细胞内钙卫蛋白（S100A8/A9）控制头颈部鳞状细胞癌中上皮分化和半胱氨酸蛋白酶介导的 EGFR 裂解。
Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma.
机构信息
Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
Division of Oral and Maxillofacial Pathology, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
出版信息
Oral Oncol. 2019 Aug;95:1-10. doi: 10.1016/j.oraloncology.2019.05.027. Epub 2019 Jun 4.
OBJECTIVES
Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC.
AIMS
(1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC.
MATERIALS AND METHODS
Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy.
RESULTS
In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased.
CONCLUSIONS
In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer.
目的
钙卫蛋白（S100A8/A9）似乎在头颈部鳞状细胞癌（HNSCC）中发挥肿瘤抑制作用，并且癌细胞中的表达与患者的生存率直接相关。我们旨在研究钙卫蛋白在 HNSCC 中的抑制作用。
目的
（1）研究口腔癌变过程中 S100A8/A9 表达的变化，（2）确定细胞内钙卫蛋白是否可以调节 HNSCC 中的表皮生长因子受体（EGFR），这是一个负预后因素。
材料和方法
使用免疫组织化学（IHC）分析了 46 例 HNSCC 标本中的 S100A8/A9，包括高分化（WD，N=19）、中分化（MD，N=14）、低分化（PD，N=5）和非角化/基底样（NK/BAS，N=8）以及癌前上皮异型增生（PED，N=16）。同样，分析了 21 例 HNSCC 中的 EGFR。为了确定钙卫蛋白和 EGFR 表达是否具有机制相关性，比较了表达 S100A8/A9 的 TR146 HNSCC 细胞或沉默（shRNA）的 S100A8/A9 细胞的 EGFR 水平和 caspase-3/7 活性，使用 Western blot 和免疫荧光显微镜。
结果
在正常口腔黏膜上皮中，S100A8/A9 在基底层细胞的细胞质和细胞核中染色强烈；基底细胞始终为 S100A8/A9 阴性。在 PED 和 HNSCC 中，S100A8/A9 的表达低于相邻的正常上皮组织（NAT），并且在 WD、MD、PD 和 NK/BAS HNSCC 中逐渐降低。S100A8/A9 和 EGFR 水平似乎呈负相关，在 TR146 细胞中沉默 S100A8/A9 时，这种相关性在体外得到模拟。沉默 S100A8/A9 显著降低了 caspase-3/7 活性，而 EGFR 水平增加。
结论
在 HNSCC 中，S100A8/A9 与细胞分化直接相关，并且似乎促进 caspase-3/7 介导的 EGFR 裂解，这可以解释为什么 S100A8/A9 高肿瘤患者的生存期更长。
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