BACKGROUND/AIMS: Sphingosine kinase 1 (SphK1), which phosphorylates sphingosine to sphingosine-1-phosphate (S1P), is overexpressed in various types of cancers, and may act as an oncogene in tumorigenesis. However, little is known about the precise role of the SphK1/S1P pathway in human liver cancer, especially regarding the metastasis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The expression of SphK1 was detected by quantitative reverse-transcription PCR. In addition, transwell cell migration and invasion assay were carried out for functional analysis. Furthermore, the level of S1P was quantified by ELISA and Rac1/Cdc42 GTPase activation was assessed by western blot analysis. RESULTS: The levels of SphK1 mRNA are commonly up-regulated in HCC patients and human liver cancer cell migration and invasion can be promoted by the overexpression of SphK1. In addition, inhibition of SphK1 with either a SphK1 inhibitor or siRNA reduced human liver cancer cell migration and invasion. Furthermore, overexpression of SphK1 increased S1P levels, and the exogenous addition of S1P increased liver cell migration and invasion through the EDG1 receptor. DISCUSSION AND CONCLUSION: The results from this study provide strong evidence of a role for the SphK1/S1P/EDG1 pathway in liver metastasis, thus making it an attractive therapeutic target for the development of new anti-HCC drugs.
BACKGROUND/AIMS: Sphingosine kinase 1 (SphK1), which phosphorylates sphingosine to sphingosine-1-phosphate (S1P), is overexpressed in various types of cancers, and may act as an oncogene in tumorigenesis. However, little is known about the precise role of the SphK1/S1P pathway in humanliver cancer, especially regarding the metastasis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The expression of SphK1 was detected by quantitative reverse-transcription PCR. In addition, transwell cell migration and invasion assay were carried out for functional analysis. Furthermore, the level of S1P was quantified by ELISA and Rac1/Cdc42 GTPase activation was assessed by western blot analysis. RESULTS: The levels of SphK1 mRNA are commonly up-regulated in HCC patients and humanliver cancer cell migration and invasion can be promoted by the overexpression of SphK1. In addition, inhibition of SphK1 with either a SphK1 inhibitor or siRNA reduced humanliver cancer cell migration and invasion. Furthermore, overexpression of SphK1 increased S1P levels, and the exogenous addition of S1P increased liver cell migration and invasion through the EDG1 receptor. DISCUSSION AND CONCLUSION: The results from this study provide strong evidence of a role for the SphK1/S1P/EDG1 pathway in liver metastasis, thus making it an attractive therapeutic target for the development of new anti-HCC drugs.
Authors: Thiago M de Assuncao; Gwen Lomberk; Sheng Cao; Usman Yaqoob; Angela Mathison; Douglas A Simonetto; Robert C Huebert; Raul A Urrutia; Vijay H Shah Journal: J Biol Chem Date: 2014-04-23 Impact factor: 5.157
Authors: K Alexa Orr Gandy; Mohamad Adada; Daniel Canals; Brittany Carroll; Patrick Roddy; Yusuf A Hannun; Lina M Obeid Journal: FASEB J Date: 2013-04-29 Impact factor: 5.191
Authors: Marcela Vettorazzi; Emilio Angelina; Santiago Lima; Tomas Gonec; Jan Otevrel; Pavlina Marvanova; Tereza Padrtova; Petr Mokry; Pavel Bobal; Lina M Acosta; Alirio Palma; Justo Cobo; Janette Bobalova; Jozef Csollei; Ivan Malik; Sergio Alvarez; Sarah Spiegel; Josef Jampilek; Ricardo D Enriz Journal: Eur J Med Chem Date: 2017-08-10 Impact factor: 6.514
Authors: Gabriela Schneider; Ewa Bryndza; Ahmed Abdel-Latif; Janina Ratajczak; Magdalena Maj; Maciej Tarnowski; Yuri M Klyachkin; Peter Houghton; Andrew J Morris; Axel Vater; Sven Klussmann; Magdalena Kucia; Mariusz Z Ratajczak Journal: Mol Cancer Res Date: 2013-04-24 Impact factor: 5.852