RESUMEN
The number of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients persists even under nucleos(t)ide analogues (NAs) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) expression has been reported in advanced chronic liver diseases as well as cancer tissues. We observed an association between related to HCC incidence and serum AKR1B10 by analyzing patients under treatment with NAs. Serum AKR1B10 levels measured by ELISA were higher in HCC cases under NA treatment compared with non-HCC cases and were associated with lamivudine- and adefovir pivoxil-, but not entecavir- or tenofovir alafenamide-treated cases. The latter drugs did not increase AKR1B10 values even in HCC cases, suggesting that they influence the reduction of AKR1B10 in any cases. This analysis was supported by in-vitro examination, which showed reduced AKR1B10 expression by entecavir and tenofovir via immunofluorescence staining. In conclusion there was a relationship between HBV-related HCC incidence and AKR1B10 under nucleos(t)ide analogues, especially in the use of lamivudine and adefovir pivoxil, but entecavir and tenofovir had suppressive effects of AKR1B10.
Asunto(s)
Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas , Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Neoplasias Hepáticas/patología , Lamivudine/uso terapéutico , Carcinoma Hepatocelular/patología , Tenofovir , Antivirales/farmacología , Antivirales/uso terapéutico , Aldo-Ceto ReductasasRESUMEN
OBJECTIVE: Aldo-keto reductase family 1 member B10 (AKR1B10) is a protein that is produced and secreted by a significant number of breast cancers. However, a potential confounder to the use of AKR1B10 as a tumor marker is its elevation in patients given cytotoxic chemotherapy. We therefore conducted a prospective study to analyze AKR1B10 levels in patients with breast cancer receiving neoadjuvant cytotoxic chemotherapy. METHODS: The study enrolled 10 patients from November 2015 to July 2017. All patients had locally advanced, but non-metastatic, breast cancer, and they received neoadjuvant chemotherapy followed by surgery. Serum AKR1B10 levels and tumor imaging were assessed before, during, and after chemotherapy. RESULTS: No increase in serum AKR1B10 levels was noted in patients receiving chemotherapy whose levels were elevated at diagnosis. CONCLUSION: The findings are complex, but the overall data suggest that AKR1B10 is suitable as a tumor marker in patients with elevated levels at the time of diagnosis.
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Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas , Neoplasias de la Mama , Humanos , Femenino , Estudios Prospectivos , Neoplasias de la Mama/tratamiento farmacológico , Transporte Biológico , Biomarcadores de TumorRESUMEN
We found several blood biomarkers through computational secretome analyses, including aldo-keto reductase family 1 member B10 (AKR1B10), which reflected the progression of nonalcoholic fatty liver disease (NAFLD). After confirming that hepatic AKR1B10 reflected the progression of NAFLD in a subgroup with NAFLD, we evaluated the diagnostic accuracy of plasma AKR1B10 and other biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) and fibrosis in replication cohort. We enrolled healthy control subjects and patients with biopsy-proven NAFLD (n = 102) and evaluated the performance of various diagnostic markers. Plasma AKR1B10 performed well in the diagnosis of NASH with an area under the receiver operating characteristic (AUROC) curve of 0.834 and a cutoff value of 1078.2 pg/mL, as well as advanced fibrosis (AUROC curve value of 0.914 and cutoff level 1078.2 pg/mL), with further improvement in combination with C3. When we monitored a subgroup of obese patients who underwent bariatric surgery (n = 35), plasma AKR1B10 decreased dramatically, and 40.0% of patients with NASH at baseline showed a decrease in plasma AKR1B10 levels to below the cutoff level after the surgery. In an independent validation study, we proved that plasma AKR1B10 was a specific biomarker of NAFLD progression across varying degrees of renal dysfunction. Despite perfect correlation between plasma and serum levels of AKR1B10 in paired sample analysis, its serum level was 1.4-fold higher than that in plasma. Plasma AKR1B10 alone and in combination with C3 could be a useful noninvasive biomarker for the diagnosis of NASH and hepatic fibrosis.
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Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/sangre , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Biomarcadores , Fibrosis , Humanos , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
Sorafenib is the standard systemic treatment for advanced hepatocellular carcinoma (HCC), and improving its therapeutic effects is crucial for addressing cancer aggression. We previously reported that epalrestat, an aldo-keto reductase 1B10 inhibitor, enhanced sorafenib's inhibitory effects on HCC xenograft in nude mice. This study aimed to elucidate the mechanism of epalrestat's anti-tumour enhancing effects on sorafenib. HepG2 cells were treated with sorafenib, epalrestat, and their combination. Cell proliferation was assessed with Cell Counting Kit-8 and colony formation assays. AKR1B10 supernate concentration and enzyme activity were detected by ELISA assay and the decrease of optical density of NADPH at 340 nm. Cell cycle and apoptosis analyses were performed with flow cytometry. Western blots clarified the molecular mechanism underlying effects on cell cycle, apoptosis, and autophagy. The anti-tumour mechanism was then validated in vivo through TUNEL and immunohistochemistry staining of HCC xenograft sections. Epalrestat combined with sorafenib inhibited HepG2 cellular proliferation in vitro, arrested the cell cycle at G0/G1, and promoted apoptosis and autophagy. Treatment with a specific mTOR activator MHY-1485 increased mTOR phosphorylation, while suppressing apoptosis and autophagy. Consistent with in vitro results, data from the HCC-xenograft nude mouse model also indicated that combined treatment inhibited the mTOR pathway and promoted apoptosis and autophagy. In conclusion, epalrestat heightens sorafenib's anti-cancer effects via blocking the mTOR pathway, thus inducing cell cycle arrest, apoptosis, and autophagy.
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Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Rodanina/análogos & derivados , Sorafenib/farmacología , Tiazolidinas/farmacología , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Western Blotting , Puntos de Control del Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Células Hep G2 , Xenoinjertos , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Rodanina/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Cancer is a well-known and well-studied disease. There are environmental as well as genetic factors that trigger cancer. All forms of cancer are associated with the deregulation of genes and proteins. Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase are homologous proteins that are overexpressed in different types of cancer. They are NADPHdependent oxidoreductases. The active site is conserved, thus there is very less substrate specificity among those proteins. In this study, novel molecules targeting the three proteins are designed. METHODS: LigBuilder V2 software is used to design novel molecules. Molecular docking is performed to study the binding affinity of each ligand towards the targets. Molecular Dynamics Simulation was done to check the stability of protein-ligand complexes in an aqueous environment. RESULTS: Six novel molecules have been designed. The six molecules studied are found to have better in silico affinity than tolrestat (known inhibitor). The designed molecules are predicted to be orally active. Finally, Molecular Dynamics Simulation showed that the protein-ligand complexes are stable in an aqueous environment. CONCLUSION: New molecules targeting Aldose reductase, Aldose Reductase like protein 1 and Aldehyde Reductase have been designed.
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Aldehído Reductasa/antagonistas & inhibidores , Aldehído Reductasa/química , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/antagonistas & inhibidores , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Sitios de Unión , Simulación por Computador , Cinética , Ligandos , Simulación del Acoplamiento Molecular , Especificidad por SustratoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide with rising rates in parallel to obesity, type 2 diabetes, and metabolic syndrome. NAFLD includes pathologies ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis and cirrhosis (NASH), which may eventually develop into hepatocellular carcinoma (HCC). Mechanically, lipids accumulation and insulin resistance act as the first hit, inflammation and fibrosis serve as the second hit. Currently, the diagnosis of NAFLD mainly depends on pathology examination and medical imaging, whereas proper gene signature classifiers are necessary for the evaluation of disease status. Here, we developed three signature classifiers to distinguish different NAFLD disease states (NAFL and NASH). Moreover, we found that B cells, DCs, and MAIT cells are key deregulated immune cells in NAFLD, which are associated with NAFLD and NAFLD-HCC progression. Meanwhile, AKR1B10 and SPP1 are closely related to the above three immune cell infiltrations and immunosuppressive cytokines expressions in NAFLD and NAFLD-HCC. Subsequently, we screened out AKR1B10 and SPP1 sensitive molecules TGX-221, which may provide a possible therapy for NAFLD and NAFLD-HCC.
Asunto(s)
Expresión Génica/inmunología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Adolescente , Adulto , Anciano , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Linfocitos B/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Citocinas/genética , Citocinas/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Hígado/inmunología , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto JovenRESUMEN
Objectives: AKR1B10, first cloned from liver cancer tissues, has recently been reported to be up-regulated significantly in hepatocellular carcinoma (HCC) tissues, but the relationship between serum level of AKR1B10 and the risk of HCC is not understood. Methods: 170 HCC patients and 120 health donors from October 2014 to March 2017 were recruited in the affiliated hospital of Guilin Medical University. Serum AKR1B10 in all cases were detected and in 30 HCC patients were analyzed preoperatively and postoperatively by Time-resolved fluoroimmunoassay. Results: The level of serum AKR1B10 was significantly higher in HCC patients (1800.24±2793.79) than in health donors (129.34±194.129), and downregulation of serum AKR1B10 in HCC patients was observed after hepatectomy. When samples were grouped according to the serum level of AKR1B10 (≥232.7pg/ml), serum AKR1B10 positively correlated to serum AFP (χ2=6.295, P=0.012), ALT (χ2=18.803, P=0.000), AST (χ2=33.421, P=0.000), tumor nodule number (χ2=6.777, P=0.009), cirrhosis (χ2=43.458, P=0.000), and tumor size (χ2=6.042, P=0.014) in the Chi-square test. Conclusions: Diagnosis of HCC could be improved using the both predictors of serum AKR1B10 and AFP. AKR1B10 was thus considered to be a new serological biomarker for HCC
Objetivos: Recientemente se ha notificado que el AKR1B10, clonado por primera vez a partir de tejidos hepáticos cancerosos, se encuentra aumentado de forma significativa en tejidos afectados por carcinoma hepatocelular (CHC), aunque no se comprende la relación entre la concentración sérica de AKR1B10 y el riesgo de CHC. Métodos: Se incluyeron 170 pacientes con CHC y 120 donantes sanos desde octubre de 2014 a marzo de 2017 en el hospital afiliado a la Guilin Medical University. Se analizó el AKR1B10 en todos los casos y en 30 pacientes con CHC antes y después de la cirugía, mediante fluoroinmunoensayo a tiempo resuelto. Resultados: La concentración sérica de AKR1B10 fue significativamente mayor en los pacientes con CHC (1.800,24±2.793,79) que en los donantes sanos (129,34±194,129), y se observó una reducción del AKR1B10 sérico en los pacientes con CHC tras la hepatectomía. Cuando se agruparon las muestras en función de la concentración sérica de AKR1B10 (≥ 232,7pg/ml), el AKR1B10 sérico se correlacionó positivamente con la AFP sérica (χ2=6,295; p=0,012), la ALT (χ2=18,803; p=0,000), la AST (χ2=33,421; p=0,000), la cifra de nódulos tumorales (χ2=6,777; p=0,009), la presencia de cirrosis (χ2=43,458; p=0,000) y el tamaño tumoral (χ2=6,042; p=0,014) en la prueba de χ2. Conclusiones: Podría mejorarse el diagnóstico del CHC usando los 2 factores pronósticos de AKR1B10 sérico y AFP. Por lo tanto, el AKR1B10 se consideró un nuevo biomarcador serológico del CHC
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/análisis , Carcinoma Hepatocelular/diagnóstico , Sensibilidad y Especificidad , Estudios Retrospectivos , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/sangre , Hepatectomía , Cirrosis Hepática/complicaciones , BiomarcadoresRESUMEN
Aldo-keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time-resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha-fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early-stage HCC and AFP-negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early-stage HCC, with better diagnostic performance than AFP.
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Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Adulto , Biomarcadores de Tumor , Biopsia con Aguja , Carcinoma Hepatocelular/diagnóstico , Estudios de Casos y Controles , China , Femenino , Hospitales Universitarios , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Curva ROC , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/ßII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway.
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Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Neoplasias de la Mama/metabolismo , Diglicéridos/metabolismo , Sistemas de Mensajero Secundario , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Lipogénesis , Sistema de Señalización de MAP Quinasas , Células MCF-7 , Ratones Desnudos , Proteína Quinasa C/metabolismo , Trasplante Heterólogo , Carga TumoralRESUMEN
2-Deoxyglucose (2DG) is a non-metabolizable glucose analog currently in clinical trials to determine its efficacy in enhancing the therapeutic effects of radiotherapy and chemotherapy of several types of cancers. It is thought to preferentially kill cancer cells by inhibiting glycolysis because cancer cells are more dependent on glycolysis for their energy needs than normal cells. However, we found that the toxicity of 2DG in cancer cells is mediated by the enzymatic activities of AKR1B1 and/or AKR1B10 (AKR1Bs), which are often overexpressed in cancer cells. Our results show that 2DG kills cancer cells because, in the process of being reduced by AKR1Bs, depletion of their cofactor NADPH leads to the depletion of glutathione (GSH) and cell death. Furthermore, we showed that compounds that are better substrates for AKR1Bs than 2DG are more effective than 2DG in killing cancer cells that overexpressed these 2 enzymes. As cancer cells can be induced to overexpress AKR1Bs, the anticancer mechanism we identified can be applied to treat a large variety of cancers. This should greatly facilitate the development of novel anticancer drugs.
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Aldehído Reductasa/metabolismo , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Desoxiglucosa/farmacología , Neoplasias/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Aldehído Reductasa/genética , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Células CACO-2 , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Desoxiglucosa/metabolismo , Glucólisis/efectos de los fármacos , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
BACKGROUND: The intrinsic heterogeneity of hepatocellular carcinoma (HCC) represents a great challenge for its molecular classification and for detecting predictive biomarkers. Aldo-keto reductase (Akr) family members have shown differential expression in human HCC, while AKR1B10 overexpression is considered a biomarker; AKR7A3 expression is frequently reduced in HCC. AIMS: To investigate the time-course expression of Akr members in the experimental hepatocarcinogenesis. METHODS: Using DNA-microarray data, we analyzed the time-course gene expression profile from nodules to tumors (4-17 months) of 17 Akr members induced by the resistant hepatocyte carcinogenesis model in the rat. RESULTS: The expression of six members (Akr1c19, Akr1b10, Akr7a3, Akr1b1, Akr1cl1, and Akr1b8) was increased, comparable to that of Ggt and Gstp1, two well-known liver cancer markers. In particular, Akr7a3 and Akr1b10 expression also showed a time-dependent increment at mRNA and protein levels in a second hepatocarcinogenesis model induced with diethylnitrosamine. We confirmed that aldo-keto reductases 7A3 and 1B10 were co-expressed in nine biopsies of human HCC, independently from the presence of glypican-3 and cytokeratin-19, two well-known HCC biomarkers. Because it has been suggested that expression of Akr members is regulated through NRF2 activity at the antioxidant response element (ARE) sequences, we searched and identified at least two ARE sites in Akr1b1, Akr1b10, and Akr7a3 from rat and human gene sequences. Moreover, we observed higher NRF2 nuclear translocation in tumors as compared with non-tumor tissues. CONCLUSIONS: Our results demonstrate that Akr7a3 mRNA and protein levels are consistently co-expressed along with Akr1b10, in both experimental liver carcinogenesis and some human HCC samples. These results highlight the presence of AKR7A3 and AKR1B10 from early stages of the experimental HCC and introduce them as a potential application for early diagnosis, staging, and prognosis in human cancer.
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Aldehído Reductasa/metabolismo , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Aldo-Ceto Reductasas/metabolismo , Carcinoma Hepatocelular/enzimología , Neoplasias Hepáticas/enzimología , Aldehído Reductasa/genética , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Aldo-Ceto Reductasas/genética , Animales , Biomarcadores/metabolismo , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Modelos Animales de Enfermedad , Humanos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , ARN Mensajero/metabolismo , Ratas Endogámicas F344RESUMEN
The AKR1B10 (aldo-keto reductase family 1 member B10) gene has important functions in carcinogen-induced neoplasia. AKR1B10 is also expressed in type 2 reaction leprosy patients (R2). We measured the expression of AKR1B10 in the skin lesions of patients with leprosy by immunohistochemistry from biopsies that encompassed the spectrum of types of leprosy, based on the Ridley and Jopling classification [10 samples each of tuberculoid (TT), borderline tuberculoid (BT), mid-borderline (BB), and borderline lepromatous (BL) lesions; four samples of lepromatous lesions (LL)], reactional leprosy [14 samples of type 1 Reaction (R1) and 10 samples of type 2 Reaction (R2)], and biopsies from 9 healthy control (HC) subjects. In addition, 46 lepromatous lesions (BL and LL), 45 lepromatous lesions in regression, and 115 R2 lesions were included. Eight of 10 R2 samples (80%), 3 of 46 active BL and LL samples (6%), 23 of 45 BL and LL samples in regression (51%), and 107 of 115 R2 samples (93%) were positive for AKR1B10, differing significantly between all groups (p < 0.05). AKR1B10 expression was highest in the cytoplasm of macrophages. Thus, AKR1B10 is overexpressed on the lepromatous side (BL and LL) in samples that are in regression, especially type 2 reaction-associated lesions, rendering it a potential marker of type 2 reactional episodes of leprosy and a target of drugs against reactional episodes.
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Biomarcadores , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas , Lepra/terapia , Lepra/complicacionesRESUMEN
BACKGROUND: Aldo-keto reductase family 1, member B10 (AKR1B10), is known to be significantly induced in the cells of various cancers such as breast cancer. However, the mechanisms of AKR1B10 promoting tumorigenesis in breast cancer remain unclear. In the present study, we demonstrated the potential role and mechanism of AKR1B10 in the invasion and migration of breast cancer cells. METHODS: The expression level of AKR1B10 in breast carcinoma, para-carcinoma and cancer tissues were detected by immunohistochemical evaluation and real-time polymerase chain reaction (RT-PCR), and the correlationships between AKR1B10 expression and clinicopathological features in breast cancer patients (n=131) were investigated. AKR1B10 was ectopically expressed in MCF-7 cells or silenced in BT-20 cells. The roles of AKR1B10 expression in the migration and invasion of MCF-7 cells and BT-20 cells were explored by wound healing assay, transwell migration assay and transwell matrigel invasion assay, and finally the activation level of extracellular signal-regulated kinase 1/2 (EKR1/2) activation and the expression level of matrix metalloproteinase-2 (MMP2) and vimentin in MCF-7 and BT-20 cells were measured by western blot. RESULTS: We found that AKR1B10 expression was increased in malignant tissues, which was correlated positively with tumor size, lymph node metastasis (p<0.05). MCF-7/AKR1B10 cells displayed a higher ability of migration (43.57±1.04%) compared with MCF-7/vector cells (29.12±1.34%) in wound healing assay, and the migrated cell number of MCF-7/AKR1B10 was more (418.43±9.62) than that of MCF-7/vector (222.43±17.75) in transwell migration assay without matrigel. We furtherly confirmed MCF-7/AKR1B10 cells invaded faster compared with MCF-7/vector cells by transwell matrigel invasion assay. Finally, we found AKR1B10 induced the migration and invasion of MCF-7 and BT-20 cells by activating EKR signaling, which promoted the expressions of MMP2 and vimentin. PD98059, a specific inhibitor of the activation of MEK, blocked the migration and invasion by inhibiting the expression of MMP2 and vimentin. CONCLUSIONS: AKR1B10 is overexpressed in breast cancer, and promotes the migration and invasion of MCF-7 and BT-20 cells by activating ERK signaling pathway.