PO_II_L: Pathology and Oncology II. Lectures
Andrea Reszegi, Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest
Zsolt Horváth, Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest
Kornélia Baghy, Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest
Ilona Kovalszky, Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest
Introduction: Hepatocellular carcinoma (HCC) represents the most frequent type of primary liver tumor, and it is the fourth most common fatal malignancy disease worldwide. The tumor microenvironment plays a determining role in cancer development by regulating multiple processes between the extracellular matrix and tumor cells. Decorin, a prototype member of the SLRP family has gained recognition for its essential roles in several disorders including cancer.
Aims: Our previous studies showed that the lack of decorin favors primary hepatocarcinogenesis resulting in higher tumor incidence. Based on these findings, we designed a new set of experiments to understand the implication of overexpressed decorin in our decorin knockout (DCN-/-), thioacetamide (TAA)-induced hepatocarcinogenesis model.
Methods: For animal experiments, pLIVE vector coding human decorin cDNA and a control vector coding serum alkaline phosphatase (SEAP) were targeted to the liver by hydrodynamic gene delivery. The SEAP detected from sera provides indirect information about the activity of the vectors. Hepatocarcinogenesis was induced by TAA administration. Receptor tyrosine kinases (RTKs) and phospho-kinases were analyzed by Proteome Profiler pRTK assay and Proteome Profiler Phospho-Kinase Array Kit. Western blot techniques were applied for quantitative comparative analysis of proteins.
Result: Human decorin was successfully transfected and expressed in the livers, confirmed by SEAP Detection Assay. Upon TAA-induced hepatocarcinogenesis, decorin transfection resulted in attenuated tumor formation in decorin expressing groups. Decorin delivery decreased the number of tumors by 83% in decorin transfected mice compared to decorin negative livers. As a mechanism of action, excessive decorin was able to reduce the activity of multiple RTKs including InsR, AXL, PDGFRα, VEGFR, MuSK, and EGFR an important player in HCC.
Conclusion: Decorin gene delivery is able to effectively inhibit tumor formation in the liver. Our results support the idea of decorin utilization as a potential anti-cancer agent in the battle of liver malignancies.
Funding: This research was funded by the National Research, Development, and Innovation Fund (ÚNKP-20-4-I-SE-26 New National Excellence Program of the Ministry of Human Capacities to A.R.).
Semmelweis University, Doctoral School of Pathological Sciences