Makino Teruhiko, Mizawa Megumi, Yoshihisa Yoko, Yamamoto Seiji, Tabuchi Yoshiaki, Miyai Masashi, Hibino Toshihiko, Sasahara Masakiyo, Shimizu Tadamichi
Department of Dermatology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Toyama, Japan.
Department of Pathology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Toyama, Japan.
Cell Death Discov. 2020 Oct 27;6:109. doi: 10.1038/s41420-020-00344-5. eCollection 2020.
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，需要各种基因的有序表达。大多数融合型S100蛋白在颗粒层表达，据推测这些蛋白可能与角质化和屏障形成有关。我们之前鉴定出一种融合型S100蛋白成员，即类毛透明蛋白1（TCHHL1）。TCHHL1分布于正常表皮的基底层。此外，在角质形成细胞过度增殖的癌性/非癌性皮肤样本中，其表达显著增加。我们在此研究了TCHHL1在正常人角质形成细胞（NHK）和鳞状细胞癌（SCC）中的作用。用TCHHL1 siRNA转染敲低TCHHL1可显著抑制NHK的增殖并诱导其早期凋亡。在敲低TCHHL1的NHK中，细胞外信号调节激酶1/2（ERK1/2）的磷酸化水平显著降低。此外，还观察到v-akt小鼠胸腺瘤病毒癌基因同源物（AKT）磷酸化受到轻微抑制，含叉头框蛋白O1（FOXO1）、B细胞淋巴瘤2（BCL2）和Bcl2样蛋白11（BCL2L11）上调。由敲低TCHHL1的NHK构建的皮肤等效模型显示表皮明显发育不全。这些发现突出表明TCHHL1在正常表皮的稳态中起重要作用。TCHHL1在皮肤SCC的增殖细胞中表达；因此，我们接下来研究了其与HSC-1细胞（一种人SCC细胞系）生长的关系。在HSC-1细胞中，敲低TCHHL1也会抑制细胞增殖并诱导凋亡。这些细胞显示ERK1/2、AKT以及信号转导和转录激活因子3的磷酸化受到抑制，FOXO1、BCL2和BCL2L11显著上调。因此，TCHHL1与皮肤SCC的存活有关。此外，我们推测TCHHL1可能是皮肤SCC的一个新的治疗靶点。
