{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:11:25Z","timestamp":1788793885564,"version":"build-2803163510"},"reference-count":40,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education Malaysia","doi-asserted-by":"crossref","award":["FRGS\/1\/2022\/SKK10\/UM\/01\/1"],"award-info":[{"award-number":["FRGS\/1\/2022\/SKK10\/UM\/01\/1"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    The prognosis for patients with oral squamous cell carcinoma (OSCC) is poor and novel ways to manage the disease are required. The density of myofibroblastic cancer-associated fibroblasts (myoCAFs) within the OSCC stroma correlates with poor prognosis, suggesting that myoCAFs could be targetted therapeutically. OSCC cells have been shown to regulate myoCAF differentiation\n                    <jats:italic>via<\/jats:italic>\n                    mechanisms involving transforming growth factor-\u03b21 (TGF-\u03b21), but the further downstream mechanisms are yet to be clearly defined. In this study, we aimed to examine the involvement of sphingosine 1-phosphate (S1P) signalling in mediating myofibroblast differentiation. Treatment of normal oral fibroblasts with OSCC conditioned media (CM) or TGF-\u03b21 induced the expression of \u03b1-smooth muscle actin (\u03b1-SMA), a well-recognised marker of fibroblast activation\/myofibroblasts. TGF-\u03b21 up-regulated expression of sphingosine kinase 1 (SK1), but not sphingosine kinase 2 (SK2). However, inhibiting either of the SKs abrogated the induction of \u03b1-SMA expression by TGF-\u03b21 and OSCC CM. The effect of inhibiting SK1\/2 could not be rescued by exogenous S1P suggesting a possible role for intracellular S1P. Normal oral fibroblasts were shown to express predominantly sphingosine 1-phosphate receptor 2 (S1PR2) and sphingosine 1-phosphate receptor 3 (S1PR3) receptors. The induction of \u03b1-SMA expression by OSCC CM was abrogated with a S1PR2 antagonist, whilst \u03b1-SMA expression was upregulated following treatment with a S1PR2 agonist. Using pharmacological modulation of \u03b1-SMA expression, our data show that SKs and S1PR2 contribute to myofibroblast differentiation in OSCC. These results highlight the potential of inhibiting S1P signalling to inhibit myoCAF development.\n                  <\/jats:p>","DOI":"10.7717\/peerj.21673","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T14:58:55Z","timestamp":1788793135000},"page":"e21673","source":"Crossref","is-referenced-by-count":0,"title":["Sphingosine 1-phosphate signalling contributes to transforming growth factor-\u03b21-induced myofibroblast differentiation in oral cancer"],"prefix":"10.7717","volume":"14","author":[{"given":"Kathyleen Hui Lin","family":"Chong","sequence":"first","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, Universiti Malaya, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wee Lin","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, Universiti Malaya, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deron R.","family":"Herr","sequence":"additional","affiliation":[{"name":"School of Medicine, Indiana University, Terre Haute, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Leng","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Science, Monash University, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee Fah","family":"Yap","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, Universiti Malaya, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian C.","family":"Paterson","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, Universiti Malaya, Kuala Lumpur, Malaysia"},{"name":"Oral Cancer Research & Coordinating Centre, Universiti Malaya, Kuala Lumpur, 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