Oncotarget

Research Papers:

HIF-1α activates hypoxia-induced BCL-9 expression in human colorectal cancer cells

Zhen Tan, Quan Huang, Jia Zang, Shi-Feng Teng, Tian-Rui Chen, Hai-Feng Wei, Dian-Wen Song, Tie-Long Liu, Xing-Hai Yang, Chuan-Gang Fu, Zhi-Qian Hu, Wang Zhou, Wang-Jun Yan and Jian-Ru Xiao _

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Oncotarget. 2017; 8:25885-25896. https://doi.org/10.18632/oncotarget.8834

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Abstract

Zhen Tan1,3,*, Quan Huang1,*, Jia Zang2,*, Shi-Feng Teng2,*, Tian-Rui Chen1, Hai-feng Wei1, Dian-Wen Song1, Tie-Long Liu1, Xing-Hai Yang1, Chuan-Gang Fu3, Zhi-qian Hu2, Wang Zhou1, Wang-Jun Yan1, Jian-Ru Xiao1

1Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China

2Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China

3Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China

*These authors contributed equally to this work

Correspondence to:

Jianru Xiao, email: jianruxiao83@163.com

Wangjun Yan, email: spinetumor@163.com

Wang Zhou, email: brilliant212@163.com

Keywords: B-cell CLL/lymphoma 9 protein, hypoxia inducible factors-1α, hypoxia, colorectal cancer

Received: December 06, 2015     Accepted: March 28, 2016     Published: April 18, 2016

ABSTRACT

B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia-responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1α but not HIF-2α. Consistently, ectopic expression of HIF-1α but not HIF-2α transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1α but not HIF-2α by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1α expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1α, which could be an important underlying mechanism for increased BCL-9 expression in CRC.


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