Hepatic Artery Embolization Induces the Local Overexpression of Transforming Growth Factor β1 in a Rat Hepatoma Model

Introduction: The underlying mechanism involved in the recurrence of hepatoma after hepatic arterial embolization (HAE) is not adequately examined. An immunosuppressive cytokine, transforming growth factor beta 1 (TGF-beta 1), can lead to tumor progression and is affected by hypoxia in various cancers. The study aimed to assess the effect of HAE on the expression of TGF-beta 1 in a rat hepatoma model. Methods: Sprague-Dawley rats bearing N1S1 hepatoma cells underwent HAE (HAE group, n = 5) or sham treatment (sham group, n = 4). The animals were euthanized at 48 h, and liver tissues were harvested. Immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR) were performed to compare the expression of TGF-beta 1 and hypoxia-inducible factor 1 alpha (HIF-1 alpha) between the HAE and sham groups. In vitro experiments with the N1S1 cell line were also performed under normoxic (21% O-2) or hypoxic (1% O-2) conditions for 48 h, and the expression of TGF-beta 1 and HIF-1 alpha was assessed with western blotting and enzyme-linked immunosorbent assay. Statistical data comparisons were performed by Student t test. Results: IHC showed that both the TGF-beta 1-positive and HIF-1 alpha-positive tumor peripheral areas were larger in the HAE group (6.59 +/- 2.49 and 10.26 +/- 4.14%; p < 0.001, respectively) than in the sham group (0.34 +/- 0.41 and 0.40 +/- 0.84% respectively). Similarly, qPCR showed that the mRNA expression levels of TGF-beta 1 and HIF-1 alpha were higher (1.95 +/- 0.38-fold and 1.62 +/- 0.37-fold; p < 0.001 and p = 0.002, respectively) in the HAE group than those in the sham group. TGF-beta 1 expression was suppressed when HIF-1 alpha inhibitors were added (p = 0.001), and HIF-1 alpha expression was upregulated when exogenous TGF-beta 1 was added (p = 0.033) in N1S1 cells. Conclusion: HAE enhanced local TGF-beta 1 expression in a rat hepatoma model. In vitro experiments suggest that HAE-induced hypoxic stress may trigger the interdependent expression of TGF-beta 1 and HIF-1 alpha.