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Prolonged and repetitive exposure to Porphyromonas gingivalis increases aggressiveness of oral cancer cells by promoting acquisition of cancer stem cell properties

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Tumor Biology

Abstract

Periodontitis is the most common chronic inflammatory condition occurring in the human oral cavity, but our knowledge on its contribution to oral cancer is rather limited. To define crosstalk between chronic periodontitis and oral cancer, we investigated whether Porphyromonas gingivalis, a major pathogen of chronic periodontitis, plays a role in oral cancer progression. To mimic chronic irritation by P. gingivalis in the oral cavity, oral squamous cell carcinoma (OSCC) cells were infected with P. gingivalis twice a week for 5 weeks. Repeated infection of oral cancer cells by P. gingivalis resulted in morphological changes of host cancer cells into an elongated shape, along with the decreased expression of epithelial cell markers, suggesting acquisition of an epithelial-to-mesenchymal transition (EMT) phenotype. The prolonged exposure to P. gingivalis also promoted migratory and invasive properties of OSCC cells and provided resistance against a chemotherapeutic agent, all of which are described as cellular characteristics undergoing EMT. Importantly, long-term infection by P. gingivalis induced an increase in the expression level of CD44 and CD133, well-known cancer stem cell markers, and promoted the tumorigenic properties of infected cancer cells compared to non-infected controls. Furthermore, increased invasiveness of P. gingivalis-infected OSCC cells was correlated with enhanced production of matrix metalloproteinase (MMP)-1 and MMP-10 that was stimulated by interleukin-8 (IL-8) release. This is the first report demonstrating that P. gingivalis can increase the aggressiveness of oral cancer cells via epithelial-mesenchymal transition-like changes and the acquisition of stemness, implicating P. gingivalis as a potential bacterial risk modifier.

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Acknowledgments

This work was supported by Basic Science Research Program through National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2A16050554).

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    Authors and Affiliations

    1. Department of Oral Pathology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan-Si, Kyeongsangnam-Do, 626-870, South Korea

      Na Hee Ha, Bok Hee Woo, Da Jeong Kim, Eun Sin Ha, Ji Hye Lee & Hae Ryoun Park

    2. Department of Periodontology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea

      Jeom Il Choi & Sung Jo Kim

    3. Department of Oral Anatomy, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea

      Bong Soo Park

    4. Institute of Translational Dental Sciences, Pusan National University, 49 Busandaehak-Ro, Yangsan, 626-870, South Korea

      Ji Hye Lee & Hae Ryoun Park

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    Na Hee Ha and Bok Hee Woo contributed equally to this work.

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    Ha, N.H., Woo, B.H., Kim, D.J. et al. Prolonged and repetitive exposure to Porphyromonas gingivalis increases aggressiveness of oral cancer cells by promoting acquisition of cancer stem cell properties. Tumor Biol. 36, 9947–9960 (2015). https://doi.org/10.1007/s13277-015-3764-9

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