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A cancer stem cell-like phenotype is associated with miR-10b expression in aggressive squamous cell carcinomas.

Cell communication and signaling : CCS (2020-04-12)
Monika Wimmer, Roland Zauner, Michael Ablinger, Josefina Piñón-Hofbauer, Christina Guttmann-Gruber, Manuela Reisenberger, Thomas Lettner, Norbert Niklas, Johannes Proell, Mila Sajinovic, Paul De Souza, Stefan Hainzl, Thomas Kocher, Eva M Murauer, Johann W Bauer, Dirk Strunk, Julia Reichelt, Albert Sleiman Mellick, Verena Wally
ABSTRACT

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. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined. MiRNA 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. Several 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. The 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
SSC Buffer 20× Concentrate, for Northern and Southern blotting, solution
Roche
Anti-Digoxigenin-Fluorescein, Fab fragments, from sheep
Sigma-Aldrich
Bovine Serum Albumin, heat shock fraction, protease free, pH 7, ≥98%