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1.
Zhonghua Bing Li Xue Za Zhi ; 48(9): 682-687, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31495087

RESUMO

Objective: To investigate the clinicopathological significance of BRAF V600E and CTNNB1 gene mutations in adamantinomatous craniopharyngiomas (ACP) and papillary craniopharyngiomas (PCP). Methods: The retrospective study included a total of 67 craniopharyngiomas diagnosed from October 2009 to August 2018 at Xuanwu Hospital, Capital Medical University. The immunohistochemical staining for ß-catenin and BRAF V600E expression, Sanger sequencing of exon 3 of CTNNB1, BRAF mutation analysis by scorpions amplification refractory mutation system (ARMS) fluorescence quantitative PCR were performed. Univariate survival analysis was used to correlate with tumor recurrence. Results: Of the 67 patients, 53 were ACPs and 14 were PCPs. Four patients underwent multiple operations and one of them presented with malignant transformation into squamous cell carcinoma. Histologically, ACPs were characterized by whorl-like cell clusters, peripheral palisaded layer, stellate reticulum, finger-shaped protrusions, ghost cells and wet keratinous substances. While PCPs usually consisted of mature squamous epithelium associated with fibrovascular stroma resulting in papillary appearance. The nuclear immunopositivity for ß-catenin was observed in 73.6% (39/53) of ACPs, and it was absent in PCPs (0/14). The nuclear translocation of ß-catenin usually presented at whorl-like structures or around ghost cells. Of all the cases, mutations analysis in exon 3 of ß-catenin gene CTNNB1 were successful in 46 cases and 42.1% (16/38) of ACP showed CTNNB1 gene mutation, while none of the PCPs harbored CTNNB1 gene mutation (0/8). The cytoplasmic immunopositivity for BRAF V600E mutant protein was found in all PCPs (14/14) and negative in all ACPs (0/53). ARMS-PCR results showed that BRAF V600E mutations were observed in 13/14 of PCPs but not seen in ACPs (0/53). Follow-up data were available in 35 patients with duration of 2 to 120 months. Ten patients experienced recurrences after the first surgery. Upon univariate survival analysis, only subtotal excision was found to be associated with increased recurrence (P=0.032), while pathological type, postoperative radiotherapy and CTNNB1 gene mutation were not (P>0.05). Conclusions: There is significant difference in the expression of BRAF V600E and CTNNB1 genes between ACP and PCP, and their immunohistochemical and molecular detection therefore can be used in the diagnosis and differential diagnoses of craniopharyngiomas.


Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Proteínas Proto-Oncogênicas B-raf/genética , beta Catenina/genética , Craniofaringioma/genética , Humanos , Mutação , Recidiva Local de Neoplasia , Neoplasias Hipofisárias/genética , Estudos Retrospectivos
2.
J Agric Food Chem ; 67(37): 10285-10295, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31443611

RESUMO

Fluoride (F) is capable of promoting abnormal proliferation and differentiation in primary cultured mouse osteoblasts (OB cells), although the underlying mechanism responsible remains rare. This study aimed to explore the roles of wingless and INT-1 (Wnt) signaling pathways and screen appropriate doses of calcium (Ca2+) to alleviate the sodium fluoride (NaF)-induced OB cell toxicity. For this, we evaluated the effect of dickkopf-related protein 1 (DKK1) and Ca2+ on mRNA levels of wingless/integrated 3a (Wnt3a), low-density lipoprotein receptor-related protein 5 (LRP5), dishevelled 1 (Dv1), glycogen synthase kinase 3ß (GSK3ß), ß-catenin, lymphoid enhancer binding factor 1 (LEF1), and cellular myelocytomatosis oncogene (cMYC), as well as Ccnd1 (Cyclin D1) in OB cells challenged with 10-6 mol/L NaF for 24 h. The demonstrated data showed that F significantly increased the OB cell proliferation rate. Ectogenic 0.5 mg/L DKK1 significantly inhibited the proliferation of OB cells induced by F. The mRNA expression levels of Wnt3a, LRP5, Dv1, LEF1, ß-catenin, cMYC, and Ccnd1 were significantly increased in the F group, while significantly decreased in the 10-6 mol/L NaF + 0.5 mg/L DKK1 (FY) group. The mRNA expression levels of Wnt3a, LRP5, ß-catenin, and cMYC were significantly decreased in the 10-6 mol/L NaF + 2 mmol/L CaCl2 (F+CaII) group. The protein expression levels of Wnt3a, Cyclin D1, cMYC, and ß-catenin were significantly increased in the F group, whereas they were decreased in the F+CaII group. However, the mRNA and protein expression levels of GSK3ß were significantly decreased in the F group while significantly increased in the F+CaII group. In summary, F activated the canonical Wnt/ß-catenin pathway and changed the related gene expression and ß-catenin protein location in OB cells, promoting cell proliferation. Ca2+ supplementation (2 mmol/L) reversed the expression levels of genes and proteins related to the canonical Wnt/ß-catenin pathway.


Assuntos
Cálcio/metabolismo , Fluoretos/efeitos adversos , Osteoblastos/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Suplementos Nutricionais/análise , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Osteoblastos/classificação , Osteoblastos/metabolismo , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
3.
APMIS ; 127(11): 699-709, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31403731

RESUMO

We aimed to assess (1)-whether nuclear ß-catenin is a marker of endometrial precancer, and (2)-the diagnostic accuracy of ß-catenin immunohistochemistry in the differential diagnosis between benign and premalignant endometrial hyperplasia (EH), defining criteria for its use. Electronic databases were searched for studies evaluating ß-catenin immunohistochemistry in normal endometrium (NE), benign and/or premalignant EH, and endometrioid carcinoma (EC). Odds ratio (OR; p < 0.05), sensitivity, specificity, diagnostic OR (DOR), positive and negative likelihood ratios (LR+, LR-) were calculated. Subgroup analyses were based on the classification system used (WHO or EIN) and criteria to define aberrant ß-catenin expression (only nuclear or cytoplasmic/nuclear). Twelve studies with 1510 specimens were included. Nuclear ß-catenin rate significantly increased from NE to benign EH (OR = 26.01; p = 0.0002, only in WHO subgroup), and from benign EH to premalignant EH (OR = 3.89; p = 0.0002; more markedly in EIN subgroup), but not from premalignant EH to EC (OR = 0.78; p = 0.29). Nuclear ß-catenin accuracy was very low in WHO subgroup (sensitivity = 0.40, specificity = 0.76, LR+ = 1.85, LR- = 0.72; DOR = 2.89) and moderate in EIN subgroup (sensitivity = 0.19, specificity = 1.00, LR+ = 14.80, LR- = 0.83; DOR = 18.14). Cytoplasmic/nuclear ß-catenin accuracy was absent in WHO subgroup (sensitivity = 0.45, specificity = 0.54, LR+ = 1.01, LR- = 1.01; DOR = 0.99) and low in EIN subgroup (sensitivity = 0.57, specificity = 0.86, LR+ = 3.63, LR- = 0.51; DOR = 8.30). Considering nuclear expression and using EIN system, ß-catenin immunohistochemistry might be reliable as rule-in test for diagnosis of endometrial precancer, with perfect specificity and moderate overall accuracy.


Assuntos
Biomarcadores/metabolismo , Núcleo Celular/metabolismo , Hiperplasia Endometrial/metabolismo , Lesões Pré-Cancerosas/metabolismo , beta Catenina/metabolismo , Núcleo Celular/genética , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , beta Catenina/genética
4.
Medicine (Baltimore) ; 98(31): e16715, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374065

RESUMO

Chromosome 8 open reading frame 4 (C8orf4) is an activator of Wnt signaling pathway, and participates in the tumorigenesis and progression of many tumors. The expression levels of C8orf4 and ß-catenin were assessed via immunohistochemical staining in 100 cervical squamous cell carcinoma (CSCC) tissues, 50 high-grade squamous intraepithelial lesions (HSILs), 50 low-grade squamous intraepithelial lesions (LSILs), and 50 normal cervical tissues. Bisulfite sequencing polymerase chain reaction analysis was used to examine the methylation status of the C8orf4 locus in CSCC and normal cervical tissues. The expression rates of C8orf4 and ß-catenin were significantly higher in CSCCs or HSILs than in LSILs or normal cervical tissues (P < .05). C8orf4 expression was positively correlated with the poor differentiation of CSCCs (P = .009), and with aberrant expression of ß-catenin in CSCCs (P = .002) and squamous intraepithelial lesions (P < .001). The methylation rate of C8orf4 in CSCCs was significantly lower than that in normal cervical tissues (P = .001). The Cancer Genome Atlas genomics data also confirmed that the mRNA expression of C8orf4 was positively associated with the copy number alteration of C8orf4 (correlation coefficient = 0.213, P < .001), and negatively correlated with the methylation level of C8orf4 (correlation coefficient = -0.408, P < .001). In conclusion, the expressions of C8orf4 and ß-catenin were synergistically increased in CSCCs and HSILs and higher than those in LSILs and normal cervical tissues. The methylation level of C8orf4 is decreased in CSCCs and is responsible for the increased expression of C8orf4.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasia Intraepitelial Cervical/genética , Proteínas de Neoplasias/biossíntese , Neoplasias do Colo do Útero/genética , beta Catenina/biossíntese , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt , Adulto Jovem , beta Catenina/genética
5.
Biol Res ; 52(1): 33, 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31255182

RESUMO

BACKGROUND: Studies have shown that cancer susceptibility candidate 11 (CASC11), a newly discovered long non-coding RNA (lncRNA), was aberrantly overexpressed in hepatic carcinoma, gastric cancer and colorectal cancer. However, its effects on cervical cancer has been kept unknown up to now. The present study was aimed to investigate the relationship between lncRNA CASC11 and cervical cancer and further explore the mechanism of CASC11 effect on cervical cancer progression. MATERIALS: Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expressions of CASC11 in cancerous and adjacent normal tissues of patients with cervical cancer as well as in cell lines. The proliferation, migration, invasion and apoptosis were assayed after transfecting the cell with si-CASC11 or pcDNA3.1-CASC11. TOP/FOP-Flash luciferase reporter assay and western blot were used to analysis the activation of Wnt/ß-catenin signaling pathway. Si-CASC11-transfected HeLa cells were subcutaneously inoculated into male athymic (nude) mice to investigate the effect of CASC11 on the tumor formation. RESULTS: We discovered that CASC11, the expression of which was positively associated with the tumor size and the FIGO staging and negatively related to the patients' survival rate, was up-regulated in the cervical cancer tissues and cell lines. Silencing CASC11 inhibited the proliferation, migration as well as invasion and promoted the cell apoptosis. Conversely, overexpression of CASC11 facilitated the cancer cell's proliferation, migration and invasion ability and suppressed the apoptosis. Further study showed that CASC11 promoted the migration and invasion of cervical cancer cells by activating Wnt/ß-catenin signaling pathway and silencing CASC11 inhibited the tumor growth in vivo. CONCLUSION: Our study demonstrated that CASC11 promoted the cervical cancer progression by activating Wnt/ß-catenin signaling pathway for the first time, which provides a new target or a potential diagnostic biomarker of the treatment for cervical cancer.


Assuntos
Predisposição Genética para Doença , MicroRNAs/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Citometria de Fluxo , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/virologia
6.
Cancer Sci ; 110(9): 2794-2805, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31336010

RESUMO

SALL4 is overexpressed in many cancers and is found to be involved in tumorigenesis and tumor progression. However, the function of SALL4 in cervical cancer remains unknown. Here, we showed that the expression of SALL4 was gradually increased from normal cervical tissue to high-grade squamous intraepithelial lesions and then to squamous cervical carcinoma. SALL4 was upregulated or downregulated in cervical cancer cells by stably transfecting a SALL4-expressing plasmid or a shRNA plasmid targeting SALL4, respectively. In vitro, cell growth curves and MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assays showed that SALL4 promoted the cell proliferation of cervical cancer cells. In vivo, xenograft experiments verified that SALL4 enhanced the tumor formation of cervical cancer cells in female BALB/c Nude mice. Cell cycle analysis by fluorescence-activated cell sorting found that SALL4 accelerates cell cycle transition from the G0 /G1 phase to the S phase. TOP/FOP-Flash reporter assay revealed that SALL4 significantly upregulates the activity of Wnt/ß-catenin pathway. Western blotting showed that the expression levels of ß-catenin and important downstream genes, including c-Myc and cyclin D1, were increased by SALL4 in cervical cancer cells. Furthermore, dual-luciferase reporter and chromatin immunoprecipitation assays confirmed that SALL4 transcriptionally activated CTNNB1 by physically interacting with its promoters. Taken together, The results of this study demonstrated that SALL4 may promote cell proliferation and tumor formation of cervical cancer cells by upregulating the activity of the Wnt/ß-catenin signaling pathway by directly binding to the CTNNB1 promoter and trans-activating CTNNB1.


Assuntos
Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica/genética , Lesões Intraepiteliais Escamosas Cervicais/patologia , Fatores de Transcrição/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Colo do Útero/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/metabolismo , Lesões Intraepiteliais Escamosas Cervicais/genética , Fatores de Transcrição/genética , Regulação para Cima , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
7.
Gastroenterology ; 157(3): 807-822, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31194980

RESUMO

BACKGROUND & AIMS: In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate ß-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically. METHODS: We studied mice with activation of ß-catenin in liver (Apcko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose, followed by 18F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet. RESULTS: Livers and tumors from Apcko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated ß-catenin were positive in 18F-fluorocholine PET, but not 18F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apcko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apcko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors. CONCLUSIONS: In mice and humans, HCCs with mutations that activate ß-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress ß-catenin.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Mutação , Tomografia por Emissão de Pósitrons , beta Catenina/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Proliferação de Células , Colina/administração & dosagem , Colina/análogos & derivados , Deficiência de Colina/complicações , Metilação de DNA , Dietilnitrosamina , Modelos Animais de Doenças , Genes APC , Predisposição Genética para Doença , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosfolipídeos/metabolismo , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/administração & dosagem , beta Catenina/metabolismo
8.
Food Chem Toxicol ; 131: 110550, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163223

RESUMO

Aberrant activation of ß-catenin-response transcription (CRT) is a well-recognized characteristic of colorectal and liver cancers and thus a potential therapeutic target for these malignancies. Broussonetia papyrifera (paper mulberry) has been used as a herbal medicine to treat various diseases. Using a sensitive cell-based screening system, we identified broussochalcone A (BCA), a prenylated chalcone isolated from Broussonetia papyrifera, as an antagonist of CRT. BCA accelerated the turnover of intracellular ß-catenin that was accompanied by its N-terminal phosphorylation at Ser33/37/Thr41 residues, marking it for ubiquitin-dependent proteasomal degradation. Pharmacological inhibition of glycogen synthase kinase-3ß could not abrogate BCA-mediated degradation of ß-catenin. BCA decreased the intracellular ß-catenin levels in colon and liver cancer cells with mutations in ß-catenin, adenomatous polyposis coli, and Axin. BCA repressed the expressions of cyclin D1, c-Myc, and Axin2, which are ß-catenin/T-cell factor-dependent genes, and thus decreased the viability of colon and liver cancer cell. Moreover, apoptosis was elicited by BCA, as indicated by the increase in the population of Annexin V-FITC positive cells and caspase-3/7 activities in colon and liver cancer cells. These findings indicate that BCA exerts its cytotoxic effects by promoting phosphorylation/ubiquitin-dependent degradation of ß-catenin and may potentially serve as a chemopreventive agent for colonrectal and liver cancers.


Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Resorcinóis/farmacologia , beta Catenina/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Serina/química , Treonina/química , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/química , beta Catenina/genética
9.
Anticancer Res ; 39(5): 2447-2451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092438

RESUMO

BACKGROUND/AIM: The insulin-like growth factor 1 (IGF1) signaling pathway as an aging mechanism related to p53 in human melanogenesis remains unclear. The aim of this study was to investigate the relationship between p53 and IGF1 signaling pathway in young, senescent and H2O2-treated cells. MATERIALS AND METHODS: The protein and gene expression in young, senescent and H2O2-treated cells were analyzed using western blot and reverse transcription polymerase chain reaction (RT-PCR) assays, respectively. RESULTS: The expression levels of (phosphoinositide 3-kinases) PI3K, v-akt murine thymoma viral oncogene homolog 1 (AKT1), mammalian target of rapamycin, ß-catenin (CTNNB1), acetylated p53 (ac-p53), p53 and p-p21 proteins, related to IGF1 and p53 signaling pathways, were higher in senescent and H2O2-treated cells than those of young cells. Furthermore, AKT reduced melanogenesis through microphthalmia-associated transcription factor (MITF) inactivation by the inhibition of CTNNB1. The gene expression levels of PI3K, TP53 and catalase (CAT) in senescent and H2O2-treated cells were increased compared to young cells. CONCLUSION: p53 protein plays a key role in the aging of melanocytes via IGF1 signaling pathways.


Assuntos
Envelhecimento/genética , Proliferação de Células/genética , Fator de Crescimento Insulin-Like I/genética , Proteína Supressora de Tumor p53/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Catalase/genética , Proliferação de Células/efeitos dos fármacos , Senescência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , beta Catenina/genética
10.
Life Sci ; 228: 242-250, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075235

RESUMO

AIMS: Osteoarthritis (OA) is a leading cause of deformity in aging people. Emerging evidence suggests that microRNAs and Wnt signaling pathway are associated with its pathogenesis. We aimed to determine whether microRNA-320c inhibits the development of osteoarthritis by suppressing Wnt signaling pathway. MATERIALS AND METHODS: MiR-320c and ß-catenin expression was assessed in human adipose derived stem cells (hADSCs) model of chondrogenesis and in normal and OA primary human chondrocytes. OA chondrocytes were transfected with miR-320c or its antisense inhibitor and ß-catenin siRNA respectively. Direct interaction between miR-320c and ß-catenin mRNA as well as activity of ß-catenin/TCF complex were confirmed by luciferase reporter assay. Mmu-miR-320-3p agomir was intra-articularly injected in collagenase-induced OA mouse model. OA progression was evaluated histologically and immunohistochemically. KEY FINDINGS: MiR-320c was decreased and ß-catenin was increased in OA chondrocytes and late stage of hADSCs chondrogenesis. Overexpression of miR-320c and knockdown of ß-catenin had similar effects that the cartilage-specific genes were elevated and hypertrophy-related genes were down-regulated in OA chondrocytes. Luciferase reporter assay confirm that miR-320c regulated the expression of ß-catenin by directly targeting 3'UTR of ß-catenin mRNA and decreased the relative transcriptional activity of the ß-catenin/TCF complex. Injection of mmu-miR-320-3p attenuated OA progression in the OA mouse model. SIGNIFICANCE: Our results supports that miR-320c can inhibits the degeneration of osteoarthritis chondrocytes via suppressing the canonical Wnt signaling pathway and indicates the potential of miR-320c as a novel therapeutic agent for osteoarthritis treatment.


Assuntos
Regulação para Baixo , MicroRNAs/genética , Osteoartrite/genética , Via de Sinalização Wnt , beta Catenina/genética , Adolescente , Adulto , Idoso , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Condrogênese , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Adulto Jovem , beta Catenina/metabolismo
11.
Nat Cell Biol ; 21(6): 721-730, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110287

RESUMO

Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit ß-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine.


Assuntos
Células-Tronco Hematopoéticas/citologia , Receptores de Neurotransmissores/genética , Proteínas Wnt/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Receptores ErbB/genética , Humanos , Fosforilação , Via de Sinalização Wnt , Peixe-Zebra/crescimento & desenvolvimento , beta Catenina/genética
12.
Mol Med Rep ; 19(6): 5440-5452, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059099

RESUMO

The aim of the present study was to investigate the effects of advanced glycation end products (AGEs) and berberine hydrochloride (BBR) on the osteogenic differentiation ability of human periodontal ligament stem cells (hPDLSCs) in vitro, and their underlying mechanisms. hPDLSCs were subjected to osteogenic induction and were treated with AGEs or AGEs + BBR. Following varying numbers of days in culture, alkaline phosphatase (ALP) activity assays, ALP staining, alizarin red staining, ELISAs, and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blot analyses were performed to determine the osteogenic differentiation ability of hPDLSCs; RT­qPCR, western blot analysis, and immunofluorescence staining were conducted to investigate the underlying mechanisms. The canonical Wnt/ß­catenin pathway inhibitor XAV­939 and agonist CHIR­99021 were used to determine the contribution of the canonical Wnt/ß­catenin pathway to differentiation. Treatment with AGEs resulted in reduced ALP activity and Collagen I protein levels, decreased ALP staining, fewer mineralized nodules, and downregulated expression of osteogenic­specific genes [Runt­related transcription factor 2 (Runx2), Osterix, ALP, osteopontin (OPN), Collagen I and osteocalcin (OCN)] and proteins (Runx2, OPN, BSP and OCN); however, BBR partially rescued the AGE­induced decrease in the osteogenic potential of hPDLSCs. Furthermore, AGEs activated the canonical Wnt/ß­catenin signaling pathway and promoted the nuclear translocation of ß­catenin; BBR partially attenuated this effect. In addition, XAV­939 partially rescued the AGE­induced reduction in the osteogenic potential of hPDLSCs, whereas CHIR­99021 suppressed the BBR­induced increase in the osteogenic potential of hPDLSCs. The present study indicated that AGEs attenuated the osteogenic differentiation ability of hPDLSCs, in part by activating the canonical Wnt/ß­catenin pathway; however, BBR attenuated these effects by inhibiting the canonical Wnt/ß­catenin pathway. These findings suggest a role for BBR in periodontal regeneration induced by hPDLSCs in patients with diabetes mellitus.


Assuntos
Berberina/farmacologia , Osteogênese/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação para Baixo/efeitos dos fármacos , Produtos Finais de Glicação Avançada/farmacologia , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Queratina-19/metabolismo , Ligamento Periodontal/citologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição Sp7/genética , Fator de Transcrição Sp7/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
13.
J Exp Clin Cancer Res ; 38(1): 186, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068208

RESUMO

BACKGROUND: Breast cancer is the most prevalent cancer among women. In triple-negative breast cancer (TNBC) cells, a novel quinone derivative, coenzyme Q0 (CoQ0), promotes apoptosis and cell-cycle arrest. This study explored the anti-epithelial-mesenchymal transition (EMT) and antimetastatic attributes of CoQ0 in TNBC (MDA-MB-231). METHODS: Invasion, as well as MTT assays were conducted. Lipofectamine RNAiMAX was used to transfect cells with ß-catenin siRNA. Through Western blotting and RT-PCR, the major signaling pathways' protein expressions were examined, and the biopsied tumor tissues underwent immunohistochemical and hematoxylin and eosin staining as well as Western blotting. RESULTS: CoQ0 (0.5-2 µM) hindered tumor migration, invasion, and progression. Additionally, it caused MMP-2/- 9, uPA, uPAR, and VEGF downregulation. Furthermore, in highly metastatic MDA-MB-231 cells, TIMP-1/2 expression was subsequently upregulated and MMP-9 expression was downregulated. In addition, CoQ0 inhibited metastasis and EMT in TGF-ß/TNF-α-stimulated non-tumorigenic MCF-10A cells. Bioluminescence imaging of MDA-MB-231 luciferase-injected live mice demonstrated that CoQ0 significantly inhibited metastasis of the breast cancer to the lungs and inhibited the development of tumors in MDA-MB-231 xenografted nude mice. Silencing of ß-catenin with siRNA stimulated CoQ0-inhibited EMT. Western blotting as well as histological analysis established that CoQ0 reduced xenografted tumor development because apoptosis induction, cell-cycle inhibition, E-cadherin upregulation, ß-catenin downregulation, and metastasis and EMT regulatory protein modulation were observed. CONCLUSIONS: CoQ0 inhibited the progression of metastasis as well as EMT (in vitro and in vivo). The described approach has potential in treating human breast cancer metastasis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ubiquinona/administração & dosagem , Animais , Antígenos CD/genética , Apoptose/efeitos dos fármacos , Caderinas/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Humanos , Metaloproteinase 9 da Matriz/genética , Camundongos , NF-kappa B/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
14.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035577

RESUMO

Cataracts are the leading cause of blindness worldwide. Although surgery is a successful method to restore vision loss due to cataracts, post-surgical complications can occur, such as secondary cataracts, also known as posterior capsular opacification (PCO). PCO arises when lens epithelial cells (LEC) are left behind in the capsular bag following surgery and are induced to undergo epithelial to mesenchymal transition (EMT). Following EMT, LEC morphology and phenotype are altered leading to a loss of transparency and vision. Transforming growth factor (TGF)-ß-induced signaling through both canonical, TGF-ß/Smad, and non-canonical, ß-catenin/Wnt and Rho/ROCK/MRTF-A, pathways have been shown to be involved in lens EMT, and thus PCO. However, the interactions between these signaling pathways in the lens have not been thoroughly explored. In the current study we use rat LEC explants as an ex vivo model, to examine the interplay between three TGF-ß-mediated pathways using α-smooth muscle actin (α-SMA) as a molecular marker for EMT. We show that Smad3 inhibition via SIS3 prevents nuclear translocation of ß-catenin and MRTF-A, and α-SMA expression, suggesting a key role of Smad3 in regulation of MRTF-A and ß-catenin nuclear transport in LECs. Further, we demonstrate that inhibition of ß-catenin/CBP interaction by ICG-001 decreased the amount of phosphorylated Smad3 upon TGF-ß stimulation in addition to significantly decreasing the expression levels of TGF-ß receptors, TBRII and TBRI. Overall, our findings demonstrate interdependence between the canonical and non-canonical TGF-ß-mediated signaling pathways controlling EMT in the lens.


Assuntos
Transição Epitelial-Mesenquimal , Cristalino/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , beta Catenina/metabolismo , Animais , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Ligação Proteica , Transporte Proteico , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/genética , Fator de Crescimento Transformador beta/farmacologia , beta Catenina/genética
15.
Dev Genes Evol ; 229(4): 89-102, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31041506

RESUMO

The Wnt/beta-catenin pathway has many key roles in the development of animals, including a conserved and central role in the specification of the primary (antero-posterior) body axis. The posterior expression of Wnt ligands and the anterior expression of secreted Wnt inhibitors are known to be conserved during the larval metamorphosis of tapeworms. However, their downstream signaling components for Wnt/beta-catenin signaling have not been characterized. In this work, we have studied the core components of the beta-catenin destruction complex of the human pathogen Echinococcus multilocularis, the causative agent of alveolar echinococcosis. We focused on two Axin paralogs that are conserved in tapeworms and other flatworm parasites. Despite their divergent sequences, both Axins could robustly interact with one E. multilocularis beta-catenin paralog and limited its accumulation in a heterologous mammalian expression system. Similarly to what has been described in planarians (free-living flatworms), other beta-catenin paralogs showed limited or no interaction with either Axin and are unlikely to function as effectors in Wnt signaling. Additionally, both Axins interacted with three divergent GSK-3 paralogs that are conserved in free-living and parasitic flatworms. Axin paralogs have highly segregated expression patterns along the antero-posterior axis in the tapeworms E. multilocularis and Hymenolepis microstoma, indicating that different beta-catenin destruction complexes may operate in different regions during their larval metamorphosis.


Assuntos
Proteína Axina/genética , Complexo de Sinalização da Axina/genética , Echinococcus multilocularis/genética , Quinase 3 da Glicogênio Sintase/genética , Proteínas de Helminto/genética , Hymenolepis/genética , beta Catenina/genética , Sequência de Aminoácidos , Animais , Proteína Axina/química , Proteína Axina/metabolismo , Complexo de Sinalização da Axina/química , Echinococcus multilocularis/crescimento & desenvolvimento , Echinococcus multilocularis/metabolismo , Perfilação da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas de Helminto/química , Humanos , Hymenolepis/crescimento & desenvolvimento , Hymenolepis/metabolismo , Larva/metabolismo , Filogenia , Alinhamento de Sequência , beta Catenina/metabolismo
16.
Cancer Immunol Immunother ; 68(7): 1121-1132, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31134297

RESUMO

Immune-cell infiltration is associated with improved survival in melanoma. Human melanoma metastases may be grouped into immunotypes representing patterns of immune-cell infiltration: A (sparse), B (perivascular cuffing), and C (diffuse). Immunotypes have not been defined for murine melanomas, but may provide opportunities to understand mechanism-driving immunotype differences. We performed immunohistochemistry with immune-cell enumeration, immunotyping, and vascular density scoring in genetically engineered (Braf/Pten and Braf/Pten/ß-catenin) and transplantable (B16-F1, B16-OVA, and B16-AAD) murine melanomas. The transplantable tumors were grown in subcutaneous (s.c.) or intraperitoneal (i.p.) locations. Braf/Pten and Braf/Pten/ß-catenin tumors had low immune-cell densities, defining them as Immunotype A, as did B16-F1 tumors. B16-OVA (s.c. and i.p.) and B16-AAD s.c. tumors were Immunotype B, while B16-AAD i.p. tumors were primarily Immunotype C. Interestingly, the i.p. location was characterized by higher immune-cell counts in B16-OVA tumors, with counts that trended higher for B16-F1 and B16-AAD. The i.p. location was also characterized by higher vascularity in B16-F1 and B16-AAD tumors. These findings demonstrate that spontaneously mutated neoantigens in B16 melanomas were insufficient to induce robust intratumoral immune-cell infiltrates, but instead were Immunotype A tumors. The addition of model neoantigens (OVA or AAD) to B16 enhanced infiltration, but this most often resulted in Immunotype B. We find that tumor location may be an important element in enabling Immunotype C tumors. In aggregate, these data suggest important roles both for the antigen type and for the tumor location in defining immunotypes.


Assuntos
Antígenos de Neoplasias/imunologia , Imunofenotipagem , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Animais , Linhagem Celular Tumoral/transplante , Humanos , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/genética , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Análise Serial de Tecidos , beta Catenina/genética
17.
Fish Shellfish Immunol ; 91: 99-107, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075405

RESUMO

ß-catenin is a multifunctional protein that participates in a variety of physiological activities, including immune regulation, sex determination, nervous system development and, cell differentiation. However, the function of ß-catenin in freshwater mussel Hyriopsis cumingii remains unclear. Herein, the gene encoding ß-catenin from H. cumingii (Hc-ß-catenin) was cloned and characterised. The full-length 5544 bp gene includes an open reading frame (ORF) of 2463 bp encoding a putative protein of 820 amino acids residues containing 12 armadillo (ARM) repeats. After injecting H. cumingii with Aeromonas hydrophila or lipopolysaccharides, Hc-ß-catenin transcription was induced in hemocytes and gills, and the greatest responses occurred at 24 h after bacterial challenge, confirming an important role in immune responses. Quantitative real-time PCR analysis showed that Hc-ß-catenin mRNA was distributed in the gill, foot, liver, kidney, mantle, adductor muscle and gonad of male and female mussels. In gonad, Hc-ß-catenin expression was markedly higher in females than males. During the embryonic period, Hc-ß-catenin expression was highest at 3 day. In 1-, 2- and 3-year-old mature mussels, Hc-ß-catenin expression in female gonad tissue was notably higher than in males. In situ hybridisation revealed a significant hybridisation signal in female gonads, indicating that Hc-ß-catenin is a pro-ovarian, anti-testis gene. Our findings demonstrate that Hc-ß-catenin is important in immune regulation and sex determination in freshwater mussel.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Processos de Determinação Sexual/genética , Unionidae/genética , Unionidae/imunologia , beta Catenina/genética , beta Catenina/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Perfilação da Expressão Gênica , Filogenia , beta Catenina/química
18.
PLoS Pathog ; 15(4): e1007575, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31002735

RESUMO

High-risk human papillomavirus (HPV) E6 proteins associate with the cellular ubiquitin ligase E6-Associated Protein (E6AP), and then recruit both p53 and certain cellular PDZ proteins for ubiquitination and degradation by the proteasome. Low-risk HPV E6 proteins also associate with E6AP, yet fail to recruit p53 or PDZ proteins; their E6AP-dependent targets have so far been uncharacterized. We found a cellular PDZ protein called Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) is targeted for degradation by both high and low-risk HPV E6 proteins as well as E6 proteins from diverse non-primate mammalian species. NHERF1 was degraded by E6 in a manner dependent upon E6AP ubiquitin ligase activity but independent of PDZ interactions. A novel structural domain of E6, independent of the p53 recognition domain, was necessary to associate with and degrade NHERF1, and the NHERF1 EB domain was required for E6-mediated degradation. Degradation of NHERF1 by E6 activated canonical Wnt/ß-catenin signaling, a key pathway that regulates cell growth and proliferation. Expression levels of NHERF1 increased with increasing cell confluency. This is the first study in which a cellular protein has been identified that is targeted for degradation by both high and low-risk HPV E6 as well as E6 proteins from diverse animal papillomaviruses. This suggests that NHERF1 plays a role in regulating squamous epithelial growth and further suggests that the interaction of E6 proteins with NHERF1 could be a common therapeutic target for multiple papillomavirus types.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/metabolismo , Fosfoproteínas/metabolismo , Proteínas Repressoras/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína Wnt1/metabolismo , beta Catenina/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Fosfoproteínas/genética , Filogenia , Complexo de Endopeptidases do Proteassoma , Proteólise , Proteínas Repressoras/genética , Trocadores de Sódio-Hidrogênio/genética , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Proteína Wnt1/genética , beta Catenina/genética
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 477-481, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998157

RESUMO

OBJECTIVE: To investigate the effecr of siRNA-interfering ß-catenin expression on drug-resistance of multiple myeloma cells. METHODS: The multiple myeloma cell line RPMI-8226 was cultured in vitro. The maphalan-resistant cell model was established by concentration gradient ascending of durg, then the drug-resistant cell line was instantaneously transfected with ß-catenin siRNA, the sensitivity of RPMI 8226 cells to maphalan was detected by CCK-8 meltod before and after the transfection with siRNA; the mRNA and protein expression of ß-catenin was detected by qRT-PCR and Western blot respectively, the apoptosis of cells was detected by flow cytometry. RESULTS: IC50 of maphalan decreased from (5.29±0.19) µmol/L to (1.88±0.64) µmol/L, suggesting that the deplation of ß-eatenin restored the sensitivity of drug-resistant cell line RPMI-8226 to malphalan. The Western blot showed that after the instaintaneous transfection with ß-catenin siRNA, the ß-catenin protein expression level obviously decreased, compared with level before transfection. After transfection, the maplalan-inducing apoptosis rate of cells increased from (35±0.5)% to (54±0.4)%, suggesting that the ß-catinin gene may correlated with drug-resistance of cells. Interfering the expression of ß-catenin gene could enhance the sensitivity of drug-resistant RPMI-8226 cells to maphalan. CONCLUSION: The ß-catenin siRNA interfereuce can inhisit the ß-catenin gene expression in Wnt/ß-catenin signaling pathway, suppress the cell proliferation, enhence the toxicity of maphalan on drug-resistant RPMI-8226 cells, thus result in increase of cell apoptosis.


Assuntos
Mieloma Múltiplo , beta Catenina/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , RNA Interferente Pequeno
20.
Nat Commun ; 10(1): 1909, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015417

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. ß-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that ß-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, ß-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of ß-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Proteína Wnt3A/genética , beta Catenina/genética , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Progressão da Doença , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Estadiamento de Neoplasias , Fatores Sexuais , Transdução de Sinais , Carga Tumoral , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo
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