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.
Highlights
Carcinoma is the most common type of cancer and arises from the transformation of epithelial cells
By using Madin-Darby Canine Kidney (MDCK) cells, an established model system to study cell-cell adhesions, we have reported that Hakai overexpression induces tumour progression and micrometastasis in vivo
The mesenchymal N-cadherin marker is upregulated in advance colon carcinoma progression compared to healthy colon tissues and the E-cadherin loss is associated to the progression from adenoma to carcinoma
Summary
Carcinoma is the most common type of cancer and arises from the transformation of epithelial cells. Cancer-EMT is characterized by the disruption of cell–cell contacts, cell–substratum adhesions and apical–basal polarity, accompanied by the reorganization of the cytoskeleton All these changes cause the loss of epithelial phenotype and the acquisition of a mesenchymal phenotype, which includes a gain of migratory and invasive capabilities, important for the dissemination of cancer cells[1,2,3]. In addition to the loss of the epithelial E-cadherin protein, the mesenchymal marker N-cadherin is upregulated during EMT, and this switch between cadherins is considered as a hallmark of cancer-related EMT program[8] It has been extensively studied the mechanism whereby E-cadherin is downregulated during EMT in cancer[9,10]. In addition to Hakai action on cell–cell contacts, it has been described its involvement in the reduction of the cell–substratum adhesions and the increase of epithelial cell invasion in vitro[16]. By using Madin-Darby Canine Kidney (MDCK) cells, an established model system to study cell-cell adhesions, we have reported that Hakai overexpression induces tumour progression and micrometastasis in vivo
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