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

Liver cancer (2020-02-20)
Eisuke Ueshima, Hideyuki Nishiofuku, Haruyuki Takaki, Yutaka Hirata, Hiroshi Kodama, Toshihiro Tanaka, Kimihiko Kichikawa, Koichiro Yamakado, Takuya Okada, Keitaro Sofue, Masato Yamaguchi, Koji Sugimoto, Takamichi Murakami

The underlying mechanism involved in the recurrence of hepatoma after hepatic arterial embolization (HAE) is not adequately examined. An immunosuppressive cytokine, transforming growth factor β1 (TGF-β1), 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-β1 in a rat hepatoma model. 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-β1 and hypoxia-inducible factor 1α (HIF-1α) between the HAE and sham groups. In vitro experiments with the N1S1 cell line were also performed under normoxic (21% O<sub>2</sub>) or hypoxic (1% O<sub>2</sub>) conditions for 48 h, and the expression of TGF-β1 and HIF-1α was assessed with western blotting and enzyme-linked immunosorbent assay. Statistical data comparisons were performed by Student t test. IHC showed that both the TGF-β1-positive and HIF-1α-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-β1 and HIF-1α 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-β1 expression was suppressed when HIF-1α inhibitors were added (p = 0.001), and HIF-1α expression was upregulated when exogenous TGF-β1 was added (p = 0.033) in N1S1 cells. HAE enhanced local TGF-β1 expression in a rat hepatoma model. In vitro experiments suggest that HAE-induced hypoxic stress may trigger the interdependent expression of TGF-β1 and HIF-1α.

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FM19G11, ≥98% (HPLC)