Endocrine Abstracts

Hepatocellular carcinoma (HCC) is the 6^th most common form of cancer and the 4^th most common cause of cancer related death. AKR1C1 is a member of the aldo-keto reductase 1C (AKR1C) subfamily and has important roles in steroid hormone metabolism and in reducing lipid peroxides. AKR1C1 is ubiquitously expressed, with high levels of expression in the liver. Studies have identified differential expression in HCC with high levels of AKR1C1 expression associated with a worse HCC prognosis as well as poor response to sorafenib chemotherapy. Using human cell hepatoma models (HepG2 and Huh), we have undertaken a series of experiments to determine the impact of AKR1C1 siRNA and CRISPR knock down and pharmacological inhibition on cell proliferation, gene expression (using RNA-sequencing) and response to treatment with the chemotherapeutic agent, sorafenib. Significant knock down of AKR1C1 gene and protein expression was achieved with both the siRNA and CRISPR approaches. AKR1C1 knock down had no impact on cell viability or proliferation. As expected, sorafenib decreased cell proliferation. Neither gene silencing of AKR1C1 nor pharmacological inhibition using 5-PBSA altered the cellular response to sorafenib treatment. Furthermore, RNA-sequencing analysis demonstrated only a very small number of differentially expressed genes when comparing AKR1C1 siRNA treated cells and scrambled controls. In conclusion, AKR1C1 knock down had a minimal impact on the proliferative phenotype in human hepatoma cell lines and failed to regulate the response to sorafenib treatment. These data would suggest that AKR1C1 in isolation has little direct impact to modulate the development and progression of HCC.