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

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

doi:10.18632/oncotarget.4543

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.

Highlights

Colorectal cancer (CRC) is one of the leading causes of cancer-related human morbidity and mortality worldwide [1]
Our findings reveal an essential role of the physiologic level of 5-HT1D receptor (5-HT1DR) in pulmonary metastasis of colorectal cancer
We demonstrated that inhibition of 5-HT1DR has potent anti-metastatic effect via Wnt signaling pathway

Summary

INTRODUCTION

Colorectal cancer (CRC) is one of the leading causes of cancer-related human morbidity and mortality worldwide [1]. The molecular mechanisms underlying CRC metastasis are not quite clear to date. It has been found that the activation of Wnt signaling in colorectal cancer correlates with more invasive tumor growth, a higher susceptibility of disease recurrence after surgery, and a lower survival rate [8]. The underlying molecular mechanism of Wnt signaling is not clear. A report has shown that 5-HT1B receptors on osteoblasts inhibit cell proliferation by activating PKA and CREB in Wnt signaling [9]. We first clarified the molecular mechanism by which 5-HT1D receptor (5-HT1DR) inhibits www.impactjournals.com/oncotarget. We demonstrated that inhibition of 5-HT1DR has potent anti-metastatic effect via Wnt signaling pathway. Our results provided the Wnt targeted mechanism to better understand CRC metastasis

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS