Oral pathogens change proliferation properties of oral tumor cells by affecting gene expression of human defensins

Abstract

The impact of oral pathogens onto the generation and variability of oral tumors has only recently been investigated. To get further insights, oral cancer cells were treated with pathogens and additionally, as a result of this bacterial cellular infection, with human defensins, which are as anti-microbial peptide members of the innate immune system. After cell stimulation, proliferation behavior, expression analysis of oncogenic relevant defensin genes, and effects on EGFR signaling were investigated. The expression of oncogenic relevant anti-microbial peptides was analyzed with real-time PCR and immunohistochemistry. Cell culture experiments were performed to examine cellular impacts caused by stimulation, i.e., altered gene expression, proliferation rate, and EGF receptor-dependent signaling. Incubation of oral tumor cells with an oral pathogen (Porphyromonas gingivalis) and human α-defensins led to an increase in cell proliferation. In contrast, another oral bacterium used, Aggregatibacter actinomycetemcomitans, enhanced cell death. The bacteria and anti-microbial peptides exhibited diverse effects on the transcript levels of oncogenic relevant defensin genes and epidermal growth factor receptor signaling. These two oral pathogens exhibited opposite primary effects on the proliferation behavior of oral tumor cells. Nevertheless, both microbe species led to similar secondary impacts on the proliferation rate by modifying expression levels of oncogenic relevant α-defensin genes. In this respect, oral pathogens exerted multiplying effects on tumor cell proliferation. Additionally, human defensins were shown to differently influence epidermal growth factor receptor signaling, supporting the hypothesis that these anti-microbial peptides serve as ligands of EGFR, thus modifying the proliferation behavior of oral tumor cells.

Role of Porphyromonas gingivalis in oral squamous cell carcinoma development: A systematic review

“…Overexpression of HNP2 and DEFA4 defensins against P gingivalis infection of human OSCC samples and of OSCC cells (BHY line) was reported by Hoppe et al These defensins promoted NF‐kB overexpression and activation of cyclin D1, an EGF receptor ligand that increases cell proliferation and tumor growth.…”

“…Studies were classified into three main groups according to oral specimen origins. In the first one, three studies (18.75%) used epithelial cells from human samples (Table ); in the second, three studies (18.75%) evaluated murine models (Table ); and in the last one, 11 studies (62.5%) were developed in pre‐established cell lines (Table ).…”

“…In a second one (promotion), tissue growth and cancer could develop throughout overexpression of receptors and growth factors, cytokines, extracellular matrix destruction, angiogenesis, etc In the last one (progression), malignant cells invade local or distant tissues, while molecular alterations continue to carry on. Steps of oral carcinogenesis in which P gingivalis play an important role (Figure ) are epithelial‐mesenchymal transition of oral epithelial cells, neoplastic cell proliferation, and tumor cell invasiveness …”

“…Alteration of two molecular pathways has been proposed to explain cell proliferation The first one, destroying collagen IV and V of the extracellular matrix, is related to MMP9, which may be activated by ZEB1 or TLR2 . The second mechanism is associated with cyclin D1, an important oncoprotein whose carcinogenic effect is also through EGF . After infection with P gingivalis , gingipains, or STAT3‐activated IL‐6, promote cyclin D1 .…”

“…Protein p38MAPK promotes cell stress, differentiation, and autophagy . ERK1/2 has a huge oncogenic activity, and finally, NF‐kB is involved in cellular immune response, provoking nuclear translocation . These molecular links (MAP‐kinase‐dependant pathways) have only been reported in very aggressive OSCC cells (SAS line) .…”