SEMA3F prevents metastasis of colorectal cancer by PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis

Zhi-hang Zhou; Jun Rao; Jing Yang; Feng Wu; Juan Tan; Sen-lin Xu; Yanqing Ding; Na Zhan; Xu-gang Hu; You-hong Cui; Xia Zhang; Weiguo Dong; Xin-dong Liu; Xiu-wu Bian

doi:10.1002/path.4541

SEMA3F prevents metastasis of colorectal cancer by PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis

J Pathol. 2015 Aug;236(4):467-78. doi: 10.1002/path.4541. Epub 2015 May 22.

Authors

Zhi-hang Zhou^{1

2}, Jun Rao^{1

2}, Jing Yang^{1

2}, Feng Wu^{1

2}, Juan Tan^{1

2}, Sen-lin Xu^{1

2}, Yanqing Ding³, Na Zhan⁴, Xu-gang Hu^{1

2}, You-hong Cui^{1

2}, Xia Zhang^{1

2}, Weiguo Dong⁴, Xin-dong Liu^{1

2}, Xiu-wu Bian^{1

2}

Affiliations

¹ Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
² Key Laboratory of Tumour Immunopathology of Ministry of Education of China, Third Military Medical University, Chongqing, People's Republic of China.
³ Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
⁴ Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.

PMID: 25866254
DOI: 10.1002/path.4541

Abstract

Semaphorin-3F (SEMA3F), an axonal repulsant in nerve development, has been shown to inhibit the progression of human colorectal cancer (CRC); however, the underlying mechanism remains elusive. In this study we found a negative correlation between the levels of SEMA3F and CXCR4 in CRC specimens from 85 patients, confirmed by bioinformatics analysis of gene expression in 229 CRC samples from the Cancer Genome Atlas. SEMA3F(high) /CXCR4(low) patients showed the lowest frequency of lymph node and distant metastasis and the longest survival. Mechanistically, SEMA3F inhibited the invasion and metastasis of CRC cells through PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis. Specifically, ASCL2 enhanced the invasion and metastasis of CRC cells in vitro and expression of ASCL2 correlated with distant metastasis, tumour size and poor overall survival in CRC patients. Treatment of CRC cells with the CXCR4 antagonist AMD3100 attenuated SEMA3F knockdown-induced invasion and metastasis of CRC cells in vitro and in vivo. Our study thus demonstrates that SEMA3F functions as a suppressor of CRC metastasis via down-regulating the ASCL2-CXCR4 axis.

Keywords: ASCL2; CXCR4; SEMA3F; colorectal cancer; metastasis.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Cell Movement* / drug effects
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / enzymology*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / mortality
Colorectal Neoplasms / pathology
Computational Biology
Female
Gene Expression Regulation, Neoplastic
Genomics
HCT116 Cells
Humans
Kaplan-Meier Estimate
Liver Neoplasms / drug therapy
Liver Neoplasms / enzymology*
Liver Neoplasms / genetics
Liver Neoplasms / mortality
Liver Neoplasms / secondary
Lymphatic Metastasis
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice, Nude
Middle Aged
Neoplasm Staging
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Phosphatidylinositol 3-Kinase / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism*
Receptors, CXCR4 / antagonists & inhibitors
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism*
Retrospective Studies
Signal Transduction* / drug effects
Time Factors
Transfection
Tumor Burden

Substances

ASCL2 protein, human
Antineoplastic Agents
Basic Helix-Loop-Helix Transcription Factors
CXCR4 protein, human
Membrane Proteins
Nerve Tissue Proteins
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Receptors, CXCR4
SEMA3F protein, human
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt