Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy.
Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2019 Jul 19;20(14):3541. doi: 10.3390/ijms20143541.
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.
正常的表皮稳态依赖于不同类别的因素的功能，例如转录调节剂和受体。这种内稳态平衡的改变可能导致皮肤鳞状细胞肿瘤发生。同源盒转录因子 DLX3 是 p53 依赖性表皮分化调节的决定因素，并调节皮肤癌发生。皮肤稳态的维持还涉及神经营养因子（NTs）及其受体 Trk 和 CD271 的作用。虽然 Trk 受体过表达是癌症的标志，但 CD271 在皮肤鳞状细胞癌（cSCC）中的表达和功能存在矛盾的数据。先前的研究报道了头颈部鳞状细胞癌（HNSCC）中 NT 受体的表达。我们表明，CD271 在原发性 cSCC 细胞中低表达，并且 CD271+细胞的数量与 SCC 球体中的细胞黏附力相关。在正常表皮中，CD271 在增殖性祖细胞中表达，DLX3 在终末分化的角质形成细胞中表达。脑源性神经营养因子（BDNF）和神经营养因子 3（NT3）增加 DLX3 的表达。在角质形成细胞中缺乏功能性 BDNF 受体 TrkB 的情况下，我们假设 BDNF 依赖性 DLX3 反应可以通过 CD271 介导。总之，我们的结果支持角质形成细胞中存在假定的 CD271-DLX3 连接，这对于预防鳞状皮肤癌可能至关重要。
