Branched-chain amino acid deficiency stabilizes insulin-induced vascular endothelial growth factor mRNA in hepatocellular carcinoma cells
| Autor: | Tatsuki Ichikawa, Hisamitsu Miyaaki, Hidetaka Shibata, Naota Taura, Motohisa Akiyama, Masashi Ootani, Kazuhiko Arima, Satoshi Miuma, Kazuhiko Nakao, Toru Muraoka, Eisuke Ozawa, Shigeyuki Takeshita, Fuminao Takeshima, Toshihisa Matsuzaki |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Vascular Endothelial Growth Factor A
medicine.medical_specialty Carcinoma Hepatocellular Time Factors medicine.medical_treatment RNA Stability Branched-chain amino acid Enzyme-Linked Immunosorbent Assay Biology Biochemistry chemistry.chemical_compound Downregulation and upregulation Valine Internal medicine Hyperinsulinemia medicine Humans Insulin RNA Messenger RNA Processing Post-Transcriptional Molecular Biology PI3K/AKT/mTOR pathway TOR Serine-Threonine Kinases Liver Neoplasms Cell Biology Hep G2 Cells medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Culture Media Vascular endothelial growth factor Endocrinology chemistry Leucine Amino Acids Branched-Chain Half-Life |
| Zdroj: | Journal of cellular biochemistry. 113(10) |
| ISSN: | 1097-4644 |
| Popis: | Abnormal sugar metabolism is closely related to chronic liver diseases, including hepatocellular carcinoma (HCC). We previously reported that fasting hyperinsulinemia is a poor prognostic factor for HCC patients. A recent large-scale study has shown that long-term administration of branched chain amino acids (BCAA) reduces the risk of HCC development in obese cirrhotic patients who have been diagnosed with diabetes mellitus, although the mechanism by which it does so is unclear. In this study, we analyzed the expression of vascular endothelial growth factor (VEGF) in HepG2 cells under high-insulin culture conditions, and examined the effect of BCAA on VEGF expression. VEGF secretion was significantly increased by 200 nM of insulin under BCAA deficient conditions, but it was repressed by the addition of BCAA. BCAA activated the mTOR pathway and increase HIF-1α expression under high-insulin culture conditions, however quantitative PCR analysis showed that insulin-induced expression of VEGF mRNAs (VEGF121 and VEGF165) decreased 2 h after the addition of BCAA. The half-lives of both VEGF121 and 165 mRNAs were shortened in the presence of BCAA compared to the absence of BCAA. Therefore it is thought that BCAA regulate VEGF expression mainly at the post-transcriptional level. We also examined which of the Valine, Leucine, and Isoleucine components of BCAA were essential for VEGF mRNA degradation. All three BCAA components were required for acceleration of insulin-induced VEGF mRNA degradation. These results suggest that administration of BCAA may downregulate VEGF expression in patients who have hyperinsulinemia and are in the process of developing HCC. |
| Databáze: | OpenAIRE |
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