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YBX1 Promotes Drug Resistance in Hepatocellular Carcinoma and Serves as a Potential Therapeutic Target
Manish Tripathi1, Veerababu Nagati1, Dennis Kwabiah1
1The University of Texas Rio Grande Valley.
Abstract:
Drug resistance has emerged as a significant factor contributing to the dismal prognosis of patients with hepatocellular carcinoma (HCC). Since tyrosine kinase Inhibitors (TKIs) are the standard first-line therapy for advanced HCC, however, its effectiveness is significantly hindered by the development of drug resistance, the mechanisms of which are still not fully understood. This study aims to investigate the potential role of the transcription factor YBX1 in mediating drug resistance and to validate it as a potential therapeutic target in HCC. We identified increased YBX1 levels in human HCC patient cohorts and found that it is associated with tumor aggressiveness, metastasis, and poor survival, and is a key transcription factor contributing to drug resistance. Our results show that YBX1 overexpression confers sorafenib resistance in HCC. Elevating YBX1 levels in HCC cell lines increased cell survival, viability, and sorafenib IC50 values, as well as tumorigenic features and drug resistance markers. Conversely, siRNA-mediated knockdown of YBX1 reduced these effects. Sorafenib-resistant cells exhibited increased YBX1 and resistance markers. Inhibiting YBX1 significantly decreased the viability of resistant cells. In vivo studies demonstrated that inhibiting YBX1 with the small-molecule SU056 reduces tumor size. Thus, YBX1 is a promising target for extending drug resistance in HCC.
Insights
Y-box binding protein 1 (YBX1) drives drug resistance in hepatocellular carcinoma (HCC). Inhibiting YBX1 with SU056 shows promise in overcoming sorafenib resistance and reducing tumor size in HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Drug resistance significantly worsens outcomes for hepatocellular carcinoma (HCC) patients.
- Tyrosine kinase inhibitors (TKIs) are first-line HCC therapy but face resistance.
- Mechanisms underlying TKI resistance in HCC remain incompletely understood.
Purpose of the Study:
- To investigate the role of transcription factor Y-box binding protein 1 (YBX1) in mediating HCC drug resistance.
- To validate YBX1 as a potential therapeutic target for overcoming drug resistance in HCC.
Main Methods:
- Analysis of YBX1 expression in human HCC patient cohorts.
- In vitro studies using HCC cell lines to assess the impact of YBX1 overexpression and knockdown on drug resistance.
- In vivo studies using small-molecule inhibitor SU056 to target YBX1 in HCC models.
Main Results:
- Increased YBX1 levels correlate with HCC aggressiveness, metastasis, and poor survival.
- YBX1 overexpression confers sorafenib resistance, enhancing cell survival and tumorigenic features.
- YBX1 knockdown or inhibition with SU056 reduces HCC cell viability and tumor growth in vivo.
Conclusions:
- Y-box binding protein 1 (YBX1) is a key transcription factor driving sorafenib resistance in hepatocellular carcinoma.
- Targeting YBX1 presents a promising therapeutic strategy to overcome drug resistance and improve HCC patient prognosis.
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