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Periostin induces epithelial?to?mesenchymal transition via the integrin ?5?1/TWIST?2 axis in cholangiocarcinoma.

ABSTRACT: 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)?5?1, 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 siITG?5 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), ?-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 ITG?5?1?knockdown cells and corresponded to reduced migration of the cancer cells. These results indicated that PN induced CCA migration through ITG?5?1/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 ITG?5?1?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.

SUBMITTER: Sonongbua J

PROVIDER: S-EPMC7057947 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Sonongbua Jumaporn J Siritungyong Suchada S Thongchot Suyanee S Kamolhan Thanpawee T Utispan Kusumawadee K Thuwajit Peti P Pongpaibul Ananya A Wongkham Sopit S Thuwajit Chanitra C

Oncology reports 20200131 4

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, we ...[more]

PMID: 32020235

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Project description:Periostin, a secreted matricellular protein, has been reported to induce epithelial-mesenchymal transition (EMT), which increases motility and invasiveness in various epithelial cancer cells. Periostin is also overexpressed in intrahepatic cholangiocarcinoma (ICC) and suggested to be a biomarker for tumor progression and poor prognosis; however, its functional role in ICC is not fully understood. Here, we investigated whether periostin influences malignant potential through the induction of EMT in ICC. Analyses of surgical resected ICC specimens revealed that the gene expression of periostin was significantly higher in ICC tumors than in adjacent nontumor liver tissues and was closely correlated with the expression of mesenchymal markers, including N-cadherin, vimentin, and fibronectin. However, the expression level of periostin varied in each case. Consistently, the expression of periostin in HuH28 (an undifferentiated ICC cell) was markedly higher than in HuCCT-1 (a moderately differentiated ICC cell). In addition, high-level secretion of periostin into culture media was observed in HuH28 but not in HuCCT-1. To identify the biological significance of periostin in EMT, gene silencing of periostin by small interfering RNA was performed in HuH28 cells. Periostin knockdown in HuH28 cells significantly down-regulated mesenchymal markers and up-regulated epithelial markers, suggesting the reversal of EMT, namely mesenchymal-epithelial transition. Along with these changes, cell proliferation was significantly suppressed by 52%. In addition, cell migration and invasion were significantly suppressed by 62% and 61%, respectively, with reduced gene expression of matrix metalloproteinase 2. Interestingly, chemosensitivity to gemcitabine was also significantly improved by periostin depletion. Conclusion: Periostin plays an important role in the regulation of malignant potential through EMT and is suggested to be a novel target for the treatment of ICC. (Hepatology Communications 2017;1:1099-1109).

Dataset Information

Periostin induces epithelial?to?mesenchymal transition via the integrin ?5?1/TWIST?2 axis in cholangiocarcinoma.

Publications

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

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