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Arq Bras Cir Dig ; 32(1): e1414, 2019 Jan 07.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30624523


BACKGROUND: It is believed that the Wnt pathway is one of the most important signaling involved in gastric carcinogenesis. AIM: To analyze the protein expression of canonical and non-canonical Wnt pathways in gastric carcinoma. METHOD: The immunohistochemistry was performed in 72 specimens of gastric carcinomas for evaluating the expression of Wnt-5a, FZD5, GSK3ß, axin, CK1, ubiquitin, cyclin D1 and c-myc. RESULTS: There were significant differences for cytoplasm and nucleus ubiquitin for moderately and well differentiated tumors (p=0.03) and for those of the intestinal type of the Lauren classification (p=0.03). The absence of c-myc was related to Lauren's intestinal tumors (p=0.03). Expression of CK1 in the cytoplasm was related to compromised margin (p=0.03). Expression of cyclin D1 protein was more intense in male patients (p=0.03) There was no relation of the positive or negative expression of the Wnt-5a, FZD5, GSK3 and Axin with any clinicopathological variables. CONCLUSION: The canonical WNT pathway is involved in gastric carcinoma.

Carcinoma/química , Proteínas de Neoplasias/análise , Neoplasias Gástricas/química , Via de Sinalização Wnt , Proteína Axina/análise , Carcinogênese , Carcinoma/patologia , Caseína Quinase I/análise , Ciclina D1/análise , Feminino , Receptores Frizzled/análise , Glicogênio Sintase Quinase 3 beta/análise , Humanos , Imuno-Histoquímica , Masculino , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-myc/análise , Valores de Referência , Neoplasias Gástricas/patologia , Ubiquitina/análise , Proteína Wnt-5a/análise
Hepatobiliary Pancreat Dis Int ; 17(3): 227-232, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29709351


BACKGROUD: Wingless-type MMTV integration site family member 5a (Wnt5a) is involved in carcinogenesis. However, little data are available in Wnt5a signaling with hepatocellular carcinoma (HCC). In the present study, we investigated the expression of hepatic Wnt5a in HCC and the role of Wnt5a in HCC progression and outcome. METHODS: Wnt5a expression and cellular distribution in HCCs and their matched paracancerous tissues from 87 patients were analyzed with tissue microarray and immunohistochemistry and compared with hepatic Wnt3a signaling. Wnt5a expression was categorized into low or high based on immunohistochemistry. Overall survival rate of HCC patients was estimated in correlation with the hepatic Wnt5a level using Kaplan-Meier method; the survival difference between patients with low and those with high Wnt5a was compared with log-rank test; and prognostic analysis was carried out with Cox regression. RESULTS: Total incidence of Wnt5a expression in the HCC tissues was 70.1%, which was significantly lower (χ2 = 13.585, P < 0.001) than that in their paracancerous tissues (88.5%). Significant difference of Wnt5a intensity was found between HCC and their paracancerous tissues (Z = 8.463, P < 0.001). Wnt5a intensity was inversely correlated with Wnt3a signaling (r = -0.402, P < 0.001) in HCC tissues. A decrease of Wnt5a expression in relation to the clinical staging from stage I to IV and low or no staining at advanced HCC were observed. Wnt5a level was related to periportal embolus (χ2 = 11.069, P < 0.001), TNM staging (χ2 = 8.852, P < 0.05), 5-year survival (χ2 = 4.961, P < 0.05), and confirmed as an independent prognosis factor of HCC patients (hazard ratio: 1.957; 95% confidence interval: 1.109-3.456; P < 0.05). CONCLUSIONS: The decrease of hepatic Wnt5a signaling is associated with HCC progression and poor prognosis.

Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/química , Neoplasias Hepáticas/química , Proteína Wnt-5a/análise , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Proliferação de Células , Distribuição de Qui-Quadrado , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Via de Sinalização Wnt , Proteína Wnt3A/análise , Adulto Jovem
World J Gastroenterol ; 23(14): 2601-2612, 2017 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-28465645


AIM: To investigate the expression and clinical pathological significance of ROR2 and WNT5a in gallbladder squamous/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC). METHODS: EnVision immunohistochemistry was used to stain for ROR2 and WNT5a in 46 SC/ASC patients and 80 AC patients. RESULTS: Poorly differentiated AC among AC patients aged > 45 years were significantly more frequent compared with SC/ASC patients, while tumors with a maximal diameter > 3 cm in the SC/ASC group were significantly more frequent compared with the AC group. Positive ROR2 and WNT5a expression was significantly lower in SC/ASC or AC with a maximal mass diameter ≤ 3 cm, a TNM stage of I + II, no lymph node metastasis, no surrounding invasion, and radical resection than in patients with a maximal mass diameter > 3 cm, TNM stage IV, lymph node metastasis, surrounding invasion, and no resection. Positive ROR2 expression in patients with highly differentiated SC/ASC was significantly lower than in patients with poorly differentiated SC/ASC. Positive ROR2 and WNT5a expression levels in highly differentiated AC were significantly lower than in poorly differentiated AC. Kaplan-Meier survival analysis showed that differentiation degree, maximal mass diameter, TNM stage, lymph node metastasis, surrounding invasion, surgical procedure and the ROR2 and WNT5a expression levels were closely related to average survival of SC/ASC or AC. The survival of SC/ASC or AC patients with positive expression of ROR2 and WNT5a was significantly shorter than that of patients with negative expression results. Cox multivariate analysis revealed that poor differentiation, a maximal diameter of the mass ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, unresected surgery and positive ROR2 or WNT5a expression in the SC/ASC or AC patients were negatively correlated with the postoperative survival rate and positively correlated with mortality, which are risk factors and independent prognostic predictors. CONCLUSION: SC/ASC or AC patients with positive ROR2 or WNT5a expression generally have a poor prognosis.

Adenocarcinoma/química , Biomarcadores Tumorais/análise , Carcinoma Adenoescamoso/química , Neoplasias da Vesícula Biliar/química , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/análise , Proteína Wnt-5a/análise , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/patologia , Carcinoma Adenoescamoso/cirurgia , Diferenciação Celular , Distribuição de Qui-Quadrado , China , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
Cancer Res ; 77(4): 996-1007, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28011620


Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996-1007. ©2016 AACR.

Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteína Wnt-5a/fisiologia , Animais , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Humanos , Camundongos , Invasividade Neoplásica , Fenótipo , Proteína Wnt-5a/análise , Proteína Wnt-5a/antagonistas & inibidores
Mol Oncol ; 10(5): 677-92, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26739507


Receptor tyrosine kinases (RTKs) have provided molecular targets for the development of novel, prognosis-improving agents in many cancers; however, resistances to these therapies occur. On the cellular level, one resistance mechanism is attributed to functional RTK redundancies and compensatory cross-signaling, leading to perception of RTKs as signaling and target networks. To provide a basis for better exploitation of this network in Ewing sarcoma, we generated comprehensive qPCR gene expression profiles of RTKs in Ewing sarcoma cell lines and 21 untreated primary tumors. Key findings confirm broad-spectrum RTK expressions with potential for signaling redundancy. Profile analyses with regard to patient risk-group further revealed several individual RTKs of interest. Among them, VEGFR3 and TIE1 showed high-level expressions and also were suggestive of poor prognosis in localized tumors; underscoring the relevance of angiogenic signaling pathways and tumor-stroma interactions in Ewing sarcoma. Of note, compared to localized disease, tumors derived from metastatic disease were marked by global high-level RTK expressions. Nine individual RTKs were significantly over-expressed, suggesting contributions to molecular mechanisms of metastasis. Of these, ROR1 is being pursued as therapeutic target in leukemias and carcinomas, but un-characterized in sarcomas. We demonstrate expression of ROR1 and its putative ligand Wnt5a in Ewing sarcomas, and of an active ROR1 protein variant in cell lines. ROR1 silencing impaired cell migration in vitro. Therefore, ROR1 calls for further evaluation as a therapeutic target in metastatic Ewing sarcoma; and described as a pseudo-kinase with several isoforms, underlines these additional complexities arising in our understanding of RTK signaling networks.

Neoplasias Ósseas/genética , Neoplasias Ósseas/terapia , Terapêutica com RNAi , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/terapia , Transcriptoma , Adolescente , Neoplasias Ósseas/patologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Linhagem Celular Tumoral , Movimento Celular , Criança , Feminino , Humanos , Masculino , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/análise , Sarcoma de Ewing/patologia , Proteína Wnt-5a/análise