5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway

Hua Sui; Hanchen Xu; Qing Ji; Xuan Liu; Lihong Zhou; Haiyan Song; Xiqiu Zhou; Yangxian Xu; Zhesheng Chen; Jianfeng Cai; Guang Ji; Qi Li

doi:10.18632/oncotarget.4543

5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway

Oncotarget. 2015 Sep 22;6(28):25975-87. doi: 10.18632/oncotarget.4543.

Authors

Hua Sui¹, Hanchen Xu², Qing Ji¹, Xuan Liu¹, Lihong Zhou¹, Haiyan Song², Xiqiu Zhou², Yangxian Xu², Zhesheng Chen³, Jianfeng Cai⁴, Guang Ji², Qi Li¹

Affiliations

¹ Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
² Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Chinese Medicine, Shanghai 200032, China.
³ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
⁴ Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.

Abstract

Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT(1D) receptor (5-HT(1D)R) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT(1D)R-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT(1D)R antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT(1D)R played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT(1D)R in pulmonary metastasis of colorectal cancer.

Keywords: 5-hydroxytryptamine (5-HT) receptor; Wnt signaling pathway; colorectal cancer; intestinal epithelium cells; metastasis.

Publication types

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

MeSH terms

Animals
Axin Protein / genetics
Axin Protein / metabolism*
Blotting, Western
Cell Line, Tumor
Cell Movement / drug effects
Cell Movement / genetics
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Female
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Humans
Immunohistochemistry
Male
Matrix Metalloproteinase 7 / genetics
Matrix Metalloproteinase 7 / metabolism*
Mice, Nude
Middle Aged
Neoplasm Metastasis
Oxadiazoles / pharmacology
Piperazines / pharmacology
Receptor, Serotonin, 5-HT1D / genetics
Receptor, Serotonin, 5-HT1D / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Serotonin Antagonists / pharmacology
Signal Transduction / drug effects
Signal Transduction / genetics
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays
beta Catenin / genetics
beta Catenin / metabolism*

Substances

AXIN1 protein, human
Axin Protein
Oxadiazoles
Piperazines
Receptor, Serotonin, 5-HT1D
Serotonin Antagonists
beta Catenin
GR 127935
MMP7 protein, human
Matrix Metalloproteinase 7