ABSTRACT
BACKGROUND: The ojective of the following study is to investigate the role of sphingosine kinase 1 (Sphk1) in the malignant transformation of breast epithelial cells and breast cancer progression and its mechanism. MATERIALS AND METHODS: Immunohistochemistry was performed to detect Sphk1 and E‑cadherin (E‑cad) in resected breast samples. Sphk1 was transfected in normal human breast epithelial cell line (MCF‑10A) by Lentivirus and silenced in breast cancer cell line (MCF‑7) using small interfering ribonucleic acid. The effect of tumor necrosis factor alpha (TNF‑α) and/or N, N‑dimethylsphingosine (DMS) on the Sphk1 and E‑cad expression, MCF‑10A cell proliferation and invasion was investigated. Real time‑polymerase chain reaction and western‑blot was used to detect messenger ribonucleic acid and protein. Cell counting kit‑8 and transwell were used to measure cell proliferation and invasion. RESULTS: Sphk1 was positive expression in 114 breast tumors (75.50%) but negative in fibroadenomas. The expression of E‑cad and Sphk1 were negatively correlated and E‑cad (−)/Sphk1 (+) carriers showed higher ratio of axillary lymph node metastasis than E‑cad (+)/Sphk1 (−) carriers. Overexpression of Sphk1 in MCF‑10A reduced E‑cad expression and improved cell proliferation and invasion, but knockdown of Sphk1 in MCF‑7 decreased cell proliferation and invasion. TNF‑α increased Sphk1 expression, enhanced the ability of Sphk1 in decreasing E‑cad expression, which could be blocked by DMS. TNF‑α promoted MCF‑10A cell proliferation and invasion.CONCLUSION: Sphk1 plays an important role in the malignant transformation of breast epithelial cells and modulates breast cancer metastasis through the regulation of E‑cad expression. TNF‑α can up‑regulate Sphk1 expression and reduce E‑cad expression through Sphk1, which can be blocked by DMS. TNF‑α/Sphk1/E‑cad pathway may be a newly discovered pathway and plays an important role in tumorigenesis and metastasis.