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- W2967207654 abstract "3943 Osteosarcoma, the most common malignant tumor of bone in teenagers, has high potential of pulmonary metastasis. Although primary osteosarcoma is effectively treated by surgery and chemotherapy, pulmonary metastasis is more difficult to control and causes the majority of patient death. Elimination of metastatic disease is essential to cure osteosarcoma patients. However, the molecular mechanisms controlling invasiveness and metastasis are not fully understood. We have identified an essential role of Notch driven Hes1 expression in osteosarcoma invasiveness and metastasis. The Notch pathway is involved in pathogenesis of several cancer types, and pharmacological blockade of Notch signaling is in the clinical trails for human T-cell leukemia. We found that γ-secretase inhibitor-mediated blockade of Notch reduced matrigel invasion in parallel with Hes1 reduction in osteosarcoma cell lines OS187 and LM7, but had no effect on proliferation, survival or anchorage-independent growth. Furthermore, overexpression of constitutively active Notch1 (ICN1, intercellular domain of Notch1), Hes1 or dominant negative Mastermind (dnMAM, an inhibitor of Notch signaling) confirmed the essential role of Notch-induced Hes1 expression in promoting invasion of osteosarcoma cells. Here, we identify the interaction of Hes1 and Deltex1. In one osteosarcoma cell line COL, which high endogenous Deltex1, γ-secretase inhibitor-mediated blockade of Notch did not reduce matrigel invasion, and did not suppress Hes1 expression. Genetic blockade of Notch signaling with dnMAM decreased Deltex1 expression, and increased Hes1 expression, promoting invasiveness of COL cells. This suggested that Deltex1 is a negative regulator of Hes1 expression. The inhibition of Hes1 expression by Deltex1 is also observed in other osteosarcoma cells. Meanwhile, overexpression of Hes1 in COL cells decreased Deltex1 expression, suggesting Hes1 acts as a direct inhibitor of Deltex1 expression. Other Notch downstream target genes, including Hes5 and Herp2, did not consistently alter their expression with transduction of either Hes1 or Deltex1, suggesting Hes5 and Herp2 are not regulated by Hes1 or Deltex1 in osteosarcoma. Our data demonstrate that Hes1 and Deltex1 can inhibit each other and control invasiveness in osteosarcoma. These studies also identify a novel mechanism for regulation of Notch signaling in osteosarcoma. Since Notch pathway inhibitors are under evaluation in clinical trails for human cancer, our work may have important implications for prediction of which patients are at increased risk for metastasis and might benefit from γ-secretase inhibitor treatment." @default.
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- W2967207654 date "2007-05-01" @default.
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- W2967207654 title "Hes1 and Deltex1: yin and yang controlling invasiveness and metastasis in osteosarcoma" @default.
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