DEC2 expression is positively correlated with HIF-1 activation and the invasiveness of human osteosarcomas

Journal of Experimental & Clinical Cancer Research

Qingcheng Yang¹  Nianli Sang²  Chengqian Yin³  Yunsong Yang⁴  Nengbin He¹  Tu Hu¹ 

[1] Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No.600, Yishan Road, Shanghai 200233, China;Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA;Departments of Biology, Pathology & Laboratory Medicine, Drexel University CoAS, 3245 Chestnut St, PISB 417, Philadelphia 19104, PA, USA;Huazhong University of Science and Technology, Wuhan, China

关键词: Prognosis;    Metastasis;    HIF-1α;    SHARP1;    DEC2;    Osteosarcoma;   

Others  :  1145667
DOI  :  10.1186/s13046-015-0135-8

 received in 2015-01-15, accepted in 2015-02-12,  发布年份 2015

【 摘 要 】

Background

Osteosarcoma is the most common malignancy of bone. HIF-1 (hypoxia-inducible factor 1) activation is critical for the metabolic reprogramming and progression of solid tumors, and DEC2 (differentiated embryonic chondrocyte gene 2) has been recently reported to suppress HIF-1 in human breast and endometrial cancers. However, the roles of HIF-1 and DEC2 in human osteosarcomas remain unclear.

Methods

We evaluated the correlation of DEC2 and HIF-1 expression to the prognosis, and studied the roles of DEC2 and HIF-1 activation in the invasiveness of osteosarcoma. Multiple approaches including immunohistochemical staining of clinical osteosarcoma tissues, siRNA-based knockdown and other molecular biology techniques were used. Particularly, by using a repetitive trans-well culture-based in vitro evolution system, we selected a more invasive subpopulation (U2OS-M) of osteosarcoma cells from U2OS and used it as a model to study the roles of DEC2 and HIF-1 in the invasiveness of osteosarcoma.

Results

We found that the expression of DEC2 was positively correlated with HIF-1α levels, and HIF-1α expression positively correlated with poor prognosis in osteosarcomas. DEC2 knockdown in osteosarcoma cell lines (U2OS, MNNG and 143B) attenuated HIF-1α accumulation and impaired the up-regulation of HIF-1 target genes in response to hypoxia. Compared with the low invasive parental U2OS, U2OS-M showed higher levels of DEC2 expression which were confirmed at both mRNA and protein levels. Importantly, we found that the increased DEC2 expression resulted in a more rapid accumulation of HIF-1α in U2OS-M cells in response to hypoxia. Finally, we found that HIF-1 activation is sufficient to upregulate DEC2 expression in osteosarcoma cells.

Conclusion

Taken together, whereas DEC2 was found to promote HIF-1α degradation in other types of tumors, our data indicate that DEC2 facilitates HIF-1α stabilization and promotes HIF-1 activation in osteosarcoma. This implies that DEC2 may contribute to the progression and metastasis of human osteosarcoma by sensitizing tumor cells to hypoxia. On the other hand, HIF-1 activation may contribute to the expression of DEC2 in osteosarcoma. This is the first demonstration of a novel DEC2-HIF-1 vicious cycle in osteosarcoma and a tumor-type specific role for DEC2.

【 授权许可】

   
2015 Hu et al.; licensee BioMed Central.

【 图 表 】

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