Sphingosine kinase 1 expression enhances colon tumor growth

Hideki Furuya,Paulette M Tamashiro,Yoshiko Shimizu,Owen T M Chan,Jacek Bielawski,Kayoko Iino,Toshihiko Kawamori,Ian Pagano

doi:10.1186/s12967-017-1220-x

Abstract

BackgroundAccumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate pathway plays a pivotal role in colon carcinogenesis.MethodsTo further support the evidence, we investigated the effects of SphK1 using three separate animal models: SphK1 knockout mice, SphK1 overexpressing transgenic mice, and SphK1 overexpression in human colon cancer xenografts. Using azoxymethane (AOM, colon carcinogen), we analyzed colon tumor development in SphK1 KO and SphK1 overexpression in intestinal epithelial cells regulated by a tet-on system. Then, we analyzed subcutaneous tumor growth using xenografts of HT-29 human colon cancer cell. Finally, immunohistochemical analyses for SphK1 and COX-2 were performed on human colon cancer tissue microarray.ResultsSphK1 KO mice, compared to wild-type mice, demonstrated a significant inhibition in colon cancer development induced by AOM (58.6% vs. 96.4%, respectively, P < 0.005). Tumor multiplicity (1.00 vs. 1.64 per colon, respectively, P < 0.05) and tumor volume (14.82 mm3 vs. 29.10 mm3, P < 0.05) were both significantly reduced in SphK1 KO mice compared to wild-type mice. Next, SphK1 overexpression in HT-29 enhanced tumor growth as compared to GFP control in nude mice (229.5 mm3 vs. 90.9 mm3, respectively, P < 0.05). Furthermore, overexpression of SphK1 in intestinal epithelial cells significantly enhances AOM-induced colon tumor formation (P < 0.05). Lastly, SphK1 and COX-2 intensity tended to reduce overall survival of late stage colon cancer patients.ConclusionsSphK1 expression regulates the early stage of colon carcinogenesis and tumor growth, thus inhibition of SphK1 may be an effective strategy for colon cancer chemoprevention.

Highlights

Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate pathway plays a pivotal role in colon carcinogenesis
SphK1 KO mice significantly reduce AOM‐induced colon carcinogenesis First, we set out to determine if SphK1 deficiency inhibits AOM-induced colon carcinogenesis
We found that 27 WT mice developed colon tumors (96%, 27/28), including adenomas in 14 mice (50%, 14/28) and adenocarcinomas in 21 mice (75%, 21/28); whereas, only 17 SphK1 KO mice developed colon tumors (59%, P < 0.001 vs. WT mice), including adenomas in 7 mice (24%, P < 0.05 vs. WT mice) and adenocarcinomas in 14 mice (48%, P < 0.05 vs. WT mice) (Fig. 1a)

Summary

Introduction

Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate pathway plays a pivotal role in colon carcinogenesis. Despite aggressive screening guidelines for early detection and detailed knowledge of several critical events underlying the pathogenesis of cancer, colorectal cancer continues to be a major health concern in developed countries. Sphingolipids, especially ceramide, sphingosine, ceramide-1-phosphate and sphingosine-1-phosphate (S1P), play key roles as regulatory molecules in cancer development [2]. Sphingosine kinase (SphK) phosphorylates sphingosine to form S1P and is a critical regulator of sphingolipid-mediated functions. An inducible SphK1 is activated by numerous growth factors and cytokines, and recent studies have revealed that the SphK1/S1P pathway regulates the COX-2/ prostaglandin E2 (PGE2) pathway [4,5,6,7,8]. SphK1 knockout (KO) mice demonstrated a lower incidence of colon cancer development in an inflammation-related

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