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

Abstract

Background: 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. Methods: 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 knockout of a dysregulated miRNA was assessed in migration and 3D-spheroid assays. Samplematched transcriptome data was generated to support the identification of disease relevant miRNA targets. Results: 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. Conclusion: The discovery that miR-10b mediates an aspect of cancer stemnessthat of enhanced tumor cell adhesion, known to facilitate metastatic colonizationprovides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.

Non-Coding Transcriptome Provides Novel Insights into the Escherichia coli F17 Susceptibility of Sheep Lamb

“…The most upregulated DE miRNAs was a novel miRNA, namely, novel_miR_107; not much is known about the novel miRNA, but the high expression of novel_miR_107 in AN lambs suggest that novel_miR_107 would make a prime candidate for future research. The most downregulated DE miRNAs was miR-10b, one of the most upregulated miRNAs in human cancers and strongly expressed in highly metastatic cancer cells [58,59]. In the present study, miR-10b was highly expressed in SE lambs.…”

Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications

“…For instance, miR-10b-5p has been shown to support self-renewal of breast CSCs by modulating the PTEN/AKT pathway 37 and can drive the stem cell phenotype of cutaneous squamous cell carcinomas. 43 We identified miR-10b-5p as a direct target of SOX2 (Fig. 3 ) and demonstrate this miRNA regulates TET2 and 5hmC levels in GSCs (Fig.…”

Epigenetic and metabolic regulation of epidermal homeostasis

“…In the context of epidermolysis bullosa (EB) – a rare genetic disorder of the skin discussed in more detail below – the role of miRNAs in disease pathogenesis is beginning to surface. To date, three miRNAs have been described to modulate EB‐associated complications such as fibrosis (miR‐29b, 86 , 87 miR‐145 88 , 89 ) and cancer (miR‐10b 90 ). The repetitive destabilization of the extracellular matrix that accompanies recessive dystrophic EB (RDEB) upon injury results in progressive soft tissue fibrosis with debilitating consequences, such as tumour development.…”

“…In this context, overexpression of miR‐10b has been attributed a role in conferring stemness to tumour cells, specifically by increasing cell adhesion in 2D and 3D functional models. While miR‐10b is the first miRNA described to be associated with RDEB‐SCCs, 90 the role of miRNAs in tumourigenesis is generally well‐accepted, and has been described for several tumour entities, among them cutaneous SCCs, affecting diverse mechanisms like migration and proliferation. 96 , 97 , 98 …”