Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells
Yeonghoon Son1,2, Na-Rae Shin1, Sung-Ho Kim3
1Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
Abstract:
Despite liver cancer being the second-leading cause of cancer-related death worldwide, few systemic drugs have been approved. Sorafenib, the first FDA-approved systemic drug for unresectable hepatocellular carcinoma (HCC), is limited by resistance. However, the precise mechanisms underlying this phenomenon are unknown. Since fibrinogen-like 1 (FGL1) is involved in HCC progression and upregulated after anticancer therapy, we investigated its role in regulating sorafenib resistance in HCC. FGL1 expression was assessed in six HCC cell lines (HepG2, Huh7, Hep3B, SNU387, SNU449, and SNU475) using western blotting. Correlations between FGL1 expression and sorafenib resistance were examined by cell viability, colony formation, and flow cytometry assays. FGL1 was knocked-down to confirm its effects on sorafenib resistance. FGL1 expression was higher in HepG2, Huh7, and Hep3B cells than in SNU387, SNU449, and SNU475 cells; high FGL1-expressing HCC cells showed a lower IC50 and higher sensitivity to sorafenib. In Huh7 and Hep3B cells, FGL1 knockdown significantly increased colony formation by 61% (p = 0.0013) and 99% (p = 0.0002), respectively, compared to that in controls and abolished sorafenib-induced suppression of colony formation, possibly by modulating ERK and autophagy signals. Our findings demonstrate that sorafenib resistance mediated by FGL1 in HCC cells, suggesting FGL1 as a potential sorafenib-resistance biomarker and target for HCC therapy.
Insights
Fibrinogen-like 1 (FGL1) promotes sorafenib resistance in hepatocellular carcinoma (HCC). Targeting FGL1 may improve treatment efficacy for liver cancer patients resistant to sorafenib therapy.
Area of Science:
- Oncology
- Hepatology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with limited systemic treatment options.
- Sorafenib, a first-line systemic therapy for unresectable HCC, faces challenges due to acquired drug resistance.
- The mechanisms driving sorafenib resistance in HCC remain incompletely understood.
Purpose of the Study:
- To investigate the role of fibrinogen-like 1 (FGL1) in mediating sorafenib resistance in hepatocellular carcinoma (HCC).
- To assess FGL1 expression levels in HCC cell lines and correlate them with sorafenib sensitivity.
- To explore FGL1's potential as a biomarker and therapeutic target for overcoming sorafenib resistance in HCC.
Main Methods:
- Western blotting was used to determine FGL1 expression in six HCC cell lines.
- Cell viability, colony formation, and flow cytometry assays were performed to assess sorafenib resistance.
- FGL1 was knocked down to evaluate its direct impact on sorafenib sensitivity and cellular signaling pathways (ERK, autophagy).
Main Results:
- Higher FGL1 expression was observed in HepG2, Huh7, and Hep3B cell lines compared to SNU387, SNU449, and SNU475.
- HCC cells with high FGL1 expression exhibited increased sensitivity to sorafenib (lower IC50).
- FGL1 knockdown in Huh7 and Hep3B cells significantly increased colony formation and abolished sorafenib's inhibitory effect, potentially via ERK and autophagy modulation.
Conclusions:
- Fibrinogen-like 1 (FGL1) plays a significant role in mediating sorafenib resistance in hepatocellular carcinoma (HCC).
- Elevated FGL1 expression is associated with increased sensitivity to sorafenib in HCC cells.
- FGL1 represents a potential predictive biomarker for sorafenib resistance and a promising therapeutic target for enhancing HCC treatment outcomes.
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