RESUMEN
Y-box binding protein 2 (YBX2) has been associated with the properties of both germ cells and cancer cells. We hypothesized that YBX2 might contribute to the characteristics of cancer stem cells (CSCs). In this study, we clarified the function of YBX2 in endometrial cancer stem cells. We established a human YBX2-expressing Ishikawa (IK) cell line (IK-YBX2 cells). We analyzed gene expression associated with stemness and isolated SP cells from IK-YBX2 cells. The SP population of IK-YBX2 cells, the expression of ALDH1 and serial sphere-forming capacity were associated with levels of YBX2 expression. IK-YBX2 cells were resistant to anti-cancer drugs. In gene expression analysis, a gene for cancer testis antigen, CT45, was generally overexpressed in IK-YBX2 cells. YBX2-mediated CT45 expression was associated with increased levels of self-renewal capacity and paclitaxel resistance. The level of CT45 expression was enhanced in high-grade and/or advanced stages of human endometrial cancer tissues. We conclude that expression of YBX2 is essential for the stem cell-like phenotype. CT45 contributes to stemness associated with YBX2 and might be related to the progression of endometrial cancer.
Asunto(s)
Antígenos de Neoplasias/genética , Resistencia a Antineoplásicos/genética , Neoplasias Endometriales/genética , Células Madre Neoplásicas/patología , Proteínas de Unión al ARN/genética , Línea Celular Tumoral , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Paclitaxel/farmacologíaRESUMEN
Background: We recently reported that WNT10A plays a pivotal role in wound healing by regulating collagen expression/synthesis, as the depletion of WNT10A dramatically delays skin ulcer formation. WNT signaling also has a close correlation with the cancer microenvironment and proliferation, since tumors are actually considered to be 'unhealing' or 'overhealing' wounds. To ascertain the in vivo regulatory functions of WNT10A in tumor growth, we examined the net effects of WNT10A depletion using Wnt10a-deficient mice (Wnt10a -/-). Methods and Results: We subjected C57BL/6J wild-type (WT) or Wnt10a -/- mice to murine melanoma B16-F10 cell transplantation. Wnt10a -/- mice showed a significantly smaller volume of transplanted melanoma as well as fewer microvessels and less collagen expression and more necrosis than WT mice. Conclusions: Taken together, our observations suggest that critical in vivo roles of Wnt10a-depleted anti-stromagenesis prevent tumor growth, in contrast with true wound healing/scarring.
Asunto(s)
Colágeno/metabolismo , Melanoma Experimental/patología , Proteínas del Tejido Nervioso/genética , Neoplasias Cutáneas/patología , Proteínas Wnt/genética , Animales , Línea Celular Tumoral , Femenino , Eliminación de Gen , Masculino , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Microvasos/metabolismo , Microvasos/patología , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/metabolismo , Células del Estroma/patología , Proteínas Wnt/metabolismoRESUMEN
Wnt10a is a member of the WNT family. Although deficiency of this gene causes symptoms related to teeth, hair, nails, and skin, we recently demonstrated a new phenotype of Wnt10a knockout (KO) mice involving bone and fat. The in vivo effect of the Wnt10a gene on bone and fat is unclear, and the relationship between bone/fat and muscle in Wnt10a signaling is also interesting. We aimed to evaluate the tissue changes in Wnt10a KO mice compared to wild-type mice and show the findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle. Trabecular bone loss in the lower limbs of Wnt10a mice and decreased bone mineralization were observed. The adipose tissue in bone marrow was also decreased, and adipocyte differentiation was reduced. The body fat mass in Wnt10a KO mice was decreased, and white adipocytes in subcutaneous fat were converted to beige adipocytes. The muscle weight of the lower limbs was not decreased despite trabecular bone loss, but Gdf8/myostatin expression was reduced in the subcutaneous fat and gastrocnemius muscles of Wnt10a KO mice. Thus, in vivo deletion of Wnt10a inhibited osteogenic activity, promoted beige adipogenesis of white adipocytes and maintained muscle mass. These results suggest that regulation of Gdf8 by Wnt10a may help maintain the muscle mass of Wnt10a KO mice. This study was the first to histologically evaluate the bone, fat and muscle phenotypes of Wnt10a KO mice. The results of this study, which were obtained by investigating the three tissues together, could influence the understanding of in vivo interactions involving the Wnt10a gene.
Asunto(s)
Tejido Adiposo/metabolismo , Huesos/metabolismo , Músculos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Wnt/metabolismo , Adipogénesis , Animales , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Eliminación de Gen , Ratones Noqueados , Modelos Biológicos , Miostatina/metabolismo , Tamaño de los Órganos , Osteogénesis , Unión ProteicaRESUMEN
BACKGROUND: We have reported that WNT10A plays a critical role in the growth of fibroblasts/myofibroblasts and microvascular endothelial cells, i.e.; wound healing/scarring. To ascertain the in vivo regulatory, central functions of WNT10A, we examined the net effects of WNT10A depletion using WNT10A-deficient mice (WNT10A-/-). METHODS AND RESULTS: We generated WNT10A-/-mice, displaying a range of unique phenotypes of morpho/organogenetic failure, such as growth retardation, alopecia, kyphosis and infertility, and then focused on the functions of WNT10A in wound healing. We subjected C57BL/6J wild-type (WT) or WNT10A-/-mice to skin ulcer formation. The WNT10A-/-mice had significantly larger injured areas and delayed wound healing, which were associated with (a) a smaller number of fibroblasts/myofibroblasts and microvessels; and (b) more reduced expression and synthesis of collagen, compared with WT mice with intact WNT10A expression, especially in those with activated myofibroblasts. CONCLUSIONS: These observations indicate that WNT10A signaling can play a pivotal in vivo role in wound healing by regulating the expression and synthesis of collagen, as one of fibrogenic factors, at least in part, and critical in vivo roles of WNT10A-mediated effective wound healing are extremely closely associated with collagen expression.
Asunto(s)
Colágeno/metabolismo , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/fisiología , Piel/metabolismo , Proteínas Wnt/fisiología , Cicatrización de Heridas/fisiología , Animales , Células Cultivadas , Femenino , Fibroblastos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Piel/patologíaRESUMEN
Zinc-finger protein 143 (ZNF143) is a transcription factor that is involved in anticancer drug resistance and cancer cell survival. In the present study, we identified a novel small molecule N-(5-bromo-2-methoxyphenyl)-3-(pyridine-3-yl) propiolamide (YPC-21661) that inhibited ZNF143 promoter activity and down-regulated the expression of the ZNF143-regulated genes, RAD51, PLK1, and Survivin, by inhibiting the binding of ZNF143 to DNA. In addition, YPC-21661 was cytotoxic and induced apoptosis in the human colon cancer cell line, HCT116 and human prostate cancer cell line, PC-3. 2-(pyridine-3-ylethynyl)-5-(2-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole (YPC-22026), a metabolically stable derivative of YPC-21661, induced tumor regression accompanied by the suppression of ZNF143-regulated genes in a mouse xenograft model. The present study revealed that the inhibition of ZNF143 activity by small molecules induced tumor regression in vitro and in vivo; therefore, ZNF143 is a promising target of cancer therapeutics.
Asunto(s)
Bibliotecas de Moléculas Pequeñas/farmacología , Transactivadores/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Células HCT116 , Células HT29 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Regiones Promotoras Genéticas/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
BACKGROUND: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) are important glycosyltransferases in cancer, but the clinical role of its individual isoforms is unclear. We investigated the clinical significance and survival relevance of one isoform, GalNAc-T6 in lung adenocarcinoma after curative resection. RESULTS: GalNAc-T6 was identified in 27.8% (55/198) of patients, and statistically indicated advanced TNM stage (P = 0.069). Multivariate analysis showed GalNAc-T6 to be an independent predictor for reduced overall survival of patients (P = 0.027), and the result was confirmed with bootstraping techniques, and on line "Kaplan-Meier Plotter" and "SurvExpress" database analysis, respectively. Moreover, ROC curve demonstrated that GalNAc-T6 expression significantly improved the accuracy of survival prediction. METHODS: With 198 paraffin-embedded tumor samples from lung adenocarcinoma patients, GalNAc-T6 expression was immunohistochemically assessed for the association with clinicopathological parameters. The prognostic significance was evaluated by Cox proportional hazards regression analysis with 1000 bootstraping. "Kaplan-Meier Plotter", "SurvExpress" database analysis, and receiver-operating characteristic (ROC) curve were performed to provide further validation. CONCLUSIONS: GalNAc-T6 expression correlated significantly with advanced TNM stage, and independently predicted worse OS for lung adenocarcinoma.
Asunto(s)
Adenocarcinoma/mortalidad , Neoplasias Pulmonares/mortalidad , N-Acetilgalactosaminiltransferasas/análisis , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. METHODS & RESULTS: Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. CONCLUSION: Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Peroxirredoxinas/metabolismo , Animales , Progresión de la Enfermedad , Intestinos/microbiología , Ratones , Ratones Transgénicos , Microbiota , Enfermedad del Hígado Graso no Alcohólico/metabolismo , ARN Ribosómico 16S/genéticaRESUMEN
The polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts) family of enzymes regulates the critical initial steps of mucin-type O-glycosylation. Among GalNAc-Ts that may significantly influence cancer biology, thus affecting cell differentiation, adhesion, invasion, and/or metastasis, GalNAc-T3 exhibits a high expression in several human cancers, closely associated with tumor progression and a poor prognosis. However, the expression pattern of GalNAc-T3 in oral squamous cell carcinoma (OSCC) remains obscure. Since postoperative recurrence of even early stage OSCC (ESOSCC) occurs at an early phase, significantly affecting their clinical course and worse outcome, the identification of clinically significant accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical GalNAc-T3 expression and various clinicopathological characteristics and recurrence using 110 paraffin-embedded tumor samples obtained from patients with surgically resected ESOSCC (T1-2N0). Recurrence was recognized in 37 of 110 (33.6 %) patients. The GalNAc-T3 expression was considered to be strongly positive when 20 % or more of the cancer cells showed positive cytoplasmic staining. Consequently, a strong expression of GalNAc-T3 was observed in 40 patients (36.4 %), showing a close relationship to poor differentiation, the presence of lymphatic and vascular invasion, and recurrence. Univariate and multivariate analyses further demonstrated that the patients with a strong GalNAc-T3+ status had markedly lower disease-free survival (DFS) rates, especially within the first 2 years postoperatively. Therefore, GalNAc-T3 might play a role in the pathogenesis of ESOSCC recurrence, and its immunohistochemical detection potentially predicts a shorter DFS and may be a useful parameter for providing clinical management against ESOSCC in the early postoperative phase.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Boca/metabolismo , N-Acetilgalactosaminiltransferasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , Adhesión Celular , Diferenciación Celular , Línea Celular Tumoral , Citoplasma/metabolismo , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Glicosilación , Humanos , Inmunohistoquímica , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Neoplasias de la Boca/mortalidad , Invasividad Neoplásica , Metástasis de la Neoplasia , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia , Pronóstico , Adulto Joven , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a broad range of solid tumors. Cisplatin may directly interact with mitochondria, which can induce apoptosis. The direct interactions between cisplatin and mitochondria may account for our understanding of the clinical activity of cisplatin and development of resistance. However, the basis for the roles of mitochondria under treatment with chemotherapy is poorly understood. In this review, we present novel aspects regarding the unique characteristics of the mitochondrial genome in relation to the use of platinum-based chemotherapy and describe our recent work demonstrating the importance of the mitochondrial transcription factor A (mtTFA) expression in cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Proteínas de Unión al ADN/metabolismo , Genoma Mitocondrial/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Neoplasias/tratamiento farmacológico , Factores de Transcripción/metabolismo , Animales , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Daño del ADN , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacos , Neoplasias/metabolismo , Estrés OxidativoRESUMEN
Mitochondrial transcription factor A (mtTFA) plays a crucial role in both the transcription and maintenance of mitochondrial DNA. A high expression of mtTFA has been demonstrated in several solid tumors, and is closely associated with cancer cell survival/apoptosis and growth. However, its expression pattern in pancreatic ductal adenocarcinoma (PAC) remains to be elucidated. Additionally, our groups have recently revealed that a subset of apoptosis-related genes is strongly regulated by mtTFA, and that two putative mtTFA binding sites are present in the promoter region of the survivin gene, which is a member of the inhibitor-of-apoptosis protein family. We therefore investigated the correlation of the immunohistochemical mtTFA expression and the survivin index with various clinicopathological variables and the prognosis, using 70 paraffin-embedded tumor samples from patients with surgically-resected PAC. The mtTFA expression or survivin index was considered to be strong or high when ≥30% or 10% of the PAC cells showed positive staining, respectively. Strong mtTFA expression and/or a high survivin index was revealed to have a significant relationship to a pathologically high tumor grading and advanced tumor stage. Moreover, mtTFA showed significantly high co-expression with survivin. Univariate and multivariate analyses demonstrated that both the strong mtTFA expression and high survivin index groups had significantly shorter survival rates, especially within the first two years postoperatively. The combination of strong mtTFA expression and a high survivin index may predict a poor prognosis in patients with PAC, and these new biomarkers might offer useful information for the early clinical management.
Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Proteínas Mitocondriales/biosíntesis , Neoplasias Pancreáticas/metabolismo , Factores de Transcripción/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/patología , Terapia Combinada , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Proteínas Inhibidoras de la Apoptosis/genética , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Neoplasias Pancreáticas/patología , Pronóstico , Análisis de Supervivencia , Survivin , Factores de Transcripción/genética , Resultado del TratamientoRESUMEN
BACKGROUND: The Y-box binding protein 1 (YB-1) possesses pleiotropic functions through its interactions with various cellular proteins, and its high expression levels make it a potential useful prognostic biomarker for cancer cells. Eukaryotic DNA topoisomerases, such as DNA topoisomerase 1 (TOPO1) and DNA topoisomerase 2 (TOPO2), are the essential DNA metabolism regulators that usually overexpressed in cancer cells, and multiple proteins have been reported to regulate the enzyme activity and the clinical efficacy of their inhibitors. The present study unraveled the interaction of YB-1 with TOPO1, and further investigated the related function and potential mechanisms during the interaction. METHODS: The direct association of TOPO1 with specific domain of YB-1 was explored by co-immunoprecipitation and GST pull-down assays. The interaction function was further clarified by DNA relaxation assays, co-immunoprecipitation and WST-8 assays with in vitro gain- and loss- of function models. RESULTS: We found that YB-1 interacts directly with TOPO1 (but not with TOPO2) and promotes TOPO1 catalytic activity. Interactions between YB-1 and TOPO1 increased when cancer cells were treated with the TOPO1 inhibitor, camptothecin (CPT), but not with the TOPO2 inhibitor, adriamycin (ADM). Furthermore, we found that the interaction is prevented by pretreatment with the antioxidant agent, N-acetyl cysteine, and that YB-1 downregulation renders cells resistant to CPT. CONCLUSIONS: Our findings suggest that nuclear YB-1 serves as an intracellular promoter of TOPO1 catalytic activity that enhances CPT sensitivity through its direct interaction with TOPO1.
Asunto(s)
Camptotecina/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Proteína 1 de Unión a la Caja Y/metabolismo , Acetilcisteína/farmacología , Antioxidantes/farmacología , Sitios de Unión , Catálisis , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/genética , Regulación hacia Abajo , Resistencia a Antineoplásicos , Activación Enzimática , Regulación Neoplásica de la Expresión Génica , Humanos , Conformación de Ácido Nucleico , Estrés Oxidativo/efectos de los fármacos , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , Transfección , Proteína 1 de Unión a la Caja Y/genéticaRESUMEN
The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADP-ribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-XL. BCL-XL was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Regulación Neoplásica de la Expresión Génica/fisiología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Humanos , Indoles , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Pirroles/farmacología , Pirroles/uso terapéutico , Interferencia de ARNRESUMEN
WNT signaling mediates various physiological and pathological processes. We previously showed that WNT10A is a novel angio/stromagenic factor involved in such processes as tumor growth, wound healing and tissue fibrosis. In this study, we investigated the role of WNT10A in promoting the fibrosis that is central to the pathology of acute interstitial nephritis (AIN). We initially asked whether there is an association between kidney function (estimated glomerular filtration rate; eGFR) and WNT10A expression using kidney biopsies from 20 patients with AIN. Interestingly, patients with WNT10A expression had significantly lower eGFR than WNT10A-negative patients. However, changes in kidney function were not related to the level of expression of other WNT family members. Furthermore, there was positive correlation between WNT10A and α-SMA expression. We next investigated the involvement of WNT10A in kidney fibrosis processes using COS1 cells, a kidney fibroblast cell line. WNT10A overexpression increased the level of expression of fibronectin and peroxiredoxin 5. Furthermore, WNT10A overexpression renders cells resistant to apoptosis induced by hydrogen peroxide and high glucose. Collectively, WNT10A may induce kidney fibrosis and associate with kidney dysfunction in AIN.
Asunto(s)
Fibroblastos/patología , Riñón/patología , Nefritis Intersticial/genética , Nefritis Intersticial/patología , Proteínas Wnt/genética , Actinas/análisis , Actinas/genética , Enfermedad Aguda , Anciano , Apoptosis , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Fibrosis , Regulación de la Expresión Génica , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Nefritis Intersticial/fisiopatología , Estrés Oxidativo , Proteínas Wnt/análisis , Proteínas Wnt/metabolismoRESUMEN
High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2- status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2- expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/patología , Proteína HMGB1/biosíntesis , Proteína HMGB2/biosíntesis , Neoplasias Pancreáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Línea Celular Tumoral , Femenino , Técnica del Anticuerpo Fluorescente , Proteína HMGB1/análisis , Proteína HMGB2/análisis , Humanos , Inmunohistoquímica , Inmunoprecipitación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , ARN Interferente Pequeño , TransfecciónRESUMEN
Itai-itai disease is thought to be the result of chronic cadmium (Cd) intoxication. Renal proximal tubules are a major target of Cd toxicity. The whole mechanism of the adverse effects of Cd remains unresolved, especially how renal damage is related to the development of bone lesions. Fibroblast growth factor 23 (FGF23) is a bone-derived phosphaturic factor that regulates vitamin D and inorganic phosphate metabolism in the kidney. To clarify the role of FGF23 on Cd toxicity, we investigated the mechanisms of Cd-induced FGF23 production in the bone. Cd injection into mice significantly increased plasma FGF23 concentrations, but did not change FGF23 mRNA expression in bone. GalNAc-T3 is involved in secreting intact FGF23. To determine potential roles of GalNAc-T3 in Cd-induced FGF23 production, we examined the effect of Cd on GalNAc-T3 mRNA expression in vivo and in vitro. GalNAc-T3 gene expression was significantly increased in the bones of Cd-injected mice. Cd also enhanced the expression of GalNAc-T3 in cultured osteosarcoma UMR106 cells and primary osteocytes. Cd activated aryl hydrocarbon receptors (AhR) and AhR were required for GalNAc-T3 gene expression induced by Cd. In addition, Cd-dependent FGF23 production was completely inhibited by an AhR antagonist. AhR siRNA markedly suppressed the stimulation of transcriptional activity by Cd. Furthermore, Cd induced AhR activation via phosphorylation of Ser-68 by p38 kinase in the nuclear export signal of AhR. Thus, Cd stimulated GalNAc-T3 gene transcription via enhanced AhR binding to the GalNAc-T3 promoter. These findings suggest that the Cd-induced increase in GalNAc-T3 suppresses proteolytic processing of FGF23 and increases serum FGF23 concentrations.
Asunto(s)
Cloruro de Cadmio/toxicidad , Fémur/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/genética , N-Acetilgalactosaminiltransferasas/genética , Osteoblastos/efectos de los fármacos , Osteocitos/efectos de los fármacos , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Femenino , Fémur/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Expresión Génica/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Osteoblastos/metabolismo , Osteocitos/metabolismo , Fosforilación , Receptores de Hidrocarburo de Aril/metabolismo , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
The aurora kinases are serine/threonine kinases that are essential for mitosis and contribute to tumorigenesis. Therefore, aurora kinases hold promise for molecularly targeted therapy. In the present study, we demonstrated that aurora B kinase (AURKB) is overexpressed in both cisplatin- and oxaliplatin-resistant cells. Downregulation of AURKB sensitized cells to both cisplatin and oxaliplatin, but not to paclitaxel, 5-FU or hydrogen peroxide. Interestingly, we found that both cisplatin- and oxaliplatin-resistant cells were hypersensitive to the AURKB specific inhibitors, AZD1152 HQPA and ZM447439, suggesting that both cisplatin- and oxaliplatinresistant cells develop an addiction to AURKB. These data provide evidence that aurora kinase inhibitors can overcome both cisplatin and oxaliplatin resistance. Therefore, AURKB inhibitors could offer potential benefits if used after first-line platinum-based chemotherapy.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasas/antagonistas & inhibidores , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Aurora Quinasas/metabolismo , Benzamidas/farmacología , Línea Celular Tumoral , Humanos , Organofosfatos/farmacología , Oxaliplatino , Quinazolinas/farmacologíaRESUMEN
Epithelioid tumors with aggressive behavior have been reported; however, the epithelioid type of malignant pleural mesothelioma (MPM) has a less aggressive behavior. Few studies have evaluated the prognostic value of epithelial-mesenchymal transition (EMT) markers in MPM. We hypothesized that mesenchymal characteristics might predominate in the tumors. Tumor specimens were collected from 33 consecutive patients. We analyzed the EMT expression levels in tumor samples by an immunohistochemical analysis. Positive expression of E-cadherin, γ-catenin, vimentin, fibronectin, Twist and YB-1 was observed in 25, 14, 21, 1, 19 and 18 patients, respectively. No significant association between these markers and the clinicopathological characteristics was found. γ-Catenin demonstrated a trend towards decreased expression in sarcomatoid tumors compared to epithelioid tumors. On the other hand, a trend was noted towards higher expression of vimentin, Twist and YB-1 in sarcomatoid tumors. The survival curves demonstrated that the patients with negative γ-catenin and positive Twist staining had a tendency to have a worse prognosis. Although the individual proteins might not significantly affect the progression of MPM, the combination of γ-catenin and Twist staining can predict the prognosis of patients with MPM.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pleurales/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , gamma Catenina/metabolismo , Anciano , Antígenos CD , Cadherinas/metabolismo , Femenino , Fibronectinas/metabolismo , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/mortalidad , Mesotelioma/patología , Mesotelioma Maligno , Análisis Multivariante , Neoplasias Pleurales/mortalidad , Neoplasias Pleurales/patología , Pronóstico , Vimentina/metabolismo , Proteína 1 de Unión a la Caja Y/metabolismoRESUMEN
Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bile duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK1-deficient (ASK1(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK1(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK1(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK1(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribiliary fibrogenic cells and peribiliary fibrosis. These observations indicate that ASK1-mediated hepatic necroinflammation and proliferation, but not apoptosis, are closely linked to liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.
Asunto(s)
Apoptosis , Cirrosis Hepática/metabolismo , MAP Quinasa Quinasa Quinasa 5/metabolismo , Transducción de Señal , Animales , Conductos Biliares/patología , Proliferación Celular , Colestasis/patología , Hepatocitos/metabolismo , Inflamación , Hígado/metabolismo , Cirrosis Hepática/patología , MAP Quinasa Quinasa Quinasa 5/genética , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación , Eliminación de SecuenciaRESUMEN
Circadian rhythms regulate a variety of physiological functions. Epidemiological evidence indicates that disruption of these circadian rhythms might be linked to cancer. In general, imbalances in homeostasis, such as immune and hormonal dysfunctions, are thought to be involved in cancer development. The results of a recent study suggested that circadian disruption may induce stromal changes associated with cancer risk, highlighting the importance of the cancer stem cell niche for protecting cancer cells. Current research provides new concepts and clarification regarding the function of the tumor niche, and the new concept of a stromal niche may help us to understand the additional functions of both cancer-associated fibroblasts and the extracellular matrix. In this review, we summarize our current knowledge regarding the role of circadian rhythms in cancer risk and the relevance of the stromal niche in cancer cell survival and progression.