RESUMO
BACKGROUND: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. METHODS: Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. RESULTS: Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. CONCLUSION: We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.
Assuntos
Ciclo Celular , Proliferação de Células , Melanoma/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a protein with important functions during embryogenesis that is dysregulated in human cancer. An intriguing feature of this receptor is that it plays opposite roles in different tumor types either promoting or inhibiting tumor progression. Understanding the complex role of this receptor requires a more profound exploration of both the altered biological and molecular mechanisms. Here, we describe that ROR2 promotes Epithelial-Mesenchymal Transition (EMT) by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. We show that ROR2 activates both p38 and ERK mitogen-activated protein kinase pathways independently of Wnt5a. Further, we demonstrated that the upregulation of EMT-related proteins depends on the hyperactivation of the ERK pathway far above the typical high constitutive activity observed in melanoma. In addition, ROR2 also promoted ERK phosphorylation, EMT, invasion, and necrosis in xenotransplanted mice. ROR2 also associates with EMT in tumor samples from melanoma patients where analysis of large cohorts revealed that increased ROR2 levels are linked to EMT signatures. This important role of ROR2 translates into melanoma patient' s prognosis since elevated ROR2 levels reduced overall survival and distant metastasis-free survival of patients with lymph node metastasis. In sum, these results demonstrate that ROR2 contributes to melanoma progression by inducing EMT and necrosis and can be an attractive therapeutic target for melanoma.
RESUMO
The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and MCL1. The role of BCL2L10, another member of this group, has been poorly studied in cancer and never has been in melanoma. We describe here that BCL2L10 is abundantly and frequently expressed both in melanoma cell lines and tumor samples. We established that BCL2L10 expression is driven by STAT3-mediated transcription, and by using reporter assays, site-directed mutagenesis, and ChIP analysis, we identified the functional STAT3 responsive elements in the BCL2L10 promoter. BCL2L10 is a pro-survival factor in melanoma since its expression reduced the cytotoxic effects of cisplatin, dacarbazine, and ABT-737 (a BCL2, Bcl-xL, and Bcl-w inhibitor). Meanwhile, both genetic and pharmacological inhibition of BCL2L10 sensitized melanoma cells to cisplatin and ABT-737. Finally, BCL2L10 inhibited the cell death upon combination treatments of PLX-4032, a BRAF inhibitor, with ABT-737 or cisplatin. In summary, we determined that BCL2L10 is expressed in melanoma and contributes to cell survival. Hence, targeting BCL2L10 may enhance the clinical efficacy of other therapies for malignant melanoma.
RESUMO
We report 72 years old woman, with adenoacamthoma of the upper osophagus who was admitted in Hospital israelita "EZRAH" in April of 1991. We performed a review of the literature on this rare tumour, that is the reason of presenting this case
Assuntos
Humanos , Feminino , Idoso , Adenocarcinoma/patologia , Neoplasias Esofágicas/patologiaRESUMO
Se describen los cambios hitológicos en los ganglios linfáticos en pacientes con evidencias de inmunodeficiencia y sarcoma angioblástico de tipo Kaposi, destacando las modificaciones previas y concomitantes a la instalación de la neoplasia y relacionando las mismas con el disturbio inmunológico. Se realizan consideraciones sobre la histogénesis de las células neoplásicas en los angiosarcomas de tipo Kaposi y se concluye que las mismas muestran caracteres hemangiopericitoides y endoteliales combinados