Details

Autor(en) / Beteiligte

• Kreiseder, Birgit
• Orel, Lukas
• Bujnow, Constantin
• Buschek, Stefan
• Pflueger, Maren
• Schuett, Wolfgang
• Hundsberger, Harald
• de Martin, Rainer
• Wiesner, Christoph

Titel

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

Ist Teil von

• International journal of cancer, 2013-02, Vol.132 (3), p.521-530

Ort / Verlag

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

Erscheinungsjahr

2013

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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. α‐Catulin (CTNNAL1) is a cytoplasmic molecule that integrates the crosstalk between nuclear factor‐kappa B and Rho signaling pathways, binds to β‐catenin and increases the level of both α‐catenin and β‐catenin and therefore has potential effects on inflammation, apoptosis and cytoskeletal reorganization. Here, we show that α‐catulin is highly expressed in melanoma cells. Expression of α‐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 α‐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, α‐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, α‐catulin may represent a key driver of the metastatic process, implicating potential for therapeutic interference. What's new? The authors showed for the first time that alpha‐catulin is highly expressed in melanoma cells. alpha‐catulin knockdown altered the expression of E‐cadherin and other genes known to be implicated in melanoma progression. Furthermore, knockdown of alpha‐catulin promoted both binding of melanoma cells to keratinocytes and spheroid formation by enhanced E‐cadherin expression. The authors also found that alpha‐catulin provoked invasion of melanoma cells in a 3D culture assay by up‐regulation of the matrix metalloproteinases 2 and 9 and activation of Rho. alpha‐catulin may thus represent a key driver of the metastatic process in human melanoma, implicating potential for therapeutic interference.