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α‐Catulin downregulates E‐cadherin and promotes melanoma progression and invasion
Author(s) -
Kreiseder Birgit,
Orel Lukas,
Bujnow Constantin,
Buschek Stefan,
Pflueger Maren,
Schuett Wolfgang,
Hundsberger Harald,
de Martin Rainer,
Wiesner Christoph
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27698
Subject(s) - downregulation and upregulation , mmp9 , gene knockdown , cadherin , microbiology and biotechnology , biology , epithelial–mesenchymal transition , cancer research , melanoma , apoptosis , cell , biochemistry , genetics , gene
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.