Inaba Hiroaki, Amano Atsuo, Lamont Richard J, Murakami Yukitaka
Department of Oral Microbiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu, 501-0296, Japan,
Med Microbiol Immunol. 2015 Oct;204(5):605-12. doi: 10.1007/s00430-015-0389-y. Epub 2015 Feb 11.
Porphyromonas gingivalis, a periodontal pathogen, is epidemiologically associated with oral squamous cell carcinoma (OSCC). Matrix metalloproteinase 9 (MMP9) which degrades the extracellular matrix and basement membrane components has been implicated in invasion and metastasis of tumor cells. We previously reported that P. gingivalis promoted cellular invasion of carcinoma SAS cells, an established cell line from patients with squamous cell carcinoma of the tongue, by induction of MMP9 production via proteinase-activated receptor 2. In this study, we further examined alternative signaling pathways mediating inactive precursor of MMP9 (proMMP9) production induced by P. gingivalis in SAS cells. Following P. gingivalis infection, PAR4 mRNA expression was increased and proMMP9 production was enhanced, leading to acceleration of SAS cell invasion. Small interfering RNA knockdown of PAR4 gene abrogated both proMMP9 expression and cellular invasion induced by P. gingivalis in SAS cells. Moreover, the phosphorylation of p38 and ERK1/2 was reduced in PAR4 gene knockdown cells infected with P. gingivalis, whereas nuclear translocation of NF-kB was not inhibited. These results suggest that P. gingivalis activates PAR4 signaling pathways, leading proMMP9 over-expression and cellular invasion in OSCC cells.
牙龈卟啉单胞菌是一种牙周病原体，在流行病学上与口腔鳞状细胞癌（OSCC）相关。基质金属蛋白酶9（MMP9）可降解细胞外基质和基底膜成分，与肿瘤细胞的侵袭和转移有关。我们之前报道过，牙龈卟啉单胞菌通过蛋白酶激活受体2诱导MMP9的产生，从而促进舌鳞状细胞癌患者来源的成熟细胞系SAS癌细胞的细胞侵袭。在本研究中，我们进一步研究了介导牙龈卟啉单胞菌诱导SAS细胞产生无活性MMP9前体（proMMP9）的替代信号通路。牙龈卟啉单胞菌感染后，PAR4 mRNA表达增加，proMMP9产生增强，导致SAS细胞侵袭加速。PAR4基因的小干扰RNA敲低消除了牙龈卟啉单胞菌在SAS细胞中诱导的proMMP9表达和细胞侵袭。此外，在感染牙龈卟啉单胞菌的PAR4基因敲低细胞中，p38和ERK1/2的磷酸化减少，而NF-κB的核转位未受抑制。这些结果表明，牙龈卟啉单胞菌激活PAR4信号通路，导致OSCC细胞中proMMP9过表达和细胞侵袭。
