Abstract 2257: Effect ofALDH1L1folate enzyme on hepatocellular carcinoma inachemical carcinogenesismodel

Background: ALDH1L1 (aldehyde dehydrogenase 1 family member L1, or cytosolic 10-formyltetrahydrofolate dehydrogenase) is an abundant enzyme in folate metabolism representing about 1% of total soluble protein in hepatocytes. Expression of this protein is strongly and ubiquitously downregulated in human cancers through the promoter methylation. Several studies indicate that patients with hepatocellular carcinoma who had low expression of ALDH1L1 had poorer prognosis than those with high expression. Hypothesis: We propose that in the absence of ALDH1L1, liver tumors proliferate faster and grow to a larger size. Methods: The effect of the Aldh1l1 knockout (Aldh1l1−/−) on hepatocellular carcinoma was investigated using DEN (diethyl nitrosamine) model of chemical carcinogenesis. Fifteen-days-old male Aldh1l1−/- mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with DEN at the dose of 15 mg/kg body weight. Mice were sacrificed 10, 20, 28- and 36-weeks post-injection and livers were examined for for histopathology. Results: Significant reduction in total body weight was observed in the DEN-injected knockout compared to wild type animals at 28 and 36 weeks. Immunohistochemical analysis reveals that tumor size was significantly bigger in Aldh1l1−/− compared to Aldh1l1+/+ mice and also indicated fibrosis in livers of knockout vs wild-type mice. Vascular involvement, highlighted by reticulin staining, was present in both Aldh1l1−/− and Aldh1l1+/+ mice as early as 20 weeks after the injection. Tumor multiplicity did not differ significantly between the Aldh1l1−/− and Aldh1l1+/+ animals. Conclusion:. Aldh1l1 knockout promoted aggressiveness of liver tumors without affecting the tumor initiation. Acknowledgement: These studies were supported by the National Institutes of Health grants DK54388 and CA095030 (S.A.K.). Citation Format: Jaspreet Sharma, Natalia I. Krupenko, Peter Pediaditakis, Kristi Helke, Kyle C. Strickland, Sergey A. Krupenko. Effect ofALDH1L1folate enzyme on hepatocellular carcinoma inachemical carcinogenesismodel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2257.