Periostin induces epithelial‑to‑mesenchymal transition via the integrin α5β1/TWIST‑2 axis in cholangiocarcinoma.

Periostin (PN) (also known as osteoblast‑specific factor OSF‑2) is a protein that in humans is encoded by the POSTN gene and has been correlated with a reduced survival of cholangiocarcinoma (CCA) patients, with the well‑known effect of inducing epithelial‑to‑mesenchymal transition (EMT). The present study investigated the effect of PN, through integrin (ITG)α5β1, in EMT‑mediated CCA aggressiveness. The alterations in EMT‑related gene and protein expression were investigated by real‑time PCR, western blot analysis and zymogram. The effects of PN on migration and the level of TWIST‑2 were assessed in CCA cells with and without siITGα5 transfection. PN was found to induce CCA cell migration and EMT features, including increments in Twist‑related protein 2 (TWIST‑2), zinc finger protein SNAI1 (SNAIL‑1), α-smooth muscle actin (ASMA), vimentin (VIM) and matrix metallopeptidase 9 (MMP‑9), and a reduction in cytokeratin 19 (CK‑19) together with cytoplasmic translocation of E-cadherin (CDH‑1). Additionally, PN markedly induced MMP‑9 activity. TWIST‑2 was significantly induced in PN‑treated CCA cells; this effect was attenuated in the ITGα5β1‑knockdown cells and corresponded to reduced migration of the cancer cells. These results indicated that PN induced CCA migration through ITGα5β1/TWIST-2‑mediated EMT. Moreover, clinical samples from CCA patients showed that higher levels of TWIST‑2 were significantly correlated with shorter survival time. In conclusion, the ITGα5β1‑mediated TWIST‑2 signaling pathway regulates PN‑induced EMT in CCA progression, and TWIST‑2 is a prognostic marker of poor survival in CCA patients.

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