Twist1-Induced Invadopodia Formation Promotes Tumor Metastasis

“…16 Moreover, Twist1 has been shown to induce RAC1 activity 22 and formation of invadopodia in cancer cells. 24 The regulatory regions of the Twist1 gene contain the g-interferoneactivated sequence, 85 a binding element shared by Stat3 and Stat5a/ b, and Stat3 has been shown to up-regulate Twist1 gene expression in breast cancer cells. 85,86 To our knowledge, the work presented herein provides the first evidence of active Stat5a/b signaling inducing Twist1 gene expression in PC.…”

Section: Discussionmentioning

confidence: 99%

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

View full text Add to dashboard Cite

Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

show abstract

“…Recently, many studies have documented a role for cortactin in promoting cancer cell motility and invasion, including a critical role in invadopodia, which are actin-rich subcellular protrusions associated with the degradation of the extracellular matrix by cancer cells [48,49]. Notably, orthotopic injection of HCC cells overexpressing cortactin into the liver resulted in an increased intrahepatic metastasis [50].…”

Section: Discussionmentioning

confidence: 99%

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

et al. 2013

View full text Add to dashboard Cite

We have previously identified 1 241 regions of somatic copy number alterations (CNAs) in hepatocellular carcinoma (HCC). In the present study, we found that a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. Notably, there is a positive correlation between the expression levels of MPZL1 and intrahepatic metastasis of the HCC specimens. MPZL1 can significantly enhance the migratory and metastatic potential of the HCC cells. Moreover, we found that one of the mechanisms by which MPZL1 promotes HCC cell migration is by inducing the phosphorylation and activation of the pro-metastatic protein, cortactin. Additionally, we found that Src kinase mediates the phosphorylation and activation of cortactin induced by MPZL1 overexpression. Taken together, these findings suggest that MPZL1 is a novel pro-metastatic gene targeted by a recurrent region of copy number amplification at 1q24.1-24.2 in HCC.

show abstract

Twist1-Induced Invadopodia Formation Promotes Tumor Metastasis

Cited by 425 publications

References 36 publications

Arsenite promotes intestinal tumor cell proliferation and invasion by stimulating epithelial-to-mesenchymal transition

Arsenite promotes intestinal tumor cell proliferation and invasion by stimulating epithelial-to-mesenchymal transition

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Contact Info

Product

Resources

About