Clostridium perfringens enterotoxin induces claudin-4 to activate YAP in oral squamous cell carcinomas

Oncotarget Volume 11, Issue 4: Treatment of human oral squamous cell carcinoma cell lines HSC3 and HSC4 with Clostridium perfringens enterotoxin, induced CLDN4 nuclear translocation to enhance epithelial-mesenchymal transition, stemness, cell proliferation, and invasive ability.

Moreover, it was revealed that the complex of YAP1, CLDN4, and zona occludens-2 was formed by CPE treatment, further suppressing YAP1 phosphorylation by LATS1 and activating it.

Dr. Yi Luo from the Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province 226001, China, Dr. Tadaaki Kirita from the Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Nara, Japan and Dr. Hiroki Kuniyasu from the Department of Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan said in their Oncotarget research article, "More than 300 species of bacteria are found in the oral cavity, 10% of which are anaerobic in nature"

The number of bacteria in the oral cavity is determined by scraping the gingiva.

Mostly the normal count of bacteria is about 1011 to 1012 cfu/ml and of these 0.1% are anaerobic.

Expression of CLDN4 in oral squamous cell carcinomas. Immunohistochemical evaluation was carried out to identify CLDN4 using anti-CLDN4 antibody, 4D3. CLDN4 was visualized by peroxidase-diaminobenzidine (DAB) method (left column) or Cy5-labeled secondary antibody (right column). Cy5 images were semi-quantified for evaluation of CLDN4 protein levels. (A) non-cancerous tongue epithelium (B) OSCC, G2, pT2pN0pM0, (C) OSCC, G2, pT3pN1pM0, (D) OSCC, G3, pT4PN2pM0. Bar, 100 μm.

It is still unclear what role oral bacteria play exactly in the development of oral cancer.

In contrast, zonula occludens -1 and ZO-2, which are lining proteins in tight junctions, activate yes-associated protein and transcriptional coactivator with PDZ-binding motif by inhibiting the Hippo signaling pathway, promoting cancer cell growth and epithelial-mesenchymal transition to enhance cancer metastasis.

In this study, the authors examined the role of the bacteria in the oral cavity, especially anaerobic bacteria, in the development of oral cancer through the action on CLDN protein.

We showed that anaerobic bacteria impair tight junctions and promote cancer progression through YAP1 activation in oral squamous cell carcinomas.

The Luo/Kirita/Kuniyasu Research Team concluded that their Oncotarget study inferred that Clostridium induced YAP1 activation, which in turn suggested that the suppression of Clostridium by antibiotics and/or oral hygiene might contribute to the suppression of carcinogenesis and cancer progression. Extensive clinical studies are required to prove this hypothesis in the future.

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Full text - https://doi.org/10.18632/oncotarget.27424

Correspondence to - Yi Luo - lynantong@hotmail.com - Tadaaki Kirita - tkirita@naramed-u.ac.jp - Hiroki Kuniyasu - cooninh@zb4.so-net.ne.jp

Keywords - lostridium perfringens enterotoxin, claudin-4, YAP, Hippo signal, oral squamous cell carcinoma, Pathology