Visfatin is involved in promotion of colorectal carcinoma malignancy through an inducing EMT mechanism

Abstract

Increasing evidences suggested visfatin, a newly discovered obesity-induced adipocytokine, is involved in promotion of cancer malignancy and correlated with worse clinical prognosis. While its effects and mechanisms on progression of colorectal cancer (CRC) remain unclear. Our clinical data show that visfatin protein is over expressed, positive associated with lymph node metastasis, high-grade tumor, and poor prognosis in 87 CRC patients. The levels of plasma visfatin are significantly upregulated in Stage IV colon cancer. Visfatin can significantly promote the in vitro migration and invasion of CRC cells via induction epithelial mesenchymal transition (EMT). It can increase the expression and nuclear translocation of Snail, a key transcription factor in regulating EMT. While silencing of Snail attenuates visfatin induced EMT. Further studies reveal visfatin can inhibit the association of Snail with GSK-3β and subsequently suppress ubiquitylation of Snail. In addition, visfatin can increase the expression and nuclear translocation of β-catenin, elevate its binding with Snail promoter, and then increase the transcription of Snail. While inhibitor of PI3K/Akt, LY294002, abolishes visfatin induced up regulation of Snail, Vimentin (Vim), β-catenin, and phosphorylated GSK-3β. In summary, our data suggest that increased expression of visfatin are associated with a more aggressive phenotype of CRC patients. It can trigger the EMT of CRC cells via Akt/GSK-3β/β-catenin signals.

<p>The role of visfatin in cancer proliferation, angiogenesis, metastasis, drug resistance and clinical prognosis</p>

“…Similar associations between serum visfatin and clinical pathologic variables were observed in breast cancer patients along with regulation of MDA-MB-231 cell migration and invasion capabilities via c-Abl and STAT3 activation 16. The induction of the epithelial–mesenchymal transition process by visfatin was investigated in CRC, and the results indicated that visfatin could upregulate Snail in CRC cells by activating Akt/GSK-3β/β-catenin signaling 15. Furthermore, visfatin was found to significantly increase the in vitro migration and invasion capability of osteosarcoma MG-63 and HOS cells, and to upregulate MMP-2 and fibronectin expression through the NF- B/IL-6 signaling axis 46.…”

“…In addition, hepatocellular carcinoma patients with high serum visfatin levels had shorter overall survival times compared with those with low serum visfatin levels ( p <0.001) 14. In colorectal carcinoma cases, the results of a Kaplan–Meier analysis of 87 patients indicated a statistically negative correlation between visfatin levels and overall survival probability ( p <0.001) 15. A study of 176 breast cancer biopsy tissues demonstrated that visfatin is a prognosis marker for its association with poor patient survival 8.…”

The roles of ING5 expression in ovarian carcinogenesis and subsequent progression: a target of gene therapy

“…Zhao et al [ 17 ] found that ING5 significantly inhibited the phosphorylation of PI3K and Akt in breast cancer cells, leading to MET. In addition, EMT is positively associated with aberrant activation of Wnt or the PI3K/Akt pathway, which activates GSK-3β and stabilizes β-catenin [ 20 , 21 ]. We found that PI3K, Akt, and β-catenin were decreased in ING5 transfectants of ovarian cancer cells.…”

The role of adipokines in systemic sclerosis: a missing link?

“…Interestingly, differentiation of fibroblasts into myofibroblasts is a reversible process, giving a potential possibility to invert it and find new drugs attenuating fibrosis [ 129 ]. It was proved that many adipokines, especially visfatin and progranuline are involved in the process of EMT, which is a transition akin to AMT process [ 21 , 128 ].…”