8877

SPHK1

sphingosine kinase 1;SPHK1;sphingosine kinase 1

SK 1|SPK 1

17q25.2

protein-coding

Sphingosine-1-phosphate (S1P) is a potent lysolipid involved in a variety of biological responses important for cancer progression. Therefore, we investigated the role of sphingosine kinase type 1 (SphK1), the enzyme that makes S1P, in the motility, growth, and chemoresistance of MCF-7 breast cancer cells. Epidermal growth factor (EGF), an important growth factor for breast cancer progression, activated and translocated SphK1 to plasma membrane. SphK1 was required for EGF-directed motility. Downregulation of SphK1 in MCF-7 cells reduced EGF- and serum-stimulated growth and enhanced sensitivity to doxorubicin, a potent chemotherapeutic agent. These results suggest that SphK1 may be critical for growth, metastasis and chemoresistance of human breast cancers.

BACKGROUND: Treatment failure for esophageal carcinoma is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in esophageal carcinoma cells in vitro and in vivo. METHODS: A metastasis model using a Matrigel invasion clonal selection approach was employed to establish a highly invasive subline EC9706-P4 from the esophageal carcinoma cell (ESCC) line EC9706. The differentially expressed genes of the subline and the parental cells determined by gene microarrays were further analyzed by RT-PCR and Western blotting. RESULTS: We identified sphingosine kinase 1 (SPHK1) as an invasion and metastasis-related gene of esophageal cancer. SPHK1 was overexpressed in the EC9706-P4 subline with high invasive capacity. Among six ESCC lines tested, KYSE2 and KYSE30 cells showed the highest SPHK1 mRNA and protein expressions as well as the most invasive phenotype. By Western blotting, in 7/12 cases (58%), SPHK1 expression was higher in esophageal carcinomas than in the companion normal tissue. In 23/30 cases (76%), SPHK1 protein expression was upregulated in the tumors compared to matched normal tissue by immunohistochemistry (IHC). Esophageal carcinoma tissue microarray analysis indicated that SPHK1 expression correlated with the depth of tumor invasion (P < 0.0001) and lymph node metastasis (P = 0.016). By Kaplan-Meier analysis, strong SPHK1 expression was significantly associated with clinical failure (P < 0.01), suggesting the involvement of SPHK1 in aggressiveness of human esophageal carcinoma. SPHK1 overexpression significantly increased the invasiveness of EC9706 cells in vitro and also increased EC9706 cell growth and spontaneous metastasis in vivo, promoting significant increases in tumor growth, tumor burden and spontaneous lung metastasis in nude mice. SPHK1 expression significantly correlated with the expression of many EGFR pathway genes associated with invasion of cancer cells. SPHK1 protein expression also significantly correlated with the phosphorylation of EGFR. CONCLUSION: In summary, our data implicate SPHK1 in the metastasis of esophageal cancer. Our study also identified downstream mediators of SPHK1 in esophageal cancer cells that may mediate enhanced malignant behavior, and several of these mediators may be useful as therapeutic targets.

OBJECTIVE: To explore the clinical significance of sphingosine kinase 1 (SPHK1) in the invasion, metastasis and prognosis of gastric cancer. METHODS: Immunohistochemistry was employed to analyze the expression of SPHK1 in 206 clinicopathologically characterized gastric cancer cases from January 2001 to December 2005 at Zhejiang Provincial Peoples Hospital. RESULTS: SPHK1 protein was detected in 3 (7.5%) of 40 human non-tumor mucosa. All samples expressed the protein at a low level. SPHK1 protein was detected in 181 (87.9%) of 206 human gastric cancer cases. An elevated expression of SPHK1 protein was detected in 126 (61.2%) tumors. And SPHK1 protein was up-regulated in gastric cancer lesions compared with adjacent noncancerous tissues (P = 0.001). The expression of SPHK1 was correlated with the depth of invasion, lymph node metastasis, distant metastasis and TNM stage (P = 0.039, 0.003, 0.020, 0.003). In stages I-II and III, the 5-year survival rate of the patients with a high expression of SPHK1 was significantly lower than those with a low expression (53.6% (15/28) vs 68.6% (24/35), 7.8% (6/77) vs 30.8% (12/39), P = 0.009, 0.006). In stage IV, the expression of SPHK1 was not correlated with the 5-year survival rate (P > 0.05). Further multivariate analysis suggested that lymph node metastasis, distant metastasis, TNM stage and the up-regulation of SPHK1 were independent prognostic indicators for gastric cancer. CONCLUSION: The expression of SPHK1 in gastric cancer is significantly associated with lymph node metastasis, distant metastasis and a poor prognosis. SPHK1 may become a useful marker of predicting tumor progression and prognosis.