Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma

作者：Okamoto Koichi^*; Tajima Hidehiro; Nakanuma Shinichi; Sakai Seisho; Makino Isamu; Kinoshita Jun; Hayashi Hironori; Nakamura Keishi; Oyama Katsunobu; Nakagawara Hisatoshi; Fujita Hideto; Takamura Hiroyuki; Ninomiya Itasu; Kitagawa Hirohisa; Fushida Sachio; Fujimura Takashi; Harada Shinichi; Wakayama Tomohiko; Iseki Shoichi; Ohta Tetsuo

来源：International Journal of Oncology, 2012, 41(2): 573-582.

DOI：10.3892/ijo.2012.1499

• angiotensin II
• hepatic stellate cell
• stromal cell-derived factor-1
• CXCR4
• epithelial-to-mesenchymal transition

We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1 alpha was released into the supernatant of LI-90 cells to which AngII had been added. SDF-1 alpha increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1 alpha and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of beta-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1 alpha, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1 alpha-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and metastasis of tumor cells expressing AT-1 and CXCR4.

• 出版日期2012-8