tailieunhanh - Báo cáo khoa học: Hypoxia-inducible factor-1a blocks differentiation of malignant gliomas

Aberrant differentiation is a characteristic feature of neoplastic transforma-tion, while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. | Hypoxia-inducible factor-1 a blocks differentiation of malignant gliomas Huimin Lu1 z Yan Li1 2 Minfeng Shu1 Jianjun Tang1 Yijun Huang1 Yuxi Zhou1 Yingjie Liang3 and Guangmei Yan1 1 Department of Pharmacology Zhongshan Schoolof Medicine Sun Yat-Sen University Guangzhou China 2 Department of Infectious Diseases Third Affiliated Hospitalof Sun Yat-Sen University Guangzhou China 3 Department of Pathology First Affiliated Hospitalof Sun Yat-Sen University Guangzhou China Keywords CREB-binding protein CBP p300 cobalt chloride differentiation HIF-1 a malignant gliomas Correspondence G. Yan Department of Pharmacology Zhongshan Schoolof Medicine Sun Yat-Sen University 74 Zhongshan Road II Guangzhou 510080 China Fax 86 20-87330578 Tel 86 20-87333258 E-mail ygm@ These authors contributed equally to this work Received 26 August 2009 revised 2 October 2009 accepted 14 October 2009 doi Aberrant differentiation is a characteristic feature of neoplastic transformation while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. Here we show that rat C6 and primary human malignant glioma cells can be induced to differentiate into astrocytes by the well-known adenylate cyclase activator forskolin. However hypoxia-inducible factor-1a expression stimulated by the hypoxia mimetics cobalt chloride or deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the hypoxia mimetics. Importantly knockdown of hypoxia inducible factor-1a by RNA interference restores the differentiation capabilities of the cells even in the presence of cobalt chloride whereas stabilization of hypoxiainducible factor-1a through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover targeting of HIF-1 using .