Abstract 5700: Simultaneous expression of MUC13 and N-Myc contributes to diethylnitrosamine-induced hepatocellular carcinoma in rats

Abstract Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with its development intricately linked to environmental factors such as chemical carcinogens and viral infections. Recent studies have highlighted a connection between obesity and non-alcoholic fatty liver disease with modern diets high in fats and processed meats. Despite this, the specific mechanisms by which dietary factors contribute to hepatocarcinogenesis remain inadequately understood. Our study demonstrates that diethylnitrosamine (DEN), a N-nitroso compound found in food additives and tobacco smoke upregulates N-Myc. N-Myc is a member of the Myc family of proto-oncogenes, essential for regulating gene expression, growth, apoptosis, energy metabolism, and differentiation. Additionally, we investigated the relationship between MUC13 and N-Myc, potential oncogenes, in human HCC tumors, proposing a potential link further facilitated by the suppression of miR-145, which contributes to hepatocarcinogenesis. Methodology: We utilized a chemically induced rat model with DEN; 200 mg/kg bw and 2-acetylaminofluorene (2-AAF; 150 mg/kg bw) to investigate N-Myc and MUC13 expression. Serum levels of AST, ALT, and ALP were measured using Span Diagnostics kits. We assessed N-Myc expression in tumor tissue through immunohistochemical staining and measured miR-145 levels via in situ hybridization. Additionally, we analyzed patient-derived tissue samples to evaluate N-Myc and MUC13 protein expression, supplemented by bioinformatics analyses from various public databases. Results: Liver sections from the DEN+2-AAF-treated group displayed hepatocyte vacuolization in the centrilobular area, accompanied by variations in nuclear size and significant nuclear atypia in adenomas. Serum levels of AST, ALT, and ALP correlated with liver cancer progression, and DEN treatment notably upregulated MUC13 and N-Myc in liver tissues. In normal tissues, MUC13 and N-Myc showed minimal staining, whereas levels were significantly higher in DEN+2-AAF-induced HCC, suggesting that MUC13 and N-Myc expression is crucial for hepatocyte malignant transformation. A strong correlation between MUC13 and N-Myc expression was observed in human HCC tumors. Additionally, miR-145, a repressor of MUC13, was significantly downregulated in tumor tissues compared to normal controls. Molecular modeling revealed that DEN forms a stable complex with N-Myc through multiple interactions. Conclusion: This study highlights the pivotal role of MUC13 and N-Myc in the progression of diethylnitrosamine induced HCC. Citation Format: Mohammed Sikander, Shabnam Malik, Swatantra K. Jain, Deepshikha P. Katare, Murali M. Yallapu, Subhash C. Chauhan. Simultaneous expression of MUC13 and N-Myc contributes to diethylnitrosamine-induced hepatocellular carcinoma in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5700.