RESUMO
Spondin 1 (SPON1) is cell adhesion protein that involved in attachment of sensory neuron cells and outgrowth of neurites. Its cellular functions and related mechanisms in cancers, however, remain largely unexplored. In this study, we first identified that SPON1 acts a critical factor in the metastatic progression of osteosarcoma through analysis of a GEO dataset. Then we demonstrated that SPON1 was significantly up-regulated in 72 osteosarcoma specimens compared with benign osteochondroma samples and elevated SPON1 was positively correlated with MMP9 expression. Knockdown of SPON1 expression in two metastatic osteosarcoma cell lines, HKOS and KRIB, dramatically suppressed cell migration and invasion. Treatment with recombinant SPON1 protein in two non-metastatic osteosarcoma cell lines, HOS and U2OS, significantly promoted cell migration and invasion in vitro. Meanwhile, suppression of SPON1 in KHOS cells resulted in decreased pulmonary metastasis in vivo. Mechanistically, we determined that the effects of SPON1 on osteosarcoma cell motility were primarily mediated through Fak and Src dependent pathway. Taken together, our study provides evidence of the contributions of SPON1 and the Fak and Src signaling to the progression of osteosarcoma and suggests that this axis may represent a potential therapeutic target for osteosarcoma.
Assuntos
Neoplasias Ósseas/genética , Proteínas da Matriz Extracelular/genética , Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Osteossarcoma/genética , Quinases da Família src/genética , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/antagonistas & inibidores , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Osteossarcoma/metabolismo , Osteossarcoma/secundário , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Tíbia/metabolismo , Tíbia/patologia , Quinases da Família src/metabolismoRESUMO
PURPOSE: The purpose of this study was to examine calcitonin gene-related peptide (CGRP) concentrations in serum and synovial fluid of patients with primary knee osteoarthritis (OA) and healthy controls and to explore their relationship with clinical and radiographic severity of OA. METHODS: Sixty-five patients with primary knee OA and 21 healthy controls were recruited. CGRP concentrations in the serum and synovial fluid were measured using enzyme-linked immunosorbent assays. The radiographic severity of OA was evaluated using the Kellgren and Lawrence (KL) classification. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess pain, stiffness and physical function. RESULTS: Serum and synovial fluid CGRP concentrations tended to be higher with the increase in KL grades (r = 0.565 and r = 0.441, P < 0.001, respectively), and were significantly positively correlated with KL grades, total WOMAC score and each subscale (pain, stiffness and physical function). CONCLUSIONS: The result demonstrated that CGRP in serum and synovial fluid was related to progressive joint damage in knee OA. CGRP can be selected as a biomarker for monitoring disease severity and could be a predictive role on prognosis and progression of knee OA.
Assuntos
Biomarcadores/análise , Peptídeo Relacionado com Gene de Calcitonina/análise , Osteoartrite do Joelho/sangue , Líquido Sinovial/química , Idoso , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina/sangue , Progressão da Doença , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Prognóstico , Radiografia , Índice de Gravidade de DoençaRESUMO
Plasmacytoid dendritic cells (pDCs) are specialized in rapid and massive secretion of type I interferon in response to foreign nuclei acids. Combined with their antigen presentation capacity, this powerful functionality enables pDCs to orchestrate innate and adaptive immune responses. Cholecystokinin octapeptide (CCK8) is a potent immunomodulator, whose role in pDCs function is unknown. In this study, we found that two different cholecystokinin receptors, CCK1R and CCK2R, are expressed on human peripheral blood pDCs. Exogenous CCK8 was able to modulate the TLR-induced activation of pDCs, including phenotypic maturation, IFN-α synthesis and secretion, and could also regulate the potential of pDCs to induce adaptive immune responses in vitro. CCK8 inhibited TLR9-induced activation of tumor-necrosis factor receptor-associated factor 6, which is an important adapter protein in activation of interferon-regulatory factor (IRF)5 and IRF7, possibly through CCK2R, by evoking the activity of protein kinase (PK)A and reducing the activity of PKC. All these results indicate that CCK8 can inhibit the TLR9-induced phenotypic maturation and activation of pDCs, acting through CCK2R by modulating the tumor-necrosis factor receptor-associated factor 6 signaling pathways.