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FBW7 increases chemosensitivity in hepatocellular carcinoma cells through suppression of epithelial-mesenchymal
1Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine; Key Laboratory of Multi-Organ Transplantation of Ministry of Public Health, Hangzhou 310003, China. zyzss@zju.edu.cn.
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 FBW7 in 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 FBW7 in Huh-7 and Hep3B cells induced the resistance to doxorubicin and enhanced cell invasion, whereas overexpression of FBW7 in SNU-449 cells restored the sensitivity to doxorubicin and significantly 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.
Insights
The tumor suppressor FBW7 (F-box and WD repeat domain-containing 7) impacts hepatocellular carcinoma (HCC) cell sensitivity to doxorubicin and invasion. Modulating FBW7 levels can alter doxorubicin resistance and epithelial-mesenchymal transition (EMT) in HCC.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- FBW7 acts as a tumor suppressor regulating key proteins in cell division, growth, and differentiation.
- Its role in hepatocellular carcinoma (HCC) chemosensitivity and epithelial-mesenchymal transition (EMT) requires further investigation.
Purpose of the Study:
- To evaluate the role of FBW7 in HCC chemosensitivity and EMT.
- To investigate the underlying mechanisms of FBW7's function in HCC.
Main Methods:
- Utilized human HCC cell lines (Hep3B, Huh-7, SNU-449).
- Assessed cell viability, FBW7 expression (mRNA and protein), EMT markers (vimentin, E-cadherin), and cell invasion.
- Manipulated FBW7 levels using plasmid or siRNA to study its effects on chemosensitivity.
Main Results:
- FBW7 expression levels correlated with doxorubicin sensitivity and invasive capacity in HCC cell lines.
- High FBW7 expression was linked to increased doxorubicin sensitivity and reduced invasion.
- Doxorubicin treatment induced EMT, and FBW7 modulated this transition.
Conclusions:
- FBW7 expression level significantly impacts HCC cell resistance to doxorubicin and invasion.
- FBW7 plays a crucial role in regulating EMT in HCC.
- FBW7 represents a potential therapeutic target for HCC chemotherapy via EMT regulation.
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