralize the effect of NLRP1 on mitochondrial dynamics. In addition, LUAD sensitivity to cisplatin was enhanced by decreased mitochondrial fission resulting from up-regulated NLRP1. In conclusion, our findings demonstrated an unexpected role of NLRP1 in LUAD by modulating mitochondrial activities, which provides strong evidence for its potential in LUAD treatment.
Asunto(s)
Adenocarcinoma del Pulmón , Inflamasomas , Neoplasias Pulmonares , Mitocondrias , Proteínas NLR , Humanos , Inflamasomas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Proteínas NLR/metabolismo , Animales , Mitocondrias/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Dinámicas Mitocondriales/efectos de los fármacos , Dinámicas Mitocondriales/fisiología , Ratones , Masculino , Proliferación Celular/efectos de los fármacos , FemeninoRESUMEN
OBJECTIVE: Cancer genomics and transcriptomics studies have provided a large volume of data that enables to test of hypotheses based on real data from cancer patients. Ezrin (encoded by the EZR gene) is a highly expressed protein in cancer that contributes to linking the actin cytoskeleton to the cell membrane and signal transduction pathways involved in oncogenesis and disease progression. NSC305787 is a pharmacological ezrin inhibitor with potential antineoplastic effects. In the present study, the authors prospected EZR mRNA levels in a pan-cancer analysis and identified potential cancers that could benefit from anti-EZR therapies. METHODS: This study analyzed TCGA data for 32 cancer types, emphasizing cervical squamous cell carcinoma and stomach adenocarcinoma. It investigated the impact of EZR transcript levels on clinical outcomes and identified differentially expressed genes. Cell lines were treated with NSC305787, and its effects were assessed through various cellular and molecular assays. RESULTS: EZR mRNA levels are highly expressed, and their expression is associated with biologically relevant molecular processes in cervical squamous carcinoma and stomach adenocarcinoma. In cellular models of cervical and gastric cancer, NSC305787 reduces cell viability and clonal growth (p < 0.05). Molecular analyses indicate that the pharmacological inhibition of EZR induces molecular markers of cell death and DNA damage, in addition, to promoting the expression of genes associated with apoptosis and inhibiting the expression of genes related to survival and proliferation. CONCLUSION: The present findings provide promising evidence that ezrin may be a molecular target in the treatment of cervical and gastric carcinoma.
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Adenocarcinoma , Proteínas del Citoesqueleto , Perfilación de la Expresión Génica , Neoplasias Gástricas , Neoplasias del Cuello Uterino , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteínas del Citoesqueleto/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Línea Celular Tumoral , Femenino , Adenocarcinoma/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , ARN Mensajero , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Apoptosis/genéticaRESUMEN
Apocrine gland anal sac adenocarcinoma is an aggressive neoplasm, and surgery remains the treatment of choice, although it is controversial in advanced cases. The prognostic factors are not well established. Human Epidermal Growth Factor Receptor 2 (HER2) is a membrane protein related to tumorigenesis, whereas Ki67 is a nuclear protein related to cell proliferation. Both are potential prognostic markers and therapeutic targets. This study aimed to evaluate the expression of HER2 and Ki67 markers in canine apocrine gland anal sac adenocarcinoma. The tumor samples were divided into four groups: largest tumor diameter less than 2.5 cm, largest tumor diameter greater than 2.5 cm, metastatic lymph nodes, and control group of non-neoplastic anal sacs. Each contained 10 samples. Immunohistochemistry was performed to verify the expression of HER2 and Ki67 markers. Positive HER2 staining was observed in 45% of the neoplastic cases and negative HER2 staining in 100% of the control group. The Ki67 expression had a median of 25% in all groups, except for the control group, which had a median of 8%. The HER2 and Ki67 expression was present in apocrine gland anal sac adenocarcinoma, making them potential therapeutic targets. However, it was not possible to determine the clinical value of either marker.
Asunto(s)
Adenocarcinoma , Sacos Anales , Glándulas Apocrinas , Biomarcadores de Tumor , Inmunohistoquímica , Antígeno Ki-67 , Receptor ErbB-2 , Antígeno Ki-67/metabolismo , Antígeno Ki-67/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Receptor ErbB-2/metabolismo , Glándulas Apocrinas/metabolismo , Glándulas Apocrinas/patología , Humanos , Biomarcadores de Tumor/metabolismo , Animales , Sacos Anales/metabolismo , Sacos Anales/patología , Perros , Femenino , Masculino , Neoplasias de las Glándulas Anales/metabolismo , Neoplasias de las Glándulas Anales/patologíaRESUMEN
Prostate cancer is one of the most common neoplasm in the male population. It is not known why some tumors become more aggressive than others. Although most studies show changes in the expression of cell adhesion molecules and the extracellular matrix correlated with the Gleason score, no study has objectively measured the tissue content of these molecules. This study aims to measure the content and tissue expression of collagen type I and IV and laminin in the extracellular matrix of patients with prostate adenocarcinoma and correlate these findings with the Gleason score and clinical characteristics. Forty-one patients who underwent radical prostate surgery at the Urology Department of a reference Hospital in Brazil between January 2015 and December 2020 were studied. The tissue protein content was estimated under light microscopy at a final magnification of 200 × . The mean collagen I score in prostate adenocarcinoma tissue samples was 7.16 ± 1.03 pixels/field. The mean type IV collagen score was 3.44 ± 0.61 pixels/field. The mean laminin score was 5.19 ± 0.79 pixels/field. The total Gleason score was correlated with both collagen and laminin. All the correlations were negative, which shows that the higher the collagen/laminin expression was, the lower the total Gleason score (p-value < 0,05). According to the Pearson correlation analysis, age has no statistical relationship with collagen and laminin content. PSA, in turn, showed a correlation only with laminin, but r = -0.378 (p = 0.015). Among the associated diseases and lifestyle habits, there is only statistical significance in the comparison of alcoholism for collagen I. For collagen IV and laminin, no statistical significance was obtained with the clinical variables analyzed.
Asunto(s)
Adenocarcinoma , Colágeno Tipo IV , Colágeno Tipo I , Matriz Extracelular , Laminina , Clasificación del Tumor , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Laminina/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Colágeno Tipo IV/metabolismo , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Anciano , Persona de Mediana EdadRESUMEN
SUMMARY: Calcium-activated chloride channel regulator 1 (CLCA1) is associated with cancer progression. The expression and immunologic function of CLCA1 in stomach adenocarcinoma (STAD) remain unclear. In this investigation, the expression of CLCA1 in STAD tissues and its involvement in the progression and immune response of STAD were examined using databases such as cBioPortal, TISIDB, and UALCAN. In order to validate the expression level of CLCA1 protein in gastric adenocarcinoma, thirty clinical tissue specimens were gathered for immunohistochemical staining. The findings indicated a downregulation of CLCA1 in STAD patients, which was correlated with race, age, cancer grade, Helicobacter pylori infection, and molecular subtype. Through the examination of survival analysis, it was identified that diminished levels of CLCA1 within gastric cancer cases were linked to decreased periods of post-progression survival (PPS), overall survival (OS), and first progression (FP) (P<0.05). The CLCA1 mutation rate was lower in STAD, but the survival rate was higher in the variant group. The correlation between the expression level of CLCA1 and the levels of immune infiltrating cells in STAD, as well as the immune activating molecules, immunosuppressive molecules, MHC molecules, chemokines, and their receptor molecules, was observed. Gene enrichment analysis revealed that CLCA1 may be involved in STAD progression through systemic lupus erythematosus (SLE), proteasome, cell cycle, pancreatic secretion, and PPAR signaling pathways. In summary, CLCA1 is anticipated to function as a prognostic marker for patients with STAD and is linked to the immunization of STAD.
El regulador 1 del canal de cloruro activado por calcio (CLCA1) está asociado con la progresión del cáncer. La expresión y la función inmunológica de CLCA1 en el adenocarcinoma de estómago (STAD) aún no están claras. En esta investigación, se examinó la expresión de CLCA1 en tejidos STAD y su participación en la progresión y respuesta inmune de STAD utilizando bases de datos como cBioPortal, TISIDB y UALCAN. Para validar el nivel de expresión de la proteína CLCA1 en el adenocarcinoma gástrico, se recolectaron treinta muestras de tejido clínico para tinción inmunohistoquímica. Los hallazgos indicaron una regulación negativa de CLCA1 en pacientes con STAD, que se correlacionó con la raza, la edad, el grado del cáncer, la infección por Helicobacter pylori y el subtipo molecular. Mediante el examen del análisis de supervivencia, se identificó que los niveles reducidos de CLCA1 en los casos de cáncer gástrico estaban relacionados con períodos reducidos de supervivencia posterior a la progresión (PPS), supervivencia general (OS) y primera progresión (FP) (P <0,05). La tasa de mutación CLCA1 fue menor en STAD, pero la tasa de supervivencia fue mayor en el grupo variante. Se observó la correlación entre el nivel de expresión de CLCA1 y los niveles de células inmunes infiltrantes en STAD, así como las moléculas activadoras inmunes, moléculas inmunosupresoras, moléculas MHC, quimiocinas y sus moléculas receptoras. El análisis de enriquecimiento genético reveló que CLCA1 puede estar involucrado en la progresión de STAD a través del lupus eritematoso sistémico (LES), el proteasoma, el ciclo celular, la secreción pancreática y las vías de señalización de PPAR. En resumen, se prevé que CLCA1 funcione como un marcador de pronóstico para pacientes con STAD y está vinculado a la inmunización de STAD.
Asunto(s)
Humanos , Neoplasias Gástricas/metabolismo , Adenocarcinoma/metabolismo , Canales de Cloruro/metabolismo , Pronóstico , Neoplasias Gástricas/inmunología , Inmunohistoquímica , Adenocarcinoma/inmunología , Biomarcadores de Tumor , Análisis de Supervivencia , Canales de Cloruro/genética , Canales de Cloruro/inmunología , Biología Computacional , MutaciónRESUMEN
BACKGROUND: The current challenge in clinical cancer treatment is chemoresistance. Colon cells have inherently higher xenobiotic transporters expression and hence can attain resistance rapidly. Increased levels of TGF-ß2 expression in patients have been attributed to cancer progression, aggressiveness, and resistance. To investigate resistance progression, we treated doxorubicin (dox) to HT-29 colon adenocarcinoma cells in the presence or absence of TGF-ß2 ligand. METHODS: After 1, 3-, and 7-day treatment, we investigated cell proliferation, viability, and cytotoxicity by MTT, trypan blue staining, and lactate dehydrogenase enzyme release. The mechanism of cell death was elucidated by hoechst33342 and propidium iodide dual staining and apoptosis assay. The development of resistance was detected by rhodamine123 efflux and P-glycoprotein (P-gp)/MDR1 antibody staining through fluorimetry and flow cytometry. The colony formation ability of the cells was also elucidated. RESULTS: Inhibition of cell proliferation was noted after day 1, while a significant reduction in viability and a significant increase in lactate dehydrogenase release was detected after day 3. Reduction of intracellular rhodamine123 levels was detected after day 3 and was significantly lower in dox with TGF-ß2 treatment compared to dox alone. Increased surface P-gp levels after days 3 and 7 were observed in the treated groups. Hoechst33342/propidium iodide staining and apoptosis assay indicated non-apoptotic cell death. The cells treated with TGF-ß2 had higher colony formation ability. CONCLUSIONS: TGF-ß2 expression might play a significant role in the development of chemoresistance to doxorubicin in Duke's type B colon adenocarcinoma cell line, HT-29.
Asunto(s)
Adenocarcinoma , Antibióticos Antineoplásicos , Apoptosis , Proliferación Celular , Neoplasias del Colon , Doxorrubicina , Resistencia a Antineoplásicos , Factor de Crecimiento Transformador beta2 , Humanos , Doxorrubicina/farmacología , Adenocarcinoma/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo , Antibióticos Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células HT29 , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
SUMMARY: Colon adenocarcinoma (COAD) is a prevalent disease worldwide, known for its high mortality and morbidity rates. Despite this, the extent of investigation concerning the correlation between COAD's CLCA1 expression and immune cell infiltration remains insufficient. This study seeks to examine the expression and prognosis of CLCA1 in COAD, along with its relationship to the tumor immune microenvironment. These findings will offer valuable insights for clinical practitioners and contribute to the existing knowledge in the field. In order to evaluate the prognostic significance of CLCA1 in individuals diagnosed with colorectal cancers, we conducted a comprehensive analysis using univariate and multivariate Cox regression models along with receiver operating characteristic curve (ROC) analysis. This study was performed on the patient data of COAD obtained from The Cancer Genome Atlas (TCGA) database. Nomograms were developed to anticipate CLCA1 prognostic influence. Furthermore, the CLCA1 association with tumor immune infiltration, immune checkpoints, immune checkpoint blockade (ICB) response, interaction network, and functional analysis of CLCA1-related genes was analyzed. We found that Colon adenocarcinoma tissues significantly had decreased CLCA1 expression compared to healthy tissues. Furthermore, the study revealed that the group with high expression of CLCA1 demonstrated a significantly higher overall survival rate (OS) as compared to the group with low expression. Multivariate and Univariate Cox regression analysis revealed the potential of CLCA1 as a standalone risk factor for COAD. These results were confirmed using nomograms and ROC curves. In addition, protein-protein interaction (PPI) network analysis and functional gene enrichment showed that CLCA1 may be associated with functional activities such as pancreatic secretion, estrogen signaling and cAMP signaling, as well as with specific immune cell infiltration. Therefor, as a new independent predictor and potential biomarker of COAD, CLCA1 plays a crucial role in the advancement of colon cancer.
El adenocarcinoma de colon (COAD) es una enfermedad prevalente a nivel mundial, conocida por sus altas tasas de mortalidad y morbilidad. Sin embargo, el alcance de la investigación sobre la correlación entre la expresión de CLCA1 de COAD y la infiltración de células inmunes sigue siendo insuficiente. Este estudio busca examinar la expresión y el pronóstico de CLCA1 en COAD, junto con su relación con el microambiente inmunológico del tumor. Estos hallazgos ofrecerán conocimientos valiosos para los profesionales clínicos y contribuirán al conocimiento existente en el campo. Para evaluar la importancia de pronóstico de CLCA1 en personas diagnosticadas con cáncer colorrectal, realizamos un análisis exhaustivo utilizando modelos de regresión de Cox univariados y multivariados junto con un análisis de la curva característica operativa del receptor (ROC). Este estudio se realizó con los datos de pacientes de COAD obtenidos de la base de datos The Cancer Genome Atlas (TCGA). Se desarrollaron nomogramas para anticipar la influencia pronóstica de CLCA1. Además, se analizó la asociación de CLCA1 con la infiltración inmunitaria tumoral, los puntos de control inmunitarios, la respuesta de bloqueo de los puntos de control inmunitarios (ICB), la red de interacción y el análisis funcional de genes relacionados con CLCA1. Descubrimos que los tejidos de adenocarcinoma de colon tenían una expresión significativamente menor de CLCA1 en comparación con los tejidos sanos. Además, el estudio reveló que el grupo con alta expresión de CLCA1 demostró una tasa de supervivencia general (SG) significativamente mayor en comparación con el grupo con baja expresión. El análisis de regresión de Cox multivariado y univariado reveló el potencial de CLCA1 como factor de riesgo independiente de COAD. Estos resultados se confirmaron mediante nomogramas y curvas ROC. Además, el análisis de la red de interacción proteína- proteína (PPI) y el enriquecimiento de genes funcionales mostraron que CLCA1 puede estar asociado con actividades funcionales como la secreción pancreática, la señalización de estrógenos y la señalización de AMPc, así como con la infiltración de células inmunes específicas. Por lo tanto, como nuevo predictor independiente y biomarcador potencial de COAD, CLCA1 desempeña un papel crucial en el avance del cáncer de colon.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Adenocarcinoma/inmunología , Neoplasias del Colon/inmunología , Canales de Cloruro/inmunología , Pronóstico , Inmunohistoquímica , Adenocarcinoma/metabolismo , Análisis de Supervivencia , Análisis Multivariante , Análisis de Regresión , Neoplasias del Colon/metabolismo , Canales de Cloruro/metabolismo , Biología ComputacionalRESUMEN
Background: Tarin, a lectin purified from Colocasia esculenta, promotes in vitro and in vivo immunomodulatory effects allied to promising anticancer and antimetastatic effects against human adenocarcinoma mammary cells. This makes this 47 kDa-protein a natural candidate against human breast cancer, a leading cause of death among women. Tarin encapsulated in pegylated nanoliposomes displays increased effectiveness in controlling the proliferation of a mammary adenocarcinoma lineage comprising MDA-MB-231 cells. Methods: The mechanisms enrolled in anticancer and antimetastatic responses were investigated by treating MDA-MB-231 cells with nano-encapsulated tarin at 72 µg/mL for up to 48h through flow cytometry and transmission electron microscopy (TEM). The safety of nano-encapsulated tarin towards healthy tissue was also assessed by the resazurin viability assay, and the effect of nanoencapsulated tarin on cell migration was evaluated by scratch assays. Results: Ultrastructural analyses of MDA-MB-231 cells exposed to nanoencapsulated tarin revealed the accumulation of autophagosomes and damaged organelles, compatible with autophagy-dependent cell death. On the other hand, the flow cytometry investigation detected the increased occurrence of acidic vacuolar organelles, a late autophagosome trait, along with the enhanced presence of apoptotic cells, activated caspase-3/7, and cell cycle arrest at G0/G1. No deleterious effects were observed in healthy fibroblast cells following tarin nanoencapsulated exposition, in contrast to reduced viability in cells exposed to free tarin. The migration of MDA-MB-231 cells was inhibited by nano-encapsulated tarin, with delayed movement by 24 h compared to free tarin. Conclusion: The nanoliposome formulation delivers tarin in a delayed and sustained manner, as evidenced by the belated and potent antitumoral and anti-migration effects on adenocarcinoma cells, with no toxicity to healthy cells. Although further investigations are required to fully understand antitumorigenic tarin mechanisms, the activation of both apoptotic and autophagic machineries along with the caspase-3/7 pathway, and cell cycle arrest may comprise a part of these mechanisms.
Asunto(s)
Adenocarcinoma , Neoplasias de la Mama , Humanos , Femenino , Caspasa 3 , Línea Celular Tumoral , Apoptosis , Neoplasias de la Mama/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , AutofagiaRESUMEN
INTRODUCTION: Several studies have shown the antiproliferative effect of iodine and 5hydroxy-6 iodo-eicosatrienoic delta lactone (IL-δ) on diverse tissues. It was demonstrated that molecular iodine (I2) and IL-δ, but not iodide (I-), exerts anti-neoplastic actions in different cancers. The underlying mechanism through which IL-δ inhibits tumor growth remains unclear. The aim of this study was to analyze the effect of IL-δ on tumor growth and angiogenesis in human HT29 colorectal cancer xenografts. METHODOLOGY AND RESULTS: HT29 cells were injected subcutaneously into the flanks of nude mice and IL-δ was i.p. injected at a dose of 15 µg three days a week. IL-δ treatment in HT29 xenografts showed time-dependent inhibition of tumor growth, decrease of mitosis and PCNA expression (p < 0.05), increase of P27 expression and Caspase 3 activity after 18 days of treatment (p < 0.05). To assess tumor Microvessel Densities (MVD), CD31 staining by immunohistochemistry was analyzed. IL-δ treatment decreased MVD by 17% and 30% after 18 and 30 days respectively (p < 0.05), as well as it decreased VEGF and VEGF-R2 expression (p < 0.05). Additionally, our findings demonstrated that IL-δ increased VEGF-R1 and Ang-1 mRNA levels (p < 0.01). CONCLUSION: The antitumor efficacy of IL-δ in vivo involves inhibition of cell proliferation as well as induction of apoptosis. IL-δ has also anti-angiogenic effect associated with VEGF and VEGF-R2 downregulation followed by Ang-1 and VEGF-R1 increased expression. High levels of Ang-1 would contribute to mature vessel stabilization and maintenance while VEGF-R1 increase would produce anti-proliferative effect on endothelial cells.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Yodo , Ratones , Animales , Humanos , Células HT29 , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratones Desnudos , Xenoinjertos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Células Endoteliales/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Neovascularización Patológica/tratamiento farmacológico , Lactonas/uso terapéutico , Yodo/uso terapéutico , Línea Celular Tumoral , Ratones Endogámicos BALB CRESUMEN
Current scientific literature lacks data on the prognostic value of the expression of RAD51 and BRCA2 in gastric adenocarcinoma. Therefore, we aimed to evaluate those and other homologous recombination-related proteins (ATM, ATR, BRCA1, CHK2, γH2AX, p53) in gastric cancer, assessing their correlation with clinical prognosis. Paraffin-embedded samples were obtained from surgical specimens collected in total or subtotal gastrectomy procedures. Between 2008 and 2017, 121 patients with advanced gastric adenocarcinoma underwent surgical resection and were included in this study. Negativity for nuclear RAD51 correlated with vascular invasion, lymph node metastasis, larger tumor size, and lower overall survival and disease-free survival in univariate analysis. However, nuclear RAD51-negative cases presented better response rates to adjuvant therapy than the positive ones. Nuclear ATR negativity correlated with larger tumor size and a higher histological grade. Positivity for ATM was associated with more prolonged disease-free survival. Positivity for nuclear BRCA2 correlated with lower overall survival and diffuse histological type, whereas its high expression was associated with vascular invasion. Nevertheless, tumors positive for nuclear BRCA2 were more frequently low grade in the intestinal histological type. Our findings indicate that RAD51 and BRCA2 are valuable immunohistochemical prognostic markers in gastric adenocarcinoma.
Asunto(s)
Adenocarcinoma/diagnóstico , Proteína BRCA2/análisis , Recombinasa Rad51/análisis , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/metabolismo , Proteína BRCA2/biosíntesis , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Recombinasa Rad51/biosíntesis , Estudios Retrospectivos , Neoplasias Gástricas/metabolismoRESUMEN
PURPOSE: To evaluate metabolic alterations along with the carcinoma ex pleomorphic adneoma (CXPA) development of lacrimal glands (LG). METHODS: Four samples of the normal LG (NLG), 9 of pleomorphic adenoma (PA), 4 of residual PA (rPA), and 4 of CXPA of LG were included. GLUT-1, HIF-1α, FASN, and adipophilin by immunohistochemical stains were performed in the selected cases. RESULTS: Was observed higher expression of markers associated with glycolytic and lipid metabolism in the tumor tissue samples when compared to the NLG samples. Additionally, GLUT-1, FASN, and Adipophilin were more expressed in CXPA samples while HIF-1α in PA samples. CONCLUSIONS: In conclusion, our results demonstrate overexpression of FASN and Adipophilin in CXPA which may reflect a metabolic shift toward lipogenesis in cancer cells.
Asunto(s)
Adenocarcinoma , Adenoma Pleomórfico , Carcinoma , Aparato Lagrimal , Adenocarcinoma/metabolismo , Carcinoma/patología , Humanos , Aparato Lagrimal/patología , Perilipina-2RESUMEN
CD44 and CD133 have been considered as cancer stem cell (CSC) markers. Stem cell markers are rarely described in healthy stomach tissues. However, the clinicopathological and prognostic value of CD44 and CD133 in gastric cancer remains controversial. This study investigated the expression of CD44 and CD133 in gastric cancer and non-neoplastic gastric mucosa. We used samples of primary gastric adenocarcinomas (n = 69), metastatic lymph nodes (n = 30), intestinal metaplasia (n = 17), and histologically normal gastric tissues of surgical margins (n = 54). The expression of CD44 and CD133 were studied in samples by immunohistochemistry. Fisher's exact test and a logistic regression model were used in this study. CD44 expression was observed in 12% of samples with intestinal metaplasia, 20% with lymph node metastases, 22% with normal mucosa, to 30% of samples with primary tumors. Most of these positive tumors showed immunostaining in less than 4% of cancerous cells, mainly in the diffuse type. CD133 expression was observed in 7% (intestinal metaplasia) to 46% (normal mucosa). In the positive cases of cancer (24%), in most of them, less than 3% of cells were marked. CD44 and CD133 expression in the histologically normal gastric mucosa was restricted to the deeper regions of the gastric crypts at the level where stem cells and progenitor cells are usually found. CD44 and CD133 expression occurs in few gastric cancer cells, mainly in diffuse carcinomas, and are expressed in histologically normal gastric mucosae. None of the markers are specific for cancer and are also present in intestinal metaplasia and the normal mucosa.
Asunto(s)
Antígeno AC133/biosíntesis , Adenocarcinoma/metabolismo , Receptores de Hialuranos/biosíntesis , Proteínas de Neoplasias/biosíntesis , Células Madre Neoplásicas/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patología , Anciano , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Neoplasias Gástricas/patologíaRESUMEN
Helicobacter pylori, a human pathogen that colonizes the stomach of 50% of the world's population, is associated with gastritis, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. Diseases are characterized by severe inflammatory responses in the stomach that are induced by various chemokines and cytokines. Recently, oncostatin M (OSM), an IL-6 family cytokine, was detected in early gastric cancer biopsies. In this study, we showed that Helicobacter pylori induced secretion of OSM and overexpression of its type II receptor OSMRß (OSM/OSMRß) in a human gastric adenocarcinoma cell line (AGS) over 24 h of infection. Furthermore, we showed that the induction of OSM and OSMRß was carried out by heat-sensitive Helicobacter pylori outer membrane vesicle (OMV) protein. Collectively, our results established, for the first time, a direct relation between Helicobacter pylori OMVs and the OSM/OSMRß signaling axis.
Asunto(s)
Adenocarcinoma , Membrana Externa Bacteriana , Infecciones por Helicobacter , Oncostatina M , Neoplasias Gástricas , Adenocarcinoma/metabolismo , Mucosa Gástrica , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/genética , Humanos , Oncostatina M/metabolismo , Subunidad beta del Receptor de Oncostatina M/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismoRESUMEN
PURPOSE: The aim of the present study was to elucidate the functional role of hsa-miR-328-3p/STAT3 pathway in the effects of propofol on gastric cancer proliferation. METHODS: Bioinformatics was used to analyze the molecular expression differences of hsa-miR-328-3p/STAT3 axis in stomach adenocarcinoma (n = 435) and normal samples (n = 41) from TCGA database. The expression of the above molecules in gastric cancer cells SGC-7901 and normal gastric mucosal cells GES-1 was verified via qPCR. The dual-luciferase assay was carried out to confirm the interaction between hsa-miR-328-3p and STAT3. Subsequently, the cell proliferation and the expression of the above molecules in SGC-7901 and GES-1 cells were evaluated after 10 µM propofol treatment. Finally, we analyzed whether propofol still inhibited the proliferation of gastric cancer by suppressing STAT3 pathway after hsa-miR-328-3p down-regulation. RESULTS: Compared with normal samples, the expression of hsa-miR-328-3p was significantly down-regulated in stomach adenocarcinoma samples, while the expression of STAT3 and downstream target genes (MMP2, CCND1 and COX2) was up-regulated. The results were consistent with those in GES-1 and SGC-7901 cell lines. Meanwhile, we found that hsa-miR-328-3p can bind to the 3'-UTR of the potential target gene STAT3. Furthermore, propofol significantly inhibited the proliferation of gastric cancer cell line SGC-7901, where hsa-miR-328-3p was up-regulated and the expression of STAT3 and downstream proliferation-related target genes were down-regulated. However, the growth inhibition of propofol on SGC-7901 cell was significantly reversed after the inhibition of hsa-miR-328-3p. CONCLUSIONS: To sum up, propofol suppressed the STAT3 pathway via up-regulating hsa-miR-328-3p to inhibit gastric cancer proliferation.
Asunto(s)
Adenocarcinoma/patología , Anestésicos Intravenosos/farmacología , Proliferación Celular/efectos de los fármacos , MicroARNs/metabolismo , Propofol/farmacología , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/patología , Regiones no Traducidas 3' , Adenocarcinoma/metabolismo , Línea Celular Tumoral , Biología Computacional , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Regulación hacia Abajo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Humanos , Luciferasas/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , MicroARNs/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Neoplasias Gástricas/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVES: The promoting roles of cyclin dependent kinase 1 (CDK1) have been revealed in various tumors, however, its effects in the progression of cancer stem cells are still confusing. This work aims to explore the roles of CDK1 in regulating the stemness of lung cancer cells. METHODS: Online dataset analysis was performed to evaluate the correlation between CDK1 exression and the survival of lung cancer patients. RT-qPCR, western blot, cell viability, sphere-formation analysis and ALDH activity detection were used to investigate the roles of CDK1 on lung cancer cell stemness, viability and chemotherapeutic sensitivity. Immunocoprecipitation (Co-IP) analysis and rescuing experiments were performed to reveal the underlying mechanisms contributing to CDK1-mediated effects on lung cancer cell stemness. RESULTS: CDK1 mRNA expression was negatively correlated with the overall survival of lung cancer patients and remarkably increased in tumor spheres formed by lung cancer cells compared to the parental cells. Additionally, CDK1 positively regulated the stemness of lung cancer cells. Mechanistically, CDK1 could interact with Sox2 protein, but not other stemness markers (Oct4, Nanog and CD133). Furthermore, CDK1 increased the phosphorylation, cytoplasm-nuclear translocation and transcriptional activity of Sox2 protein in lung cancer cells. Moreover, CDK1 positively regulated the stemness of lung cancer cells in a Sox2-dependent manner. Finally, we revealed that inhibition of CDK1 enhanced the chemotherapeutic sensitivity, which was also rescued by Sox2 overexpression. CONCLUSIONS: This work reveals a novel CDK1/Sox2 axis responsible for maintaining the stemness of lung cancer cells.
Asunto(s)
Proteína Quinasa CDC2/metabolismo , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Factores de Transcripción SOXB1/metabolismo , Células A549 , Antígeno AC133/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Aldehído Deshidrogenasa/metabolismo , Proteína Quinasa CDC2/antagonistas & inhibidores , Proteína Quinasa CDC2/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Supervivencia Celular , Progresión de la Enfermedad , Humanos , Inmunoprecipitación/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Proteína Homeótica Nanog/metabolismo , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Fosforilación , ARN Mensajero/metabolismo , Esferoides Celulares/patologíaRESUMEN
Esophageal cancer (EC) is an aggressive disease, presenting two main histological subtypes: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). The two EC subtypes widely differ concerning virtually all factors. ESCC development is mainly associated with tobacco and alcohol abuse, whereas obesity and chronic gastroesophageal reflux disease (GERD) are important risk factors not only for EAC, but also for for Barrett's esophagus (BE), an intestinal metaplasia that precedes EAC. Obesity triggers ectopic lipid droplets (LD) accumulation in non-adipose tissues. LD are organelles involved in cell metabolism, signaling, proliferation and production of inflammatory mediators. Therefore, the aim of this work was to investigate LD occurrence and role in EC. This study shows progressive LD levels increase along EAC development, in esophageal samples from non-obese through obese individuals, as well as BE, and EAC patients, whereas no significant changes were observed in ESCC samples, when compared to non-tumor samples. Additionally, in order to mimic BE and EAC risk factors exposure, a non-tumor esophageal cell line was incubated with oleic acid (OA) and acidified medium and/or deoxycholic acid (DCA), revealing a significant increment in LD amount as well as in COX-2 and CXCL-8 expression, and in IL-8 secretion. Further, COX-2 expression and LD amount presented a significant positive correlation and were detected co-localized in EAC, but not in ESCC, suggesting that LD may be the site for eicosanoid production in EAC. In conclusion, this study shows that obesity, and BE- and EAC-associated inflammatory stimuli result in a gradual increase of LD, that may be responsible for orchestrating inflammatory mediators' production and/or action, thus contributing to BE and EAC genesis and progression.
Asunto(s)
Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Ciclooxigenasa 2/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Gotas Lipídicas/metabolismo , Transducción de Señal/fisiología , Adenocarcinoma/patología , Esófago de Barrett/patología , Línea Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Esófago/metabolismo , Esófago/patología , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Factores de RiesgoRESUMEN
Some prostate cancers (PCas) are histo-pathologically grouped within the same Gleason Grade (GG), but can differ significantly in outcome. Herein, we aimed at identifying molecular biomarkers that could improve risk prediction in PCa. LC ESI-MS/MS was performed on human PCa and benign prostatic hyperplasia (BPH) tissues and peptide data was integrated with omic analyses. We identified high YWHAZ and NDRG1 expression to be associated with poor PCa prognosis considering all Gleason scores (GS). YWHAZ and NDRG1 defined two subpopulations of PCa patients with high and intermediate risk of death. Multivariable analyses confirmed their independence from GS. ROC analysis unveiled that YWHAZ outperformed GS beyond 60 months post-diagnosis. The genomic analysis of PCa patients with YWHAZ amplification, or increased mRNA or protein levels, revealed significant alterations in key DNA repair genes. We hereby state the relevance of YWHAZ in PCa, showcasing its role as an independent strong predictor of aggressiveness.
Asunto(s)
Proteínas 14-3-3/metabolismo , Adenocarcinoma/metabolismo , Proteínas de Ciclo Celular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasias de la Próstata/metabolismo , Adenocarcinoma/mortalidad , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Neoplasias de la Próstata/mortalidad , Proteoma , Medición de RiesgoRESUMEN
Despite current achievements and innovations in cancer treatment, conventional chemotherapy has several limitations, such as unsatisfactory long-term survival, cancer drug resistance and toxicity against non-tumoral cells. In the search for safer therapeutic alternatives, docosahexaenoic acid (DHA) has shown promising effects inhibiting tumor growth without significant side effects in several types of cancer, but in gastric cancer (GC) its effects have not been completely described. In this study, we characterized the effects of DHA in GC using in vivo and in vitro models. Among all of the evaluated Ω-3 and Ω-6 fatty acids, DHA showed the highest antiproliferative potency and selectivity against the GC-derived cell line AGS. 10-100 µM DHA decreased AGS cell viability in a concentration-dependent manner but had no effect on non-tumoral GES-1 cells. To evaluate if the effects of DHA were due to apoptosis induction, cells were stained with Annexin V-PI, observing that 75 and 100 µM DHA increased apoptosis in AGS, but not in GES-1 cells. Additionally, levels of several proapoptotic and antiapoptotic regulators were assessed by qPCR, western blot and activity assays, showing similar results. In order to evaluate DHA efficacy in vivo, xenografts in an immunodeficient mouse model (BALB/cNOD-SCID) were used. In these experiments, DHA treatment for six weeks consistently reduced subcutaneous tumor size, ascitic fluid volume and liver metastasis. In summary, we found that DHA has a selective antiproliferative effect on GC, being this effect driven by apoptosis induction. Our investigation provides promising features for DHA as potential therapeutic agent in GC.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.
Asunto(s)
Adenocarcinoma/metabolismo , Antineoplásicos/farmacología , Neoplasias del Colon/metabolismo , Ácidos Grasos/metabolismo , Glutamina/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Diazooxonorleucina/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Acido Graso Sintasa Tipo I/antagonistas & inhibidores , Acido Graso Sintasa Tipo I/metabolismo , Femenino , Glutaminasa/antagonistas & inhibidores , Glutaminasa/metabolismo , Glucólisis/efectos de los fármacos , Hexoquinasa/antagonistas & inhibidores , Hexoquinasa/metabolismo , Indazoles/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Terapia Molecular Dirigida/métodos , Orlistat/administración & dosificación , SmegmamorphaRESUMEN
PURPOSE: It is postulated that patients with different types of pituitary neuroendocrine tumors (PitNETs) may present a higher incidence of cancer. Factors underlying individuals becoming overweight, such as insulin resistance, hyperleptinemia, and low-grade inflammation, may play a role in the risk of differentiated thyroid carcinoma (DTC) in such patients. This study aimed to investigate the frequency of and obesity-related risk factors associated with DTC in patients with PitNETs. METHODS: This cross-sectional study involved 149 patients with nonacromegalic PitNETs (AG group), 71 patients with acromegaly (ACRO group), and 156 controls (CG group). All participants underwent insulin and blood glucose measurements with the determination of the homeostatic model assessment-insulin resistance (HOMA-IR) index, leptin, and high-sensitivity C-reactive protein (hsCRP), and they also underwent thyroid ultrasound. Clinically significant nodules were biopsied for subsequent cytopathological evaluation, and participants were operated on when indicated. RESULTS: Patients in the AG group had high levels of insulin resistance and significantly higher levels of leptin and hsCRP compared with those of patients in the ACRO group. There were no cases of DTC in the AG group; two findings, one incidental, of DTC occurred in the CG group, and three cases of DTC were present in the ACRO group. Acromegaly was associated with DTC after adjusted analysis. CONCLUSIONS: Our findings in patients with nonacromegalic PitNETs do not indicate a high risk for DTC despite the presence of metabolic and inflammatory risk factors for neoplastic events. In contrast, acromegaly promotes a greater risk of DTC.