Silva Emmanuel J, Argyris Prokopios P, Zou Xianqiong, Ross Karen F, Herzberg Mark C
Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA; Mucosal and Vaccine Research Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Int J Biochem Cell Biol. 2014 Oct;55:279-87. doi: 10.1016/j.biocel.2014.09.007. Epub 2014 Sep 16.
Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility.
细胞内钙卫蛋白（S100A8/A9）在G2/M期细胞周期检查点的控制中发挥作用。S100A8/A9的失调似乎导致检查点丧失，这在头颈部鳞状细胞癌（HNSCC）中很常见。在本研究中，我们分析了癌细胞中其他由S100A8/A9介导的恶性表型变化。使用S100A8/A9阴性的人癌细胞系（KB），转染以表达S100A8和S100A9导致MMP-2选择性下调，并抑制体外侵袭和迁移。相反，在高分化的HNSCC细胞系TR146细胞中沉默内源性S100A8和S100A9表达，可增加MMP-2活性以及体外侵袭和迁移能力。当MMP-2表达被沉默时，细胞似乎呈现出恶性程度较低的表型。为了更紧密地模拟体内细胞生长的结构，将细胞在3D胶原基质中培养，并与2D培养进行比较。在3D基质上生长会导致更高的MMP-2表达。虽然HNSCC中经常发生CpG岛的高甲基化，但MMP-2的S100A8/A9依赖性调节无法用MMP2或TIMP2上游启动子的修饰来解释。总体而言，这些结果表明细胞内S100A8/A9通过调节MMP-2表达和活性来调节细胞迁移和移动性，从而促成癌细胞表型。
