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 β-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, β-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion. Moreover, we showed that β-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 β-catenin and MAP kinase signaling. Overall, our data suggest that β-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.

由于其高度转移倾向，尽管最近开发了靶向和免疫治疗策略，黑色素瘤仍然是最致命的皮肤癌形式。因此，了解黑色素瘤侵袭的分子机制仍然至关重要。我们之前对 Tspan8 进行了表征，因为它能够促使黑色素瘤细胞脱离微环境并引发黑色素瘤细胞侵袭，但 Tspan8 调节侵袭过程的信号事件仍然未知。在这里，我们证明β-连环蛋白稳定是Tspan8表达开始后的分子信号，反过来，β-连环蛋白触发Tspan8表达的直接转录激活，导致黑色素瘤侵袭。此外，我们还发现，β-连环蛋白的激活与转基因 Nras 黑色素瘤病变中 Tspan8 蛋白的高表达存在系统相关性。 bcat* 小鼠以及深部穿透性痣（一种人类黑色素瘤前肿瘤，其特征是 β-连环蛋白和 MAP 激酶信号传导的联合激活）。总的来说，我们的数据表明β-连环蛋白和Tspan8是正反馈环的一部分，它维持Tspan8的高表达水平，赋予黑色素瘤细胞肿瘤进展和扩散所需的侵袭特性。