Epidermal differentiation is a complex process that requires the regulated and sequential expression of various genes. Most fused-type S100 proteins are expressed in the granular layer and it is hypothesized that these proteins may be associated with cornification and barrier formation. We previously identified a member of the fused-type S100 proteins, Trichohyalin-like 1 (TCHHL1) protein. TCHHL1 is distributed in the basal layer of the normal epidermis. Furthermore, the expression is markedly increased in cancerous/non-cancerous skin samples with the hyperproliferation of keratinocytes. We herein examined the role of TCHHL1 in normal human keratinocytes (NHKs) and squamous cell carcinoma (SCC). The knockdown of TCHHL1 by transfection with TCHHL1 siRNA significantly inhibited proliferation and induced the early apoptosis of NHKs. In TCHHL1-knockdown NHKs, the level of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was markedly decreased. In addition, the slight inhibition of v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation and upregulation of forkhead box-containing protein O1(FOXO1), B-cell lymphoma2 (BCL2) and Bcl2-like protein 11 (BCL2L11) was observed. Skin-equivalent models built by TCHHL1-knockdown NHKs showed a markedly hypoplastic epidermis. These findings highlight that TCHHL1 plays an important role in homeostasis of the normal epidermis. TCHHL1 was expressed in the growing cells of cutaneous SCC; therefore, we next examined an association with the cell growth in HSC-1 cells (a human SCC line). In HSC-1 cells, the knockdown of TCHHL1 also suppressed cell proliferation and induced apoptosis. These cells showed an inhibition of phosphorylation of ERK1/2, AKT and signal transducers and activator of transcription 3, and the significant upregulation of FOXO1, BCL2, and BCL2L11. Accordingly, TCHHL1 is associated with survival of cutaneous SCC. In addition, we hypothesize that TCHHL1 may be a novel therapeutic target in cutaneous SCC.

表皮分化是一个复杂的过程，需要各种基因的调控和顺序表达。大多数融合型S100蛋白在颗粒层中表达，据推测这些蛋白可能与角质形成和屏障形成有关。我们之前确定了融合型S100蛋白的一种，即Trichohyalin-like 1（TCHHL1）蛋白。TCHHL1分布在正常表皮的基底层。此外，随着角质形成细胞的过度增殖，在癌性/非癌性皮肤样品中该表达显着增加。我们在这里检查了TCHHL1在正常人角质形成细胞（NHK）和鳞状细胞癌（SCC）中的作用。通过用TCHHL1 siRNA转染敲低TCHHL1，可显着抑制NHKs的增殖并诱导其早期凋亡。在TCHHL1击倒NHKs，细胞外信号调节激酶1/2（ERK1 / 2）磷酸化的水平明显降低。此外，观察到对v-akt鼠胸腺瘤病毒癌基因同源物（AKT）的磷酸化有轻微抑制作用，并且含有叉头盒的蛋白O1（FOXO1），B细胞淋巴瘤2（BCL2）和Bcl2样蛋白11（BCL2L11）上调。 。由TCHHL1基因敲除的NHK建立的皮肤等效模型显示出明显的发育不良的表皮。这些发现表明，TCHHL1在正常表皮的稳态中起着重要作用。TCHHL1在皮肤SCC的生长细胞中表达。因此，我们接下来检查了HSC-1细胞（人类SCC系）中细胞生长的相关性。在HSC-1细胞中，TCHHL1的敲低也抑制细胞增殖并诱导凋亡。这些细胞显示出ERK1 / 2，AKT和信号转导子以及转录激活因子3的磷酸化受到抑制，并且FOXO1，BCL2和BCL2L11明显上调。因此，TCHHL1与皮肤SCC的存活有关。此外，我们假设TCHHL1可能是皮肤SCC中的新型治疗靶标。