Yang Jing, Zhang Kun, Song Haixing, Wu Mingbo, Li Jingyi, Yong Ziyi, Jiang Sheng, Kuang Xi, Zhang Tao
School of Biomedical Sciences, Chengdu Medical College, Chengdu, China.
School of Pharmacy, Chengdu Medical College, Chengdu, China.
Oncotarget. 2016 May 31;7(22):32306-17. doi: 10.18632/oncotarget.8615.
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.
越来越多的证据表明,内脂素是一种新发现的肥胖诱导脂肪因子,参与促进癌症恶性发展,并与较差的临床预后相关。然而,其对结直肠癌(CRC)进展的影响和机制仍不清楚。我们的临床数据显示,在87例CRC患者中,内脂素蛋白过度表达,与淋巴结转移、高级别肿瘤和预后不良呈正相关。IV期结肠癌患者血浆内脂素水平显著上调。内脂素可通过诱导上皮-间质转化(EMT)显著促进CRC细胞的体外迁移和侵袭。它可增加调控EMT的关键转录因子Snail的表达和核转位。而沉默Snail可减弱内脂素诱导的EMT。进一步研究表明,内脂素可抑制Snail与GSK-3β的结合,进而抑制Snail的泛素化。此外,内脂素可增加β-连环蛋白的表达和核转位,提高其与Snail启动子的结合,从而增加Snail的转录。而PI3K/Akt抑制剂LY294002可消除内脂素诱导的Snail、波形蛋白(Vim)、β-连环蛋白和磷酸化GSK-3β的上调。总之,我们的数据表明,内脂素表达增加与CRC患者更具侵袭性的表型相关。它可通过Akt/GSK-3β/β-连环蛋白信号触发CRC细胞的EMT。