Myocyte enhancer factor 2D promotes colorectal cancer angiogenesis downstream of hypoxia-inducible factor 1α

Junyu Xiang; Hui Sun; Li Su; Limei Liu; Juanjuan Shan; Junjie Shen; Zhi Yang; Jun Chen; Xing Zhong; Matías A Ávila; Xiaochu Yan; Chungang Liu; Cheng Qian

doi:10.1016/j.canlet.2017.04.037

Myocyte enhancer factor 2D promotes colorectal cancer angiogenesis downstream of hypoxia-inducible factor 1α

Cancer Lett. 2017 Aug 1:400:117-126. doi: 10.1016/j.canlet.2017.04.037. Epub 2017 May 4.

Authors

Junyu Xiang¹, Hui Sun², Li Su³, Limei Liu², Juanjuan Shan¹, Junjie Shen¹, Zhi Yang¹, Jun Chen¹, Xing Zhong¹, Matías A Ávila⁴, Xiaochu Yan⁵, Chungang Liu⁶, Cheng Qian⁷

Affiliations

¹ Center of Biotherapy, Southwest Hospital, Third Military Medical University, Chongqing, China.
² Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
³ Department of Oncology, Chinese Traditional Medicine Hospital, Chongqing, China.
⁴ Center of Investigation for Applied Medcine, University of Navarra, Pamplona, Spain.
⁵ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: yxcwq@163.com.
⁶ Center of Biotherapy, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: liuchungang@zju.edu.cn.
⁷ Center of Biotherapy, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: cqian8634@gmail.com.

PMID: 28478181
DOI: 10.1016/j.canlet.2017.04.037

Abstract

Myocyte enhancer factor 2D (MEF2D) is involved in many aspects of cancer progression, including cell proliferation, invasion, and migration. However, little is known about the role of MEF2D in tumor angiogenesis. Using clinical specimens, colorectal cancer (CRC) cell lines and a mouse model in the present study, we found that MEF2D expression was positively correlated with CD31-positive microvascular density in CRC tissues. MEF2D promoted tumor angiogenesis in vitro and in vivo and induced the expression of proangiogenic cytokines in CRC cells. MEF2D was found to be a downstream effector of hypoxia-inducible factor (HIF)-1α in the induction of tumor angiogenesis. HIF-1α transactivates MEF2D expression by binding to the MEF2D gene promoter. These results demonstrate that the HIF-1α/MEF2D axis can serve as a therapeutic target for the treatment of CRC.

Keywords: Angiogenesis; Colorectal cancer; HIF-1α; MEF2D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Caco-2 Cells
Colorectal Neoplasms / blood supply
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Culture Media, Conditioned / metabolism
Cytokines / metabolism
Female
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
MEF2 Transcription Factors / genetics
MEF2 Transcription Factors / metabolism
Male
Mice, Inbred BALB C
Mice, Nude
Microvessels / metabolism
Microvessels / pathology
Middle Aged
Neovascularization, Pathologic*
Paracrine Communication
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
Prognosis
Promoter Regions, Genetic
RNA Interference
Signal Transduction
Time Factors
Transcriptional Activation
Transfection
Tumor Burden
Tumor Hypoxia
Tumor Microenvironment

Substances

Biomarkers, Tumor
Culture Media, Conditioned
Cytokines
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
MEF2 Transcription Factors
MEF2D protein, human
Platelet Endothelial Cell Adhesion Molecule-1