FBW7 increases chemosensitivity in hepatocellular carcinoma cells through suppression of epithelial-mesenchymal transition

• Published in: Hepatobiliary & pancreatic diseases international 2014-04, Vol.13 (2), p.184-191
• Main Authors: Yu, Jun, Zhang, Wu, Gao, Feng, Liu, Yuan-Xing, Chen, Zhi-Yun, Cheng, Long-Yu, Xie, Shang-Fen, Zheng, Shu-Sen
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - pharmacology; Cadherins - metabolism; carcinoma; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; doxorubicin; Doxorubicin - pharmacology; drug; drug resistance; Drug Resistance, Neoplasm; Endocrinology & Metabolism; epithelial-mesenchymal; Epithelial-Mesenchymal Transition; F-Box Proteins - genetics; F-Box Proteins - metabolism; F-Box-WD Repeat-Containing Protein 7; FBW7; Gastroenterology and Hepatology; Gene Expression Regulation, Neoplastic; hepatocellular; hepatocellular carcinoma; Humans; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mutation; Neoplasm Invasiveness; resistance; RNA Interference; Transfection; transition; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Vimentin - metabolism
• ISSN: 1499-3872
• DOI: 10.1016/S1499-3872(14)60029-1

BACKGROUND: FBW7 is a tumor suppressor which regulates a network of proteins with central roles in cell division, cell growth and differentiation. This study aimed to evaluate the role of FBW7in chemosensitivity and epithelial-mesenchymal transition (EMT) in different hepatocellular carcinoma (HCC) cell lines and to investigate the relevant underlying mechanisms.METHODS: Different human HCC cell lines (Hep3B, Huh-7,and SNU-449) were cultured. The cell viability was evaluated by cell counting kit-8, and FBW7 mRNA transcription and protein expression were quantitated by real-time PCR and Western blotting. Expressions of vimentin (mesenchymal biomarker)and E-cadherin (epithelial biomarker) were evaluated by Western blotting and immunocytochemistry. Cell invasion was assayed by Transwell migration, and FBW7 plasmid or siRNA was used to evaluate the effect of FBW7 overexpression or silencing on cell chemosensitivity.RESULTS: FBW7 expression affected tumor cell chemosensitivity to doxorubicin and tumor cell invasive capacity in different HCC cell lines. FBW7hi (high FBW7 expression) Hep3B and FBW7mi (median FBW7 expression) Huh-7 cells were more sensitive to doxorubicin and lower in invasive capacity than FBW7lo (low FBW7 expression) SNU-449 cells. Silencing of FBW7in Huh-7 and Hep3B cells induced the resistance to doxorubicin and enhanced cell invasion, whereas overexpression of FBW7in SNU-449 cells restored the sensitivity to doxorubicin andsignificantly reduced invasive capacity. Furthermore, doxorubicin induced EMT toward mesenchyme in HCC cells. Downregulation of FBW7 in Huh-7 and Hep3B cells or upregulation of FBW7 in SNU-449 cells altered the direction of EMT.CONCLUSIONS: The level of FBW7 expression impacted the tumor resistance to doxorubicin and the invasion capability of HCC cells. FBW7 therefore may be a potential target for the chemotherapy of HCC through the regulation of EMT.