Effect of modulating the extracellular matrix cross linkage by genipin on tumor cell resistance and survival in thioacetamide-induced hepatocellular carcinoma in rats

Abstract

Background: Previous studies on patients and rats with hepatocellular carcinoma (HCC) have shown significant changes in the extracellular matrix (ECM). Versican, a component of the ECM, forms extensive multimolecular interactions with other ECM components, particularly hyaluronan, through specific domains in its core protein. However, disturbances in the hyaluronan-versican interaction may affect cancer development. We aimed to examine the effect of modulating matrix cross-linkage between hyaluronan and versican using genipin on tumor cell survival, resistance, and renewal. Methods: Following the induction of HCC in rats using thioacetamide, an oral dose of 10 mg/kg of genipin was administered. Liver impairment was evaluated by measuring serum α-fetoprotein (AFP) levels and examining liver sections stained with hematoxylin/eosin and anti-versican and anti-fibronectin antibodies. Additionally, hepatic expression levels of mRNA and proteins, including epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), fibronectin, glycogen synthase kinase-3 beta (GSK-3β), protein kinase B (PKB), and versican, were analyzed. Results: Genipin enhances rats' survival, leading to reduction in serum AFP levels and number of hepatic nodules. Micro-imaging examinations reveal that genipin reduces vacuolated cytoplasm, apoptotic nuclei, and necrotic nodules. Additionally, it significantly lowers EGF, EGFR, fibronectin, GSK-3β, PKB, and versican expression levels. Conclusion: Genipin may be considered novel anticancer agent with hepatoprotective effects. This is achieved by reducing versican-free forms. Additionally, genipin decreases tumor cells' resistance by lowering the expression of EGF, EGFR, PKB, and GSK-3β. Finally, it reduces tumor cell survival by decreasing the expression of fibronectin.