Sphingosine kinase 1 mediates head & neck squamous cell carcinoma invasion through sphingosine 1-phosphate receptor 1

Cancer Cell International

Toshihiko Kawamori²  Yoshiko Shimizu¹  Hideki Furuya¹  Paulette M Tamashiro³ 

[1] Clinical and Translational Research Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu 96813, HI, USA;Department of Pathology, Ichinomiya Nishi Hospital, 1 Hira, Kaimei, Ichinomiya Pref., 494-0001, Aichi, Japan;Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu 96813, HI, USA

关键词: SCC-25 cells;    IL-6;    Sphingosine 1-phosphate receptor 1;    Sphingosine 1-phosphate;    STAT3;    EGFR;    HNSCC;    Invasion;    Sphingosine kinase1;   

Others  :  1121666
DOI  :  10.1186/s12935-014-0076-x

 received in 2014-04-25, accepted in 2014-07-24,  发布年份 2014

【 摘 要 】

Background

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive loco-regional invasion. Sphingosine kinase1 (SphK1), an enzyme in sphingolipid metabolism, is emerging as a key player in HNSCC pathology. The observation that SphK1 is overexpressed in all HNSCC stages and is associated with depth of tumor invasion, metastasis and clinical failure underscores the importance of SphK1 in HNSCC pathology. Still, the mechanisms underlying SphK1 regulation of invasion have not been delineated. Therefore, we sought to mechanistically describe how SphK1 regulates invasion in HNSCC.

Methods

Invasion assays were used to measure invasive ability of SphK1 overexpressing human tongue squamous cell carcinoma (SCC-25 cells). Western blotting, quantitative qPCR, ELISA and zymography were used to measure the effect of SphK1 and sphingosine 1-phoshate receptor 1 (S1P₁) on invasion measures, MMP-2/9, E-cadherin, EGFR, IL-6/STAT3, in SCC-25 cells.

Results

SphK1 expression is elevated in cells with an invasive phenotype as compared to non-invasive phenotype. We show SphK1 overexpression increased EGF-induced EGFR/ERK and AKT activity, increased matrix metalloproteinase (MMP)-2/9 mRNA and reduced E-cadherin. SphK1 overexpression also increased IL-6 concentration and EGF-induced STAT3 phosphorylation, exemplifying that SphK1 modulates IL-6/STAT3 signaling. Notably, we show that S1P₁ knockdown reduced IL-6/STAT3 signaling, representing another pathway by which SphK1/S1P regulates invasion.

Conclusions

Taken together, our data suggest that SphK1 sits at the hub of multiple key signaling cascades, all which have been implicated in the regulation of invasiveness, making SphK1 an attractive target for the development of HNSCC therapies.

【 授权许可】

   
2014 Tamashiro et al.; licensee Springer

【 图 表 】

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