{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T19:36:49Z","timestamp":1776713809754,"version":"3.51.2"},"reference-count":25,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,10,25]],"date-time":"2018-10-25T00:00:00Z","timestamp":1540425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16H0699219"],"award-info":[{"award-number":["16H0699219"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K1722500"],"award-info":[{"award-number":["18K1722500"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1\/2 (pERK1\/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that the inhibition of monocarboxylate transporter 4 (MCT4) by short hairpin (shRNA) transduction suppressed the HNSCC-BP, the lactate level in bone marrow, and the pERK1\/2 expression in DRG. The sensory nerves also expressed increased levels of the acid-sensing receptor TRPV1. DRG neurons co-cultured with SAS cells showed increased neurite outgrowth, and were inhibited by MCT4 silencing with shRNA. Collectively, our results show that HNSCC induced an acidic bone microenvironment that evokes HNSCC-BP via MCT4 expression.<\/jats:p>","DOI":"10.3390\/ijms19113317","type":"journal-article","created":{"date-parts":[[2018,10,26]],"date-time":"2018-10-26T03:16:16Z","timestamp":1540523776000},"page":"3317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"19","author":[{"given":"Kazuaki","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7640-3274","authenticated-orcid":false,"given":"Tatsuo","family":"Okui","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Shimo","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soichiro","family":"Ibaragi","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hotaka","family":"Kawai","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoji","family":"Ryumon","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Kishimoto","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Okusha","sequence":"additional","affiliation":[{"name":"Departments of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-723X","authenticated-orcid":false,"given":"Nur Mohammad","family":"Monsur Hassan","sequence":"additional","affiliation":[{"name":"School of Dentistry &amp; Health Sciences, Charles Sturt University, Sydney, NSW 2678, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Departments of Oral and Maxillofacial Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8525, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1002\/hed.10062","article-title":"Patterns of invasion and routes of tumor entry into the mandible by oral squamous cell carcinoma","volume":"24","author":"Brown","year":"2002","journal-title":"Head Neck"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cho, S.F., Rau, K.M., Shao, Y.Y., Yen, C.J., Wu, M.F., Chen, J.S., Chang, C.S., Yeh, S.P., Chiou, T.J., and Hsieh, R.K. 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