Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients.

PURPOSE: The present study was to investigate the clinical significance of sphingosine kinase 1 (SPHK1), an oncoenzyme, in the development and progression of gastric cancer. EXPERIMENTAL DESIGN: mRNA and protein levels of SPHK1 expression in normal gastric epithelial cells, gastric cancer cell lines, and paired gastric cancer lesions and the adjacent noncancerous tissues were examined using reverse transcription-PCR and Western blotting. Immunohistochemistry was employed to analyze SPHK1 expression in 175 clinicopathologically characterized gastric cancer cases. Statistical analyses were applied to derive prognostic and diagnostic associations. RESULTS: Levels of SPHK1 mRNA and protein were higher in gastric cancer cell lines than in normal gastric epithelial cells. SPHK1 protein level was up-regulated in gastric cancer lesions compared with that in the paired adjacent noncancerous tissues. Gastric cancer tissues from 115 of 175 (65.7%) patients revealed high level of SPHK1 protein expression in contrast to the undetectable or marginally detectable expression of SPHK1 in the adjacent noncancerous gastric tissues. Significantly different expression levels of SPHK1 were found in patients at different clinical stages (P=0.003), T classification (P=0.035), and M classification (P=0.020). Patients with higher SPHK1 expression had shorter overall survival time, whereas those with lower SPHK1 expression survived longer. Further multivariate analysis suggested that SPHK1 up-regulation was an independent prognostic indicator for the disease. CONCLUSIONS: SPHK1 protein could be a useful marker for the prognosis of gastric cancer. Further study on the potential use of SPHK1 as a therapeutic target is also warranted.

Downregulation of BMI-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells.

5-Fluorouracil (5-FU) is an important chemotherapeutic agent for nasopharyngeal carcinoma (NPC). However, drug resistance may occur after several cycles of 5-FU-based chemotherapy. The oncogene B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI-1) has been shown to be involved in the protection of cancer cells from apoptosis. In this study, 5-FU treatment could increase the percentage of apoptotic NPC cells among BMI-1/RNAi-transfected cells than that among cells transfected with the empty vector. The 50% inhibitory concentration (IC(50)) values of 5-FU were significantly decreased to a greater extent in the cells transfected with BMI-1/RNAi. Most importantly, the expression of phospho-AKT and the anti-apoptotic protein BCL-2 were downregulated in the cells in which BMI-1 expression was inhibited, whereas the apoptosis-inducer BAX was observed to be upregulated. Abrogation of AKT pathway by a PI3K inhibitor could not further increase the sensitivity to 5-FU in the cells with reduced BMI-1 expression. Taken together, BMI-1 depletion enhanced the chemosensitivity of NPC cells by inducing apoptosis; which is associated with inhibition of the PI3K/AKT pathway.

Upregulation of CENP-H in tongue cancer correlates with poor prognosis and progression.

BACKGROUND: Centromere protein H (CENP-H) is one of the fundamental components of the human active kinetochore. Recently, CENP-H was identified to be associated with tumorigenesis. This study was aimed to investigate the clinicopathologic significance of CENP-H in tongue cancer. METHODS: RT-PCR, real time RT-PCR and Western blot were used to examine the expression of CENP-H in tongue cancer cell lines and biopsies. CENP-H protein level in paraffin-embedded tongue cancer tissues were tested by immunohistochemical staining and undergone statistical analysis. CENP-H-knockdown stable cell line was established by infecting cells with a retroviral vector pSuper-retro-CENP-H-siRNA. The biological function of CENP-H was tested by MTT assay, colony formation assay, and Bromodeoxyuridine (BrdU) incorporation assay. RESULTS: CENP-H expression was higher in tongue cancer cell lines and cancer tissues (T) than that in normal cell and adjacent noncancerous tongue tissues (N), respectively. It was overexpressed in 55.95% (94/168) of the paraffin-embedded tongue cancer tissues, and there was a strong correlation between CENP-H expression and clinical stage, as well as T classification. CENP-H can predict the prognosis of tongue cancer patients especially those in early stage. Depletion of CENP-H can inhibit the proliferation of tongue cancer cells (Tca8113) and downregulate the expression of Survivin. CONCLUSION: These findings suggested that CENP-H involves in the development and progression of tongue cancer. CENP-H might be a valuable prognostic indicator for tongue cancer patients within early stage.