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

## TL;DR

Genipin, a compound, may help reduce liver cancer in rats by altering the extracellular matrix and reducing tumor cell survival and resistance.

## Contribution

This study introduces genipin as a novel hepatoprotective and anticancer agent by modulating ECM cross-linkage.

## Key findings

- Genipin improves survival and reduces liver nodules and serum AFP levels in HCC rats.
- Genipin lowers the expression of EGF, EGFR, fibronectin, GSK-3β, PKB, and versican.
- Genipin reduces tumor cell resistance and survival by targeting ECM components and signaling pathways.

## Abstract

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.

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.

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.

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.