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Hakai overexpression effectively induces tumour progression and metastasis in vivo.

Hakai overexpression effectively induces tumour progression and metastasis in vivo.
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Castosa R, Martinez-Iglesias O, Roca-Lema D, Casas-Pais A, Díaz-Díaz A, Iglesias P, Santamarina I, Graña B, Calvo L, Valladares-Ayerbes M, Concha Á, Figueroa A,


Castosa R, Martinez-Iglesias O, Roca-Lema D, Casas-Pais A, Díaz-Díaz A, Iglesias P, Santamarina I, Graña B, Calvo L, Valladares-Ayerbes M, Concha Á, Figueroa A, (click to view)

Castosa R, Martinez-Iglesias O, Roca-Lema D, Casas-Pais A, Díaz-Díaz A, Iglesias P, Santamarina I, Graña B, Calvo L, Valladares-Ayerbes M, Concha Á, Figueroa A,

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Scientific reports 2018 02 228(1) 3466 doi 10.1038/s41598-018-21808-w

Abstract

At early stages of carcinoma progression, epithelial cells undergo a program named epithelial-to-mesenchymal transition characterized by the loss of the major component of the adherens junctions, E-cadherin, which in consequence causes the disruption of cell-cell contacts. Hakai is an E3 ubiquitin-ligase that binds to E-cadherin in a phosphorylated-dependent manner and induces its degradation; thus modulating cell adhesions. Here, we show that Hakai expression is gradually increased in adenoma and in different TNM stages (I-IV) from colon adenocarcinomas compared to human colon healthy tissues. Moreover, we confirm that Hakai overexpression in epithelial cells drives transformation in cells, a mesenchymal and invasive phenotype, accompanied by the downregulation of E-cadherin and the upregulation of N-cadherin, and an increased proliferation and an oncogenic potential. More importantly, for the first time, we have studied the role of Hakai during cancer progression in vivo. We show that Hakai-transformed MDCK cells dramatically induce tumour growth and local invasion in nude mice and tumour cells exhibit a mesenchymal phenotype. Furthermore, we have detected the presence of micrometastasis in the lung mice, further confirming Hakai role during tumour metastasis in vivo. These results lead to the consideration of Hakai as a potential new therapeutic target to block tumour development and metastasis.

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