ABSTRACT
Due to its high proclivity to metastasize, and despite the recent development of targeted and immune therapy strategies, melanoma is still the deadliest form of skin cancer. Therefore, understanding the molecular mechanisms underlying melanoma invasion remains crucial. We previously characterized Tspan8 for its ability to prompt melanoma cell detachment from their microenvironment and trigger melanoma cell invasiveness, but the signaling events by which Tspan8 regulates the invasion process still remain unknown. Here, we demonstrated that ß-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, ß-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion. Moreover, we showed that ß-catenin activation systematically correlates with a high expression of Tspan8 protein in melanoma lesions from transgenic Nras; bcat* mice, as well as in deep penetrating naevi, a type of human pre-melanoma neoplasm characterized by a combined activation of ß-catenin and MAP kinase signaling. Overall, our data suggest that ß-catenin and Tspan8 are part of a positive feedback loop, which sustains a high Tspan8 expression level, conferring to melanoma cells the invasive properties required for tumor progression and dissemination.
Subject(s)
Melanoma/metabolism , Melanoma/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tetraspanins/metabolism , beta Catenin/metabolism , Animals , Feedback, Physiological , Gene Expression Regulation, Neoplastic , Humans , Melanoma/genetics , Mice, Transgenic , Promoter Regions, Genetic , Protein Stability , Skin Neoplasms/genetics , Tetraspanins/genetics , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , beta Catenin/genetics , Melanoma, Cutaneous MalignantABSTRACT
Tetraspanins are transmembrane proteins that interact laterally with each other and with different partners such as integrins, immunoglobulin (Ig)-domain-containing proteins, growth factors and cytokine receptors. Such tetraspanin-partner complexes help to organize dynamic membrane networks called "tetraspanin web", which trigger different signalling pathways. Despite the fact that tetraspanins seem abundantly and widely expressed, their function remained unclear. However, it is well established that they control fundamental cellular processes including cell survival, adhesion, migration, invasion or viral infection, but the underlying molecular mechanisms are not well elucidated. This review focuses on tetraspanins that are expressed in epidermis and the roles they play in normal and pathological conditions, specifically in skin cancer.
