Clinical Significance of Sphingosine Kinase-1 Expression in Human Astrocytomas Progression and Overall Patient Survival

Abstract

Purpose: To characterize the expression of sphingosine kinase-1 (SPHK1) in human astrocytomas and to investigate the association between SPHK1 expression and progression of astrocytomas. Experimental Design: The expression of SPHK1in normal human astrocytes, astrocytoma cell lines, and four pairs of matched astrocytoma tissues and their adjacent normal brain tissues were detected by quantitative reverse transcription-PCR and Western blot. In addition, SPHK1protein expression was examined in 243 cases of histologically characterized astrocytomas by immunohistochemistry. Statistical analyses were applied to test for prognostic and diagnostic associations. Results: SPHK1in astrocytoma cell lines was elevated at both mRNA and protein levels, and the SPHK1mRNA and protein were significantly up-regulatedby up to 6.8-and 40-fold, respectively, in primary astrocytomas compared with those in the adjacent noncancerous brain tissues. Immunohistochemical analysis showed that 100 of 243 (41.2%) paraffin-embedded archival astrocytoma biopsies exhibited high expression of SPHK1. Statistical analysis suggested that the up-regulation of SPHK1was significantly correlated with the histologic grade of astrocytoma (P = 0.000) and that patients with high SPHK1level exhibited shorter survival time (P < 0.001). Multivariate analysis revealed that SPHK1up-regulation might be an independent prognostic indicator for the survival of patients with astrocytoma. Conclusions: SPHK1might represent a novel and useful prognostic marker for astrocytoma and play a role during the development and progression of the disease.

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

“…SPHK1 overexpression results in oncogenic transformation of normal fibroblasts (15,16), whereas the absence of SPHK1 in mice protects against the development of colon adenomas (17,18). Up-regulation of SPHK1 has been observed in many different tumors, including breast (19,20), lung (21,22), colon (17,18), and glioma (23,24), and increased SPHK1 expression has been associated with a poor survival outcome in GBM (24) as well as breast (20) and lung cancer (22). This has made SPHK1 a target of interest in cancer for biotechnology and pharmaceutical companies.…”

Expressions of Sphingosine-1-phosphate (S1P) Receptors, Sphingosine Kinases in Malignant Bone and Soft Tissue Tumors, and The role of Sphingosine Kinase-1 in Growth of MFH Cell Lines

“…S1P is generated by phosphorylation of sphingosine catalyzed by SPHK1. Previous studies have confirmed that overexpression of SPHK1 and increased S1P production promotes cell growth [29][30][31]. SPHK1 is frequently overexpressed in a varietly of solid tumors, suggesting a potential oncogenic function and an important role in human tumorigenesis.…”

Circulating sphingosine-1-phosphate inversely correlates with chemotherapy-induced weight gain during early breast cancer

“…Similarly, separating our patients by S1P/weight ratio demonstrated two distinct groups of patients, with low (<10, 3.80-8. 26) and high (>10, 10.13-18.75) S1P/weight ratios who had 2.015±0.81 kg vs -0.14±0.77 kg weight change respectively, p=0.049 (Fig. 1 B).…”

“…SphK1 has been found to be a tumor-associated enzyme: high levels of SphK1 expression have been shown in various human tumor tissues such as brain, breast, colon, lung, ovary, stomach, uterus, kidney, rectum and small intestine [22,23]. High levels of SphK1 expression and activity is associated with a poor prognosis in breast cancer [24], glioblastoma multiforme [25], astrocytoma [26] and gastric cancer [27].…”