Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?

Abstract

Well-regulated epidermal homeostasis depends on the function of different classes of factors, such as transcription regulators and receptors. Alterations in this homeostatic balance may lead to the development of cutaneous squamous tumorigenesis. The homeobox transcription factor DLX3 is determinant for a p53-dependent regulation of epidermal differentiation and modulates skin carcinogenesis. The maintenance of skin homeostasis also involves the action of neurotrophins (NTs) and their receptors, Trk and CD271. While Trk receptor overexpression is a hallmark of cancer, there are conflicting data on CD271 expression and function in cutaneous SCC (cSCC). Previous studies have reported NT receptors expression in head and neck SSC (HNSCC). We show that CD271 is expressed at low levels in primary cSCC cells and the number of CD271+ cells correlates with cell cohesion in SCC spheroids. In normal epidermis, CD271 is expressed in proliferative progenitor cells and DLX3 in terminally differentiated keratinocytes. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) increase DLX3 expression. In the absence of a functional BDNF receptor TrkB in keratinocytes, we hypothesize that the BDNF-dependent DLX3 response could be mediated via CD271. Altogether, our results support a putative CD271-DLX3 connection in keratinocytes, which might be crucial to preventing squamous skin cancer.

Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus‐induced keratinocyte carcinomas

“…In normal epithelium, CD271 contributes to epidermal homeostasis and the "switch" between stem cells and their progeny. 62 The positive staining was in conjunction with increased levels of CD44, which mediates intercellular interactions with the extracellular matrix. 63 Co-expression of both proteins is considered a marker for CSCs, which are closely associated with EMT.…”

Investigating Cutaneous Squamous Cell Carcinoma in vitro and in vivo: Novel 3D Tools and Animal Models

“…The use of primary cSCC cells should be done in the early passages to avoid a progressive adaptation to monolayer culture conditions and consequent modification of the cells in terms of growth or response to stimuli. Progress in cancer research provide evidence that cancer cells, including cSCC cells ( 52 ), can grow as spheroids or organoids ( 54 – 58 ), indicating that it is possible to maintain the architecture of cell-to-cell interaction as well the tissue organization with respect to the external environment, which is important for both functional studies, based on gene silencing or overexpression or gene editing, and drug development ( 59 ). The use of spheroids also permits the evaluation of cancer cell invasiveness through cellular or acellular matrix-based assays ( 60 – 62 ).…”

“…Recently, tumor derived spheroids have been prepared from different cancer cell types ( 99 – 102 ), including cSCC ( 52 , 103 ), and have been widely employed for the study of tumor pathology, progression, invasion, and for drug screening and development ( 60 , 61 , 98 , 104 ).…”

Wnt/CTNNB1 Signal Transduction Pathway Inhibits the Expression of ZFP36 in Squamous Cell Carcinoma, by Inducing Transcriptional Repressors SNAI1, SLUG and TWIST

“…The skin is the largest organ in the human body. To maintain its homeostasis, it relies on keratinocyte stem cells (KSCs), that have potential for self-renewal and differentiation [ 12 , 13 ]. Epithelial differentiation is finely regulated in healthy skin, through a balance between transcription factors, growth factors, structural molecules and enzymes [ 14 , 15 ].…”