Abstract
BackgroundCutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined.MethodsMiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression or knock-out of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Sample-matched transcriptome data was generated to support the identification of disease relevant miRNA targets.ResultsSeveral miRNAs were identified as dysregulated in cSCCs compared to control skin. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin- and tubulin cytoskeleton-associated protein DIAPH2.ConclusionThe discovery that miR-10b mediates an aspect of cancer stemness – that of enhanced tumor cell adhesion, known to facilitate metastatic colonization – provides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.
Highlights
Cutaneous squamous cell carcinomas are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population
Wimmer et al Cell Communication and Signaling (2020) 18:61 suffering from the rare genodermatosis recessivedystrophic epidermolysis bullosa (RDEB). These patients are at high risk of developing a aggressive type of Cutaneous squamous cell carcinomas (cSCC) with a high metastatic potential that is linked to changes in the extracellular matrix (ECM), caused by lossof-function mutations in the COL7A1 gene [2]
Despite the fact that miR-10a appeared to be the most deregulated miRNA in RDEB-cSCCs in microarray analysis, but not in subsequent qPCR, we assume that high microarray scores most likely derived from a certain hybridization error rate, as miRs-10a and -10b differ in only one nucleotide (Fig. 1e, Supplementary Fig. S1C-E, Additional File 1)
Summary
Cutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by impaired skin integrity. Wimmer et al Cell Communication and Signaling (2020) 18:61 suffering from the rare genodermatosis recessivedystrophic epidermolysis bullosa (RDEB) These patients are at high risk of developing a aggressive type of cSCC with a high metastatic potential that is linked to changes in the extracellular matrix (ECM), caused by lossof-function mutations in the COL7A1 gene [2]. To which extent these inflammatory changes are linked to the aggressive form of cSCC associated with RDEB, and if these tumors have characteristics in common with cSCCs that present with an aggressive behaviour in otherwise healthy people, remains unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
