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RNA interference-mediated downregulation of hypoxia-inducible factor-1 inhibits angiogenesis and survival of oral squamous cell carcinoma in vitro and in vivo

Zhou, Haoa; Fei, Weib; Bai, Yuna; Zhu, Songsonga; Luo, Ena; Chen, Kaic; Hu, Jinga

European Journal of Cancer Prevention: May 2012 - Volume 21 - Issue 3 - p 289–299
doi: 10.1097/CEJ.0b013e32834dbbda
Research Papers: Oral cancer

Hypoxia-inducible factor-α (HIF-1α) is the key transcription factor involved in the adaptive response to hypoxia. It has been established that HIF-1α is overexpressed in various human cancers, including oral squamous cell carcinoma (OSCC), and orchestrates a wide spectrum of many key cancer molecular pathways involved in diverse tumor progression. In this study, RNA interference (RNAi) was introduced to downregulate the expression of HIF-1α in OSCC in vitro and in vivo. The mRNA and protein expression levels of HIF-1α and vascular epidermal growth factor were detected by quantitative real-time reverse transcription-PCR, western blot, and immunohistochemistry, and cell proliferation activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tumor growth, microvascular density, apoptosis, and the expression of proliferation-related gene Ki-67 in tumor xenografts were evaluated. Our data demonstrated that small interfering RNA targeting HIF-1α significantly inhibited the mRNA and protein expression levels of HIF-1α and vascular epidermal growth factor. In addition, marked suppression of tumor cell prolifeation and xenograft growth, significant microvascular density suppression, reduced expression of Ki-67, and increased cell apoptosis were observed. These findings suggest that RNAi targeting HIF-1α could effectively inhibit the progression of OSCC. Thus, it may be used as a potent and specific therapy for oral cancer, especially in inhibiting and preventing cancer cell angiogenesis and survival.

aDepartment of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, Sichuan University West China College of Stomatology

bDepartment of Oral and Maxillofacial Surgery, Sichuan Provincial People’s Hospital, Sichuan Provincial Academy of Medical Science, Chengdu

cDepartment of Stomatology Institute, Luzhou Medical College, Luzhou Sichuan, China

Correspondence to Dr Jing Hu, PhD, MD, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University. NO.14, Sec.3, Renminnan Road, Chengdu Sichuan 610041, People’s Republic of China Tel: +86 28 8550 2334; fax: +86 28 8558 2167; e-mail: dr_hujing@yahoo.com.cn; drhu@vip.sohu.com

Received June 9, 2011

Accepted September 20, 2011

© 2012 Lippincott Williams & Wilkins, Inc.