Irbesartan inhibits metastasis by interrupting the adherence of tumor cell to endothelial cell induced by angiotensin II in hepatocellular carcinoma
Long-Hai Feng, Hui‐Chuan Sun, Xiao‐Dong Zhu, Shi-Zhe Zhang, Xiao‐Long Li, Kangshuai Li, Xuefeng Liu, Ming Lei, Yan Li, Zhao–You Tang
Abstract
BACKGROUND: The use of angiotensin II inhibitors is associated with a low risk of recurrence and metastasis in hepatocellular carcinoma (HCC) patients. Vascular cell adhesion molecule-1 (VCAM-1) is a key factor in tumor metastasis. METHODS: The effects of angiotensin II and irbesartan (an angiotensin II inhibitor) on HCC were explored with a xenograft model, microarray analysis and cell adhesion experiments. The relationship between the expression of VCAM-1 in HCC tissues and prognosis was analyzed with public and our institutional clinical databases. The effects of angiotensin II, irbesartan and VCAM-1 on adhesion and metastasis in HCC were explored with a xenograft model and cell adhesion experiments. The regulatory mechanisms were analyzed by Western blot analysis. RESULTS: Angiotensin II type 1 receptor and VCAM-1 were expressed in HCC tissues. Irbesartan inhibited HCC growth and metastasis in vivo and weakened the adhesion of HCC cells to endothelial cells, an effect that was enhanced by angiotensin II. VCAM-1 was found to be an independent risk factor for recurrence and survival in HCC patients with microvascular invasion. Angiotensin II upregulated VCAM-1 expression, and this upregulation was inhibited by irbesartan. Angiotensin II enhanced adhesion mainly by promoting the expression of VCAM-1 in HCC cells. Irbesartan inhibited the expression of VCAM-1 by reducing p38/MAPK phosphorylation activated by angiotensin II in HCC cells. CONCLUSIONS: Irbesartan attenuates metastasis by inhibiting angiotensin II-activated VCAM-1 via the p38/MAPK pathway in HCC.