HIF-1α activates hypoxia-induced BCL-9 expression in human colorectal cancer cells
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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
Jianru Xiao, email: email@example.com
Wangjun Yan, email: firstname.lastname@example.org
Wang Zhou, email: email@example.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
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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