α‐Catulin downregulates E‐cadherin and promotes melanoma progression and invasion

Abstract

Metastasis is associated with poor prognosis for melanoma responsible for about 90% of skin cancer-related mortality. To metastasize, melanoma cells must escape keratinocyte control, invade across the basement membrane and survive in the dermis by resisting apoptosis before they can intravasate into the circulation. a-Catulin (CTNNAL1) is a cytoplasmic molecule that integrates the crosstalk between nuclear factor-kappa B and Rho signaling pathways, binds to b-catenin and increases the level of both a-catenin and b-catenin and therefore has potential effects on inflammation, apoptosis and cytoskeletal reorganization. Here, we show that a-catulin is highly expressed in melanoma cells. Expression of a-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. Knockdown of a-catulin promoted adhesion to and inhibited migration away from keratinocytes in an E-cadherin-dependent manner and decreased the transmigration through a keratinocyte monolayer, as well as in Transwell assays using collagens, laminin and fibronectin coating. Moreover, knockdown promoted homotypic spheroid formation and concomitantly increased E-cadherin expression along with downregulation of transcription factors implicated in its repression (Snail/Slug, Twist and ZEB). Consistent with the molecular changes, a-catulin provoked invasion of melanoma cells in a three-dimensional culture assay by the upregulation of matrix metalloproteinases 2 and 9 and the activation of ROCK/Rho. As such, a-catulin may represent a key driver of the metastatic process, implicating potential for therapeutic interference.

Lattice-free descriptions of collective motion with crowding and adhesion

“…These differences are associated with changing the degree of agent-to-agent adhesion in our model. The fact that our model captures these differences is relevant to biological experiments, since different types of cells often reveal different amounts of spreading over the same time period, just as we observe in the discrete simulations [28][29][30]. Such differences, when observed experimentally, are often attributed to differences in cell-to-cell adhesion strength.…”

SYK Allelic Loss and the Role of Syk-Regulated Genes in Breast Cancer Survival

“…We have also made the novel observation of SYK and CTNNAL1 (alpha-catulin, located on chromosome 9q) co-loss in this study. Alpha-catulin is an E-cadherin-regulating cell-cell adhesion protein that has been recently implicated in melanoma invasion and metastasis [85].…”

Decrease of ZEB1 expression inhibits the B16F10 cancer stem-like properties

“…In this study, we focused on the melanoma B16F10 CD133 + CD44 + CSC-like properties, and wanted to know whether the inhibition of the B16F10 CSC-like properties would alter cellular tumorigenicity and metastasis potential. We selected the transcription factor ZEB1 as a target to inhibit the B16F10 CSC-like properties because this is the role of ZEB1 and is tightly related with the melanoma' CSC-like properties as described by previous reports (5,6,17,18,30). Since self-renewal is one of the main B16F10 CSClike properties, we first assessed the clone formation capability and proliferative activity of B16F10 shZEB1-CD133 + CD44 + CSCs.…”

“…Zinc-finger E-box binding homeobox 1 (ZEB1), a transcription factor, is essential for the physiological processes of differentiation, cell growth, and cell death (15,16), and plays a key function in regulating EMT processes of melanoma cells together with miR-200c feedback loop (5,6,17,18). Thus, ZEB1 function is closely associated with the melanoma CSC-like property maintenance.…”