TY - JOUR
T1 - Bmi-1 is essential for the tumorigenicity of neuroblastoma cells
AU - Cui, Hongjuan
AU - Hu, Bo
AU - Li, Tai
AU - Ma, Jun
AU - Alam, Goleeta
AU - Gunning, William T.
AU - Ding, Han Fei
PY - 2007/4
Y1 - 2007/4
N2 - Activation of oncogenes underlies the pathogenesis of most human cancers. In neuroblastoma, amplification of the oncogene MYCN occurs in ∼22% of cases and is associated with advanced stages of the disease and poor prognosis. Identification of other oncogenes that are consistently mutated or overexpressed in neuroblastoma is crucial for a molecular understanding of the pathogenic process. Here, we report that the oncogene Bmi-1 is highly expressed in human neuroblastoma cell lines and primary tumors. Neuroblastoma development in MYCN transgenic mice, an animal model for the human disease, was associated with a marked increase in the levels of Bmi-1 expression. Bmi-1 cooperated with MYCN in transformation of benign S-type neuroblastoma cells and avian neural crest cells by inhibiting the apoptotic activity of MYCN. Importantly, down-regulation of Bmi-1 impaired the ability of neuroblastoma cells to grow in soft agar and induce tumors in immunodeficient mice. Moreover, Bmi-1-knockdown neuroblastoma xenografts were characterized by a significant increase in the amount of Schwannian stroma, a histological feature associated with clinically favorable neuroblastomas. These findings suggest a crucial role for Bmi-1 in neuroblastoma pathogenesis and provide insights into the molecular basis of neuroblastoma heterogeneity.
AB - Activation of oncogenes underlies the pathogenesis of most human cancers. In neuroblastoma, amplification of the oncogene MYCN occurs in ∼22% of cases and is associated with advanced stages of the disease and poor prognosis. Identification of other oncogenes that are consistently mutated or overexpressed in neuroblastoma is crucial for a molecular understanding of the pathogenic process. Here, we report that the oncogene Bmi-1 is highly expressed in human neuroblastoma cell lines and primary tumors. Neuroblastoma development in MYCN transgenic mice, an animal model for the human disease, was associated with a marked increase in the levels of Bmi-1 expression. Bmi-1 cooperated with MYCN in transformation of benign S-type neuroblastoma cells and avian neural crest cells by inhibiting the apoptotic activity of MYCN. Importantly, down-regulation of Bmi-1 impaired the ability of neuroblastoma cells to grow in soft agar and induce tumors in immunodeficient mice. Moreover, Bmi-1-knockdown neuroblastoma xenografts were characterized by a significant increase in the amount of Schwannian stroma, a histological feature associated with clinically favorable neuroblastomas. These findings suggest a crucial role for Bmi-1 in neuroblastoma pathogenesis and provide insights into the molecular basis of neuroblastoma heterogeneity.
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U2 - 10.2353/ajpath.2007.060754
DO - 10.2353/ajpath.2007.060754
M3 - Article
C2 - 17392175
AN - SCOPUS:34247891673
SN - 0002-9440
VL - 170
SP - 1370
EP - 1378
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -