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BACKGROUND: Tumor suppressive let-7 miRNAs are universally down-regulated in human hepatocellular carcinoma (HCC) versus normal tissues; however, the roles and related molecular mechanisms of let-7 in HCC stem cells are poorly understood. METHODS: We examined the inhibitory effect of let-7 miRNAs on the proliferation of MHCC97-H and HCCLM3 hepatic cancer cells by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, which was further confirmed by apoptosis and cell cycle studies. The sphere-forming assay was used to study the effects of let-7a on stem like cells. Through western blot, immunofluorescence and the luciferase-reporter assay, we explored the activity of epithelial-mesenchymal transition (EMT) signaling factors in HCC cells. qRT-PCR was applied to detect miRNA expression levels in clinical tissues. RESULTS: Let-7a effectively repressed cell proliferation and viability, and in stem-like cells, also let-7a decreased the efficiency of sphere formation.in stem-like cells. The suppression of EMT signaling factors in HCC cells contributed to let-7's induced tumor viability repression and Wnt activation repression. Besides, Wnt1 is critical and essential for let-7a functions, and the rescue with recombinant Wnt1 agent abolished the suppressive roles of let-7a on hepatospheres. In clinical HCC and normal tissues, let-7a expression was inversely correlated with Wnt1 expression. CONCLUSIONS: Let-7 miRNAs, especially let-7a, will be a promising therapeutic strategy in the treatment of HCC through eliminating HCC stem cells, which could be achieved by their inhibitory effect on the Wnt signaling pathway.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Transición Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Vía de Señalización Wnt , Apoptosis/genética , Carcinoma Hepatocelular/patología , Ciclo Celular/genética , Línea Celular Tumoral , Autorrenovación de las Células/genética , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/efectos de los fármacos , Platino (Metal)/farmacología , Interferencia de ARN , Proteína Wnt1/genéticaRESUMEN
BACKGROUND/AIMS: To evaluate the efficacy of different therapeutic methods for finding a promising treatment to this satanic disease and determined the prognostic factors affecting the survival time. METHODOLOGY: A retrospective study was carried out on 589 patients who underwent different treatment for Primary hepatocellular carcinoma with portal vein tumor thrombus from January, 2005 to June, 2013. Patients were divided into 4 groups according to the initial treatment: Group A (N = 48), conservative treatment; Group B (N = 86), chemotherapy; Group C (N = 122), surgical resection; and Group D (N = 333), surgical resection with postoperative chemotherapy. RESULTS: There was no significant differences in clinical information (i.e., the number of tumor, the size of tumor, and the state of portal vein tumor thrombus) among the 4 groups (P > 0.05). Both surgical resection and chemotherapy can improve the survival rate of the patients, and comprehensive treatments are of greater effect over surgical resection or chemotherapy alone. Univariate and multiple analyses revealed that the levers of AFP(p=.001), the size of tumor (p < .001), the number of tumor(p < .001), the state of portal vein tumor thrombus(p < .001), and the number of chemotherapy(p = .000) affected the conditions of prognosis: CONCLUSIONS: Positive operation treatment is the most effective therapeutic strategy for this advanced disease. Surgical resection followed by postoperative chemotherapy would increase the survival rate.
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Carcinoma Hepatocelular/cirugía , Quimioembolización Terapéutica , Embolectomía , Hepatectomía , Neoplasias Hepáticas/cirugía , Células Neoplásicas Circulantes/patología , Vena Porta/cirugía , Trombectomía , Trombosis de la Vena/cirugía , Adulto , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Quimioembolización Terapéutica/efectos adversos , Quimioembolización Terapéutica/mortalidad , Quimioterapia Adyuvante , Embolectomía/efectos adversos , Embolectomía/mortalidad , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Selección de Paciente , Vena Porta/patología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Trombectomía/efectos adversos , Trombectomía/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Trombosis de la Vena/etiología , Trombosis de la Vena/mortalidad , Trombosis de la Vena/patologíaRESUMEN
IMPORTANCE: Due to their small size and special chemical features, small open reading frame (smORF)-encoding peptides (SEPs) are often neglected. However, they may play critical roles in regulating gene expression, enzyme activity, and metabolite production. Studies on bacterial microproteins have mainly focused on pathogenic bacteria, which are importance to systematically investigate SEPs in streptomycetes and are rich sources of bioactive secondary metabolites. Our study is the first to perform a global identification of smORFs in streptomycetes. We established a peptidogenomic workflow for non-model microbial strains and identified multiple novel smORFs that are potentially linked to secondary metabolism in streptomycetes. Our multi-integrated approach in this study is meaningful to improve the quality and quantity of the detected smORFs. Ultimately, the workflow we established could be extended to other organisms and would benefit the genome mining of microproteins with critical functions for regulation and engineering useful microorganisms.
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Streptomyces , Streptomyces/genética , Sistemas de Lectura Abierta/genética , Metabolismo Secundario , Péptidos/genética , GenomaRESUMEN
Buffalo exhibits great efficiency in utilizing low-quality roughage, which can be due to the combined effect of host physiological feature and roughage diet fed. The present study was designed to compare the ruminal fiber degradation and the bacterial community attached to straws in buffalo and Holstein when fed with the same high-roughage diet using in situ ruminal incubation technique. Rice and wheat straws were selected as the incubation substrates and sampled at 0, 4, 12, 24, 48, 72, 120, and 216 h of incubation time to measure the kinetics of dry matter (DM) and neutral detergent fiber (NDF) disappearance. Additional two bags were incubated and sampled at 4 and 48 h of incubation time to evaluate the bacterial community attached to straws. The results showed that buffalo exhibited a greater (p ≤ 0.05) fraction of rapidly soluble and washout nutrients and effective ruminal disappearance for both DM and NDF of straw than Holstein, together with a greater (p ≤ 0.05) disappearance rate of potentially degradable nutrient fraction for NDF. Principal coordinate analysis indicated that both host and incubation time altered the bacterial communities attached to straws. Buffalo exhibited greater (p ≤ 0.05) 16S rRNA gene copies of bacteria and greater (p ≤ 0.05) relative abundance of Ruminococcus attached to straw than Holstein. Prolonging incubation time increased (p ≤ 0.05) the 16S rRNA gene copies of bacteria, and the relative abundance of phyla Proteobacteria and Fibrobacters by comparing 4 vs. 48 h of incubation time. In summary, buffalo exhibits greater ruminal fiber degradation than Holstein through increasing bacterial population and enriching Ruminococcus, while prolonging incubation time facilitates fiber degradation through enriching phyla Proteobacteria and Fibrobacteres.
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BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). METHODS: Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. RESULTS: High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. CONCLUSIONS: PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.
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BACKGROUND: The use of angiotensin II inhibitors is associated with a low risk of recurrence and metastasis in hepatocellular carcinoma (HCC) patients. Vascular cell adhesion molecule-1 (VCAM-1) is a key factor in tumor metastasis. METHODS: The effects of angiotensin II and irbesartan (an angiotensin II inhibitor) on HCC were explored with a xenograft model, microarray analysis and cell adhesion experiments. The relationship between the expression of VCAM-1 in HCC tissues and prognosis was analyzed with public and our institutional clinical databases. The effects of angiotensin II, irbesartan and VCAM-1 on adhesion and metastasis in HCC were explored with a xenograft model and cell adhesion experiments. The regulatory mechanisms were analyzed by Western blot analysis. RESULTS: Angiotensin II type 1 receptor and VCAM-1 were expressed in HCC tissues. Irbesartan inhibited HCC growth and metastasis in vivo and weakened the adhesion of HCC cells to endothelial cells, an effect that was enhanced by angiotensin II. VCAM-1 was found to be an independent risk factor for recurrence and survival in HCC patients with microvascular invasion. Angiotensin II upregulated VCAM-1 expression, and this upregulation was inhibited by irbesartan. Angiotensin II enhanced adhesion mainly by promoting the expression of VCAM-1 in HCC cells. Irbesartan inhibited the expression of VCAM-1 by reducing p38/MAPK phosphorylation activated by angiotensin II in HCC cells. CONCLUSIONS: Irbesartan attenuates metastasis by inhibiting angiotensin II-activated VCAM-1 via the p38/MAPK pathway in HCC.
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BACKGROUND: Numerous clinical models have been proposed to evaluate and predict recurrence and survival of hepatocellular carcinoma (HCC) patients in different stages after resection, but no model for very early-stage HCC. METHODS: The data of 661 very early-stage HCC patients after curative resection in our hospital were retrospectively reviewed. Kaplan-Meier curves and Cox proportional hazards regression models were used to analyze recurrence and survival. The risk classifications for recurrence and survival were established by using classification and regression tree analysis. The nomograms were constructed and validated using bootstrap resampling and an independent 186-patient validation cohort from the same institution. RESULTS: According to the results of multivariate analysis for prognosis after resection, decision trees and 3-stratification classifications that satisfactorily determined the risk of recurrence and survival were established. Based on these two risk classifications, a six-factor nomogram for predicting recurrence and a six-factor nomogram for predicting survival were created. The concordance indexes were 0.64 for recurrence nomogram, with a 95% confidence interval of 0.60-0.67, and 0.76 for survival nomogram, with a 95% confidence interval of 0.70-0.82. The calibration curves showed good agreement between the predictions made by the nomograms and the actual survival outcomes. These predicting results for recurrence and survival were better than three common classical HCC stages and were confirmed in the independent validation cohort. CONCLUSIONS: The 3-stratification classifications enabled satisfactory risk evaluations of recurrence and survival, and the nomograms showed considerably accurate predictions of the risk of recurrence and survival in very early-stage HCC patients after curative resection.
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Carcinoma Hepatocelular/cirugía , Hepatectomía , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia , Factores de Edad , Anciano , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/patología , ADN Viral , Supervivencia sin Enfermedad , Femenino , Anticuerpos contra la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatitis B Crónica/sangre , Hepatitis B Crónica/complicaciones , Humanos , Relación Normalizada Internacional , Estimación de Kaplan-Meier , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Nomogramas , Recuento de Plaquetas , Pronóstico , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.
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5'-Nucleotidasa/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Progresión de la Enfermedad , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Unión Proteica/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Análisis de Supervivencia , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The activation of the renin-angiotensin system (RAS) promotes tumor progression. In this study, we aimed to assess whether RAS inhibitors (RASIs) could improve the outcome of hepatocellular carcinoma (HCC) patients with primary hypertension after curative liver resection. METHODS: Data on 387 consecutive patients with primary hypertension who underwent curative liver resection for HCC were reviewed. The study population was divided into two groups based on the type of anti-hypertensive medications: the RASI group (patients using RASIs) and the non-RASI group (patients using other anti-hypertensive drugs but not RASIs). Kaplan-Meier curves, log-rank tests and cox proportional hazards regression models were used to analyze time to recurrence (TTR) and overall survival (OS). RESULTS: There were 144 (37.2%) patients in RASI group and 243 (62.8%) in non-RASI group. The preoperative clinicopathological features were comparable between the two groups. Kaplan-Meier curves demonstrated HCC patients with RASIs had a longer TTR and OS than the patients with non-RASIs (both P<0.001). On multivariate analysis, RASIs administration was identified as an independent prognostic factor for TTR [hazard ratio (HR) =0.52, 95% confidence interval (CI), 0.38-0.70, P<0.001] and OS (HR =0.50, 95% CI, 0.34-0.74, P<0.001). Patients in the RASI group had lower rates of extrahepatic metastases than patients in the non-RASI group (2.8% vs. 7.8%, P<0.042). CONCLUSIONS: Targeting the RAS was associated with a reduced risk of recurrence, decreased rate of extrahepatic metastases and prolonged survival of HCC patients with primary hypertension after curative liver resection.
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Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key molecule of glucose metabolism in cytoplasm, has been found in various tumors. Emerging evidence has suggested that PFKFB3 is also located in the nucleus and apparent in regulatory functions other than glycolysis. In this study, we found that PFKFB3 expression is associated with hepatocellular carcinoma (HCC) growth and located mainly in the nucleus of tumor cells. PFKFB3 overexpression was associated with large tumor size (p = 0.04) and poor survival of patients with HCC (p = 0.027). Knockdown of PFKFB3 inhibited HCC growth, not only by reducing glucose consumption but also by damaging the DNA repair function, leading to G2/M phase arrest and apoptosis. In animal studies, overexpression of PFKFB3 is associated with increased tumor growth. Mechanistically, PFKFB3 silencing decreased AKT phosphorylation and reduced the expression of ERCC1, which is an important DNA repair protein. Moreover, PFK15, a selective PFKFB3 inhibitor, significantly inhibited tumor growth in a xenograft model of human HCC. PFKFB3 is a potential novel target in the treatment of HCC.
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Carcinoma Hepatocelular/patología , Proliferación Celular , Reparación del ADN , Neoplasias Hepáticas/patología , Fosfofructoquinasa-2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Fosfofructoquinasa-2/antagonistas & inhibidores , Fosfofructoquinasa-2/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de SeñalRESUMEN
Rnd1, a member of Rho GTPases, was found to be downregulated in human malignancies and downregulation of Rnd1 promotes tumor invasion via various mechanisms. However, the role of Rnd1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, our results demonstrated that Rnd1 was downregulated in HCC cells and in human HCC tissues. Low expression of Rnd1 was associated with aggressive clinic-pathologic characteristics, such as vascular invasion, and poor prognosis in patients who underwent curative surgery for HCC. Overexpression of Rnd1-suppressed cell growth, migration, invasion, and EMT processes in vitro and in vivo. Furthermore, Rnd1 blocked HCC progression by restricting EMT process through inhibition of the Raf/MEK/ERK cascade, and this was correlated with a reduction in RhoA activity. Combination of Rnd1 overexpression with sorafenib, a Raf signaling pathway inhibitor, showed a more potent inhibition on HCC metastasis. Moreover, epigenetic inhibitors (5-Aza and SAHA) increased the expression of Rnd1, and potentiated sorafenib-induced toxicity in HCC cells. In a conclusion, Rnd1-suppressed EMT-mediated metastasis of HCC by reducing the activity of the RhoA/Raf/MEK/ERK signaling pathway, functioning as a favorable anti-metastasis target for HCC patients. Rnd1 overexpression in combination with sorafenib may result in enhanced anti-metastasis efficacy in HCC.
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Carcinoma Hepatocelular/enzimología , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas/enzimología , Proteínas de Unión al GTP rho/metabolismo , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Movimiento Celular , Proliferación Celular , Decitabina/farmacología , Epigénesis Genética , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Terapia Molecular Dirigida , Invasividad Neoplásica , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Sorafenib/farmacología , Vorinostat/farmacología , Quinasas raf/antagonistas & inhibidores , Quinasas raf/metabolismo , Proteínas de Unión al GTP rho/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) is a well-known marker of endothelial cells and a key factor for adhesion and accumulation of platelets. CD31 plays roles in cell proliferation, apoptosis, migration, and cellular immunity. CD31 is also expressed on tumor cells, such as breast cancer cells and non-Hodgkin's lymphomas, and contributes to tumor cell invasion. Here, our experiments show that CD31 promotes metastasis by inducing the epithelial-mesenchymal transition in hepatocellular carcinoma by up-regulating integrin ß1 via the FAK/Akt signaling pathway.
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Carcinoma Hepatocelular/tratamiento farmacológico , Cicloheximida/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Proteínas Adaptadoras Transductoras de Señales , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Inhibidores de la Síntesis de la Proteína/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
The original article [1] contains an error in Fig. 5a whereby the Western blot bands representing CyclinD1 have mistakenly been duplicated over the Western blot bands intended to represent SGK.
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BACKGROUND: High frequency of recurrence is the major cause of the poor outcomes for patients with hepatocellular carcinoma (HCC). microRNA (miR)-182-5p emerged as a high-priority miRNA in HCC and was found to be related to HCC metastasis. Whether the expression of miR-182-5p in tumor tissue correlated with early recurrence in HCC patients underwent curative surgery was unknown. METHODS: Real-time PCR (RT-PCR) and in situ hybridization (ISH) were conducted to assess the expression of miR-182-5p in HCC cells and tissues. Cell Counting Kit-8 (CCK-8), transwell assays were performed to detected cells proliferation and migration ability. Flow cytometry assays were used to detect cell apoptosis rate, and xenograft model was employed to study miR-182-5p in HCC growth and lung metastasis. The target of miR-182-5p was validated with a dual-luciferase reporter assay and western blotting. Immunohistochemistry, immumoblotting, and immunoprecipitation were performed to test relative protein expression. RESULTS: We showed that high expression of miR-182-5p in tumor tissues correlated with poor prognosis as well as early recurrence in HCC patients underwent curative surgery. miR-182-5p enhanced motility and invasive ability of HCC cells both in vitro and in vivo. miR-182-5p directly targets 3'-UTR of FOXO3a and repressed FOXO3a expression, activating AKT/FOXO3a pathway to promote HCC proliferation. Notably, miR-182-5p activated Wnt/ß-catenin signaling by inhibiting the degradation of ß-catenin and enhancing the interaction between ß-catenin and TCF4 which was mediated by repressed FOXO3a. CONCLUSIONS: Consistently, miR-182-5p can be a potential predictor of early recurrence for HCC patients underwent curative surgery, and FOXO3a plays a key mediator in miR-182-5p induced HCC progression.