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Cancer and Immunology

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Cancer and Immunology

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Staff

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Cancer and Immunology

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Cancer and Immunology

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Cancer and Immunology

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Biomedical Science

Abstract

Background: Drug resistance is a leading cause of mortality in cancer, responsible for up to 90% of cancer-related deaths. Understanding the mechanisms behind drug resistance is crucial for enhancing the efficacy of cancer therapies. Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and a major contributor to liver cancer-related fatalities. While early-stage HCC can often be cured with surgical interventions like liver transplantation or hepatectomy, advanced stages are challenging due to drug resistance. Sorafenib, an FDA-approved multi-tyrosine kinase inhibitor for treatment of advanced HCC, has shown limited effectiveness in prolonging overall survival in advanced HCC patients. However, the mechanisms underlying sorafenib resistance in advanced HCC remain poorly understood. Our research group identified YBX1 as a pivotal transcription factor involved in regulating drug resistance in various cancers, including gastric and prostate cancers. This led us to investigate the potential role of YBX1 in sorafenib resistance in HCC

Methods: Analysis of HCC patient cohorts from The Cancer Genome Atlas (TCGA) revealed an elevated expression of YBX1 in tumors compared to normal tissues, correlating with disease progression, metastasis, and poorer survival rates. To delve deeper using in-vitro models, we developed sorafenib-resistant HCC cell lines in the lab and measured their IC50 against non-resistant parental cell lines using MTT assay. Additionally, we manipulated YBX1 expression levels through transfection experiments in parental HCC cell lines and assessed their IC50 values relative to control groups. RNA analyses were performed using RTPCR for the expression of YBX1 and associated drug resistant markers. Western blots were used to assess the protein expression of YBX1 in the cells.

Results: Our findings showed increased IC50 levels in sorafenib-resistant cell lines compared to their non-resistant counterparts. RNA analysis using RTPCR experiments further demonstrated upregulation of YBX1 and other drug resistance markers such as MDR1 in sorafenib-resistant cells. Overexpression of YBX1 through lentiviral transfection enhanced cell survival and viability, leading to higher IC50 values for sorafenib at 24 and 48-hour time points.

Conversely, siRNA mediated knockdown of YBX1 resulted in decreased cell survival, viability, IC50 values, and reduced expression of YBX1 and associated drug resistance markers such as PDL1.

Conclusion: These results support our hypothesis that YBX1 plays a crucial role in mediating resistance to sorafenib in advanced HCC. Therefore, targeting YBX1 could potentially enhance the sensitivity of advanced HCC to sorafenib treatment, suggesting YBX1 as a promising therapeutic target for improving outcomes in HCC patients.

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Poster

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YB1 Modulates Sorafenib Sensitivity in Hepatocellular Carcinoma Cell Lines

Background: Drug resistance is a leading cause of mortality in cancer, responsible for up to 90% of cancer-related deaths. Understanding the mechanisms behind drug resistance is crucial for enhancing the efficacy of cancer therapies. Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and a major contributor to liver cancer-related fatalities. While early-stage HCC can often be cured with surgical interventions like liver transplantation or hepatectomy, advanced stages are challenging due to drug resistance. Sorafenib, an FDA-approved multi-tyrosine kinase inhibitor for treatment of advanced HCC, has shown limited effectiveness in prolonging overall survival in advanced HCC patients. However, the mechanisms underlying sorafenib resistance in advanced HCC remain poorly understood. Our research group identified YBX1 as a pivotal transcription factor involved in regulating drug resistance in various cancers, including gastric and prostate cancers. This led us to investigate the potential role of YBX1 in sorafenib resistance in HCC

Methods: Analysis of HCC patient cohorts from The Cancer Genome Atlas (TCGA) revealed an elevated expression of YBX1 in tumors compared to normal tissues, correlating with disease progression, metastasis, and poorer survival rates. To delve deeper using in-vitro models, we developed sorafenib-resistant HCC cell lines in the lab and measured their IC50 against non-resistant parental cell lines using MTT assay. Additionally, we manipulated YBX1 expression levels through transfection experiments in parental HCC cell lines and assessed their IC50 values relative to control groups. RNA analyses were performed using RTPCR for the expression of YBX1 and associated drug resistant markers. Western blots were used to assess the protein expression of YBX1 in the cells.

Results: Our findings showed increased IC50 levels in sorafenib-resistant cell lines compared to their non-resistant counterparts. RNA analysis using RTPCR experiments further demonstrated upregulation of YBX1 and other drug resistance markers such as MDR1 in sorafenib-resistant cells. Overexpression of YBX1 through lentiviral transfection enhanced cell survival and viability, leading to higher IC50 values for sorafenib at 24 and 48-hour time points.

Conversely, siRNA mediated knockdown of YBX1 resulted in decreased cell survival, viability, IC50 values, and reduced expression of YBX1 and associated drug resistance markers such as PDL1.

Conclusion: These results support our hypothesis that YBX1 plays a crucial role in mediating resistance to sorafenib in advanced HCC. Therefore, targeting YBX1 could potentially enhance the sensitivity of advanced HCC to sorafenib treatment, suggesting YBX1 as a promising therapeutic target for improving outcomes in HCC patients.

 

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