Dan Cao1,2, Xinhua Song2,3, Li Che2, Xiaolei Li2,4, Maria G Pilo5, Gianpaolo Vidili5, Alberto Porcu5, Antonio Solinas6, Antonio Cigliano7, Giovanni M Pes5, Silvia Ribback7, Frank Dombrowski7, Xin Chen2, Lei Li8, Diego F Calvisi5. 1. Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 2. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. 3. Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China. 4. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. 5. Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy. 6. Department of Biomedical Sciences, University of Sassari, Sassari, Italy. 7. Institute of Pathology, University Medicine Greifswald, Greifswald, Germany. 8. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract
BACKGROUND & AIMS: Although it is well established that fatty acids (FA) are indispensable for the proliferation and survival of cancer cells in hepatocellular carcinoma (HCC), inhibition of Fatty Acid Synthase (FASN) cannot completely repress HCC cell growth in culture. Thus, we hypothesized that uptake of exogenous FA by cancer cells might play an important role in the development and progression of HCC. Lipoprotein lipase (LPL) is the enzyme that catalyses the hydrolysis of triglycerides into free fatty acids (FFA) and increases the cellular uptake of FA. METHODS: We used immunohistochemistry and quantitative reverse transcription real-time polymerase chain reaction to evaluate LPL expression in human and mouse HCC samples. Using lipoprotein-deficient medium as well as siRNAs against LPL and/or FASN, we investigated whether human HCC cells depend on both endogenous and exogenous fatty acids for survival in vitro. RESULTS: We found that LPL is upregulated in mouse and human HCC samples. High expression of LPL in human HCC samples is associated with poor prognosis. In HCC cell lines, silencing of FASN or LPL or culturing the cells in lipoprotein-deficient medium significantly decreased cell proliferation. Importantly, when FASN suppression was coupled to concomitant LPL depletion, the growth restraint of cell lines was further augmented. CONCLUSIONS: The present study strongly suggests that both de novo synthetized and exogenous FA play a major role along hepatocarcinogenesis. Thus, combined suppression of LPL and FASN might be highly beneficial for the treatment of human HCC.
BACKGROUND & AIMS: Although it is well established that fatty acids (FA) are indispensable for the proliferation and survival of cancer cells in hepatocellular carcinoma (HCC), inhibition of Fatty Acid Synthase (FASN) cannot completely repress HCC cell growth in culture. Thus, we hypothesized that uptake of exogenous FA by cancer cells might play an important role in the development and progression of HCC. Lipoprotein lipase (LPL) is the enzyme that catalyses the hydrolysis of triglycerides into free fatty acids (FFA) and increases the cellular uptake of FA. METHODS: We used immunohistochemistry and quantitative reverse transcription real-time polymerase chain reaction to evaluate LPL expression in human and mouseHCC samples. Using lipoprotein-deficient medium as well as siRNAs against LPL and/or FASN, we investigated whether humanHCC cells depend on both endogenous and exogenous fatty acids for survival in vitro. RESULTS: We found that LPL is upregulated in mouse and humanHCC samples. High expression of LPL in humanHCC samples is associated with poor prognosis. In HCC cell lines, silencing of FASN or LPL or culturing the cells in lipoprotein-deficient medium significantly decreased cell proliferation. Importantly, when FASN suppression was coupled to concomitant LPL depletion, the growth restraint of cell lines was further augmented. CONCLUSIONS: The present study strongly suggests that both de novo synthetized and exogenous FA play a major role along hepatocarcinogenesis. Thus, combined suppression of LPL and FASN might be highly beneficial for the treatment of humanHCC.
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