Abstract
Despite significant advancements in the diagnosis and treatment of osteosarcoma, the molecular mechanisms underpinning disease progression remain unclear. This work presents strong clinical and experimental evidence demonstrating that Notch signaling contributes to osteosarcoma progression. First, using a cohort of 12 patients, Notch genes were upregulated in tumors compared with adjacent normal tissue, and high tumor expression of Notch1 intercellular domain (NICD1) and the Notch target gene Hes1 correlated with poor chemotherapy response. Data mining of publicly available datasets confirmed that expression of Notch pathway genes is related to poor prognosis in osteosarcoma. On the basis of in vitro analysis, Notch signaling promoted osteosarcoma proliferation, enhanced chemoresistance, facilitated both migration and invasion, and upregulated stem cell-like characteristics. Xenograft models demonstrated that Notch signaling promotes primary tumor growth and pulmonary metastasis, and Notch inhibition is effective in reducing tumor size and preventing metastasis. Mechanistically, activated Notch signaling induces the expression of ephrinB1 and enhances the tumor-promoting ephrin reverse signaling. Overall, these findings provide functional evidence for Notch pathway genes as candidate biomarkers to predict prognosis in patients with osteosarcoma, and suggest a mechanistic rationale for the use of Notch inhibitors to treat osteosarcoma. IMPLICATIONS: The study provides preclinical evidence for Notch pathway as a molecular marker to predict osteosarcoma prognosis and as a therapeutic target against osteosarcoma. In addition, we identified a novel mechanism that ephrin reverse signaling acts as a key mediator of Notch pathway.
Highlights
Osteosarcoma is the most common primary malignant bone tumor, with an initial peak in diagnosis in the late adolescent and young adult period [1]
Notch pathway genes correlate with osteosarcoma progression The mean expression of Hes1 was 15.49% in primary osteosarcoma biopsy samples, in contrast, only low levels of Hes1þ cells were detected in the adjacent normal bone marrow and muscular cells (Fig. 1A)
We manifested the regulatory activity of NICD1 on the ephrinB1 promoter via dual-luciferase reporter assays, we found that ephrinB1 promoter activity was decreased in the 143B cells transfected with no binding site and with a mutated CBF1-binding motif in -1438 to -1431 compared with the control cells transfected with the wild-type CBF1-binding motif in -1438 to -1431 (Fig. 4F)
Summary
Osteosarcoma is the most common primary malignant bone tumor, with an initial peak in diagnosis in the late adolescent and young adult period [1]. Despite significant advances in the diagnosis and treatment of osteosarcoma, overall survival has remained relatively constant for the last 4 decades [2]. Patients with metastatic disease at diagnosis or those with recurrent disease have a poor prognosis, with only 20% surviving 5 years [3]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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