基质金属蛋白酶12由不均一核核糖核蛋白K诱导，并促进鼻咽癌的迁移和侵袭。
Matrix metalloproteinase 12 is induced by heterogeneous nuclear ribonucleoprotein K and promotes migration and invasion in nasopharyngeal carcinoma.
作者信息
Chung I-Che, Chen Lih-Chyang, Chung An-Ko, Chao Mei, Huang Hsin-Yi, Hsueh Chuen, Tsang Ngan-Ming, Chang Kai-Ping, Liang Ying, Li Hsin-Pai, Chang Yu-Sun
机构信息
Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa Ist Road, Taoyuan, Kwei-shan 333, Taiwan.
出版信息
BMC Cancer. 2014 May 20;14:348. doi: 10.1186/1471-2407-14-348.
BACKGROUND
Overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC.
METHODS
We studied hnRNP K-regulated MMPs by analyzing the expression profiles of MMP family genes in NPC tissues and hnRNP K-knockdown NPC cells using Affymetrix microarray analysis and quantitative RT-PCR. The association of hnRNP K and MMP12 expression in 82 clinically proven NPC cases was determined by immunohistochemical analysis. The hnRNP K-mediated MMP12 regulation was determined by zymography and Western blot, as well as by promoter, DNA pull-down and chromatin immunoprecipitation (ChIP) assays. The functional role of MMP12 in cell migration and invasion was demonstrated by MMP12-knockdown and the treatment of MMP12-specific inhibitor, PF-356231.
RESULTS
MMP12 was overexpressed in NPC tissues, and this high level of expression was significantly correlated with high-level expression of hnRNP K (P = 0.026). The levels of mRNA, protein and enzyme activity of MMP12 were reduced in hnRNP K-knockdown NPC cells. HnRNP K interacting with the region spanning -42 to -33 bp of the transcription start site triggered transcriptional activation of the MMP12 promoter. Furthermore, inhibiting MMP12 by MMP12 knockdown and MMP12-specific inhibitor, PF-356231, significantly reduced the migration and invasion of NPC cells.
CONCLUSIONS
Overexpression of MMP12 was significantly correlated with hnRNP K in NPC tissues. HnRNP K can induce MMP12 expression and enzyme activity through activating MMP12 promoter, which promotes cell migration and invasion in NPC cells. In vitro experiments suggest that NPC metastasis with high MMP12 expression may be treated with PF-356231. HnRNP K and MMP12 may be potential therapeutic markers for NPC, but additional validation studies are warranted.
背景
异质性核核糖核蛋白K（hnRNP K）是一种DNA/RNA结合蛋白，其过表达与鼻咽癌（NPC）转移相关。然而，hnRNP K介导转移的潜在机制尚不清楚。本研究旨在确定基质金属蛋白酶（MMP）在hnRNP K介导的NPC转移中的作用。
方法
我们通过使用Affymetrix微阵列分析和定量逆转录-聚合酶链反应（RT-PCR）分析NPC组织和hnRNP K敲低的NPC细胞中MMP家族基因的表达谱，研究hnRNP K调节的MMP。通过免疫组织化学分析确定82例经临床证实的NPC病例中hnRNP K与MMP12表达的相关性。通过酶谱法、蛋白质印迹法以及启动子、DNA下拉和染色质免疫沉淀（ChIP）试验确定hnRNP K介导的MMP12调节。通过MMP12敲低和MMP12特异性抑制剂PF-356231的处理，证明MMP12在细胞迁移和侵袭中的功能作用。
结果
MMP12在NPC组织中过表达，这种高水平表达与hnRNP K的高水平表达显著相关（P = 0.026）。在hnRNP K敲低的NPC细胞中，MMP12的mRNA、蛋白质和酶活性水平降低。hnRNP K与转录起始位点-42至-33 bp区域相互作用，触发MMP12启动子的转录激活。此外，通过MMP12敲低和MMP12特异性抑制剂PF-356231抑制MMP12，显著降低了NPC细胞的迁移和侵袭。
结论
NPC组织中MMP12的过表达与hnRNP K显著相关。hnRNP K可通过激活MMP12启动子诱导MMP12表达和酶活性，促进NPC细胞的迁移和侵袭。体外实验表明，高表达MMP12的NPC转移可能可用PF-356231治疗。hnRNP K和MMP12可能是NPC的潜在治疗标志物，但需要进一步的验证研究。
Zotero 插件