RESUMO
BACKGROUND AND PURPOSE: Bone marrow-derived cells (BMDC) have been demonstrated to play a critical role in intestine regeneration. However, organ fibrosis was one of the major side effects of bone marrow (BM) transplantation. It warrants further investigation on the mechanisms of BM cell therapy in radiation induced intestine damage. MATERIALS AND METHODS: We established three murine models to evaluate BMDC within intestines after radiation, including cre-loxP system of transgenic mice. In vitro co-culture between murine BM with human intestine stromal cells was also performed to measure the level of fusion and fibrosis after treatment with anti-fibrotic agents or after macrophage depletion. RESULTS: Despite complete recovery of epithelial mucosa from radiation damage, we found persistent proliferation and repopulation of BMDC within the lamina propria. Fusion between BM derived monocytic and intestine stromal cells correlated with the level of fibrosis and proliferation index. Depleting macrophages genetically using CD11b-DTR mouse model or pharmacologically using clodronate liposome reduced the level of cell fusion and intestine fibrosis. CONCLUSIONS: Fibrotic cues from intestine enhance fusion between BM-derived monocytes/macrophages with intestine stromal cells. The fusion hybrids promote cell cycle re-entry, proliferation and reinforce fibrosis signal. Depleting macrophages interferes with cell fusion and ameliorates radiation-induced intestine fibrosis.
Assuntos
Células da Medula Óssea/fisiologia , Fusão Celular , Intestinos/patologia , Macrófagos/fisiologia , Animais , Antígeno CD11b/análise , Proliferação de Células , Doença Crônica , Fibrose , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Estromais/fisiologiaRESUMO
Oral carcinoma is a serious public health problem and the leading cause of head and neck cancer mortality worldwide. Moreover, oral cancer patients often present symptoms at a late stage and show a high recurrence rate after treatment. Therefore, there is an urgent need to identify novel biomarkers for early diagnosis or clinical oral cancer therapy. In this study, we employed a subset of lentiviral short hairpin RNAs targeted against various kinases and phosphatases, designed by The RNAi Consortium, to screen systemically and in a high-throughput manner for potential growth regulators of oral cancer cells. The screen revealed a total of 50 candidate genes, for which more than 90% of growth inhibition in human oral squamous cancer HSC-3 cells was obtained. Furthermore, bioinformatic analysis of these candidate genes identified transforming growth factor-ß receptor type II- and fms-related tyrosine kinase 3-related molecular pathways that are involved in NF-κB-mediated growth of HSC-3 cells. These candidate genes may be potential biomarkers for early diagnosis of oral cancer. In addition, these candidate genes represent potential targets for anticancer drug design helping to develop a personalized treatment to combat oral cancer.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Monoéster Fosfórico Hidrolases/genética , Fosfotransferases/genética , RNA Interferente Pequeno/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/enzimologia , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Vetores Genéticos/genética , Ensaios de Triagem em Larga Escala , Humanos , Quinase I-kappa B/metabolismo , Lentivirus/genética , Neoplasias Bucais/enzimologia , NF-kappa B/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Fosfotransferases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transporte Proteico , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Reprodutibilidade dos Testes , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresRESUMO
Berberine (BBR) is a natural alkaloid with significant antitumor activities against many types of cancer cells. This study investigated the molecular mechanisms by which BBR suppresses the growth of HER2-overexpressing breast cancer cells. The results show that BBR induces G1-phase cell cycle arrest by interfering with the expression of cyclins D1 and E and that it induces cellular apoptosis through the induction of a mitochondria/caspase pathway. The data also indicate that BBR inhibits cellular growth and promotes apoptosis by down-regulating the HER2/PI3K/Akt signaling pathway. Furthermore, it is also shown that a combination of taxol and BBR significantly slows the growth rate of HER2-overexpressing breast cancer cells. In conclusion, this study suggests that BBR could be a useful adjuvant therapeutic agent in the treatment of HER2-overexpressing breast cancer.
Assuntos
Berberina/farmacologia , Neoplasias da Mama/metabolismo , Regulação para Baixo/efeitos dos fármacos , Substâncias de Crescimento/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptor ErbB-2/metabolismoRESUMO
The up-regulation of HER2/neu is associated with human malignancies and is a useful target for developing anticancer drugs. Overexpression of human manganese superoxide dismutase (MnSOD) has been demonstrated to effectively suppress various carcinoma cells, including breast carcinomas, in vitro and in vivo. This study demonstrates that MnSOD effectively suppresses HER2/neu oncogene expression at the transcriptional level. Additionally, stable transfection was used and the MnSOD-transfected human breast cancer clones were found to be able to down-regulate the endogenous production of p185(HER2/neu). Furthermore, the MnSOD-overexpressing stable transfectants exhibited reduced soft-agarose colony-forming ability and metastatic properties, unlike control cell lines. These data suggest that MnSOD may be useful in treating HER2/neu-mediated human breast tumor malignancy.