Matrix metalloproteinase 12 is induced by heterogeneous nuclear ribonucleoprotein K and promotes migration and invasion in nasopharyngeal carcinoma

Abstract

BackgroundOverexpression 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.MethodsWe 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.ResultsMMP12 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.ConclusionsOverexpression 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.

Down‐regulation of DAB2IP promotes colorectal cancer invasion and metastasis by translocating hnRNPK into nucleus to enhance the transcription of MMP2

“…Our preliminary results also showed that DAB2IP could be functioned as an independent prognostic factor in CRC patients . hnRNPK is increased in nasopharyngeal carcinoma, liver cancer and lung cancer and closely related to the prognosis of patients . The expression of p‐hnRNPK is positively related to tumor grade and negatively related to CRC prognosis .…”

“…hnRNPK regulates the transcription activities of MMP3 and MMP10 in the nucleus to affect the proliferation and migration of fibroma cells in vitro . hnRNPK combines with MMP12 promoter and regulates its transcription to promote tumor invasion, in addition to its regulation of MMP2 expression in nasopharyngeal carcinoma . In our study, we found that hnRNPK enhanced the transcription activity of MMP2 and increased the level of activated MMP2 in CRC cells.…”

“…Recent data shows that hnRNPK promotes tumor metastasis by regulating the transcription activities of MMP3 and MMP10 . hnRNPK also enhances MMP12 transcription activity to induce invasion in nasopharyngeal carcinoma . So we asked whether hnRNPK enhances the transcription activity of MMP2 in CRC cells.…”

“…hnRNPK is a member of multifunctional protein family and exerts biological function both inside and outside the nucleus, shares the founctions of regulating translation and processing of RNA with other members of the family . hnRNPK participates in regulating cell cycle, cell apoptosis and tumor metastasis and upregulation of hnRNPK in gastric cancer, liver cancer or lung cancer is related to poor prognosis . MMPs promote tumor growth, metastasis and angiogenesis in the processes of tumor metastasis .…”

Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells

“…23 Downregulation of MMP12 by siRNA or specific inhibitor PF-356231 can significantly inhibit the migration and invasion of nasopharyngeal carcinoma cells. 24 We further evaluated the function of MMP12 in LAC cells and found that knockdown of MMP12 also decreased cell proliferation and invasion of LAC cells. MMP12-engineered endothelial progenitor cells (EPCs) inhibit tumor growth, tumor angiogenesis, and development of lung metastasis.…”