Legumain‐Mediated Activation of PAR 2 Contributes to Mechanical Hypersensitivity in a Rat Model of Tongue Cancer

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OBJECTIVE: Legumain, also known as asparaginyl endopeptidase or δ-secretase, is a cysteine protease that plays a significant role in various biological and pathological processes. This study investigated the role of the legumain-protease-activated receptor 2 (PAR2) signaling pathway in mechanical hypersensitivity in a rat model of tongue cancer. METHODS: Squamous cell carcinoma (SCC) cells were injected subcutaneously into the tongue. Mechanical head withdrawal reflex threshold (MHWT) was recorded after SCC inoculation or activated-legumain administration. The expression of legumain in the cancerous tongue and PAR2 in the trigeminal ganglion was measured. The effects of legumain inhibition on the MHWT in SCC-inoculated tongues were assessed. RESULTS: The SCC-inoculated tongue resulted in a significant decrease in MHWT. Legumain levels were elevated in the SCC-inoculated tongue, and administration of activated-legumain induced mechanical allodynia. Conversely, legumain inhibitor administration mitigated SCC-induced reduction in MHWT. PAR2 was identified in trigeminal ganglion neurons that innervate the tongue, and its blockade reduced mechanical hypersensitivity in the SCC-inoculated tongue. CONCLUSIONS: These findings suggest that legumain released from SCC cells activates PAR2 on primary afferent terminals, leading to the mechanical sensitization of cancerous tongues. This study provides novel insights into the peripheral mechanisms of oral SCC pain.

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