{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T07:14:07Z","timestamp":1788506047557,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS\u20102026\u201025481629"],"award-info":[{"award-number":["RS\u20102026\u201025481629"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hypoxia and nutrient deprivation are fundamental drivers of tumor aggressiveness and therapeutic resistance in hepatocellular carcinoma (HCC). While the involvement of neural components in the tumor microenvironment (TME) is increasingly recognized, the molecular transducers linking metabolic stress to neuron\u2013tumor crosstalk remain elusive. Here, we identify ADAM23 (A disintegrin and metalloproteinase 23) as a hypoxia\u2010responsive mediator that mediates communication between HCC cells and neuronal cells. ADAM23 expression was markedly upregulated in HCC cells under both chemical (CoCl\n                    <jats:sub>2<\/jats:sub>\n                    ) and physical hypoxia (1% O\n                    <jats:sub>2<\/jats:sub>\n                    ), a process further amplified by glucose deprivation and directly modulated by HIF\u20101\u03b1. Functional assays revealed that ADAM23 overexpression promotes epithelial\u2013mesenchymal transition (EMT) and enhances cell viability under metabolic stress. Notably, sorafenib\u2010resistant HCC cells (Huh7SR) exhibited high levels of ADAM23 secretion, which triggered proliferative and metabolic activation in neuronal SH\u2010SY5Y cells. In 3D co\u2010culture spheroid models, Huh7SR cells mixed with SH\u2010SY5Y cells displayed significantly larger spheroid volumes and enhanced neuronal fluorescence compared with parental controls, suggesting that ADAM23\u2010mediated interactions facilitate a supportive neural niche. Analysis of The Cancer Genome Atlas (TCGA) datasets and patient microarrays confirmed that ADAM23 is significantly overexpressed in HCC and positively correlates with HIF\u20101\u03b1 expression. Moreover, elevated expression of ADAM23 was significantly correlated with poor overall survival. Collectively, our findings underscore ADAM23 as a critical metabolic\u2010neural linker that promotes HCC progression and drug resistance. These findings suggest that the ADAM23\u2010mediated neuron\u2013tumor axis may represent a potential therapeutic target in aggressive HCC.\n                  <\/jats:p>","DOI":"10.1002\/mc.70174","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T06:46:56Z","timestamp":1788504416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia\u2010Induced ADAM23 Drives Neuron\u2013Tumor Crosstalk and Therapeutic Resistance in Hepatocellular Carcinoma"],"prefix":"10.1002","author":[{"given":"Taehyun","family":"Park","sequence":"first","affiliation":[{"name":"Division of Life Sciences, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunjung","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4107-7470","authenticated-orcid":false,"given":"Johyeon","family":"Nam","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayoung","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9208-2127","authenticated-orcid":false,"given":"Misu","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"},{"name":"Institute for New Drug Development, College of Life Science and Bioengineering Incheon National University Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"issue":"4","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/j.gastro.2016.11.048","article-title":"Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis","volume":"152","author":"Sia D.","year":"2017","journal-title":"Gastroenterology"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","DOI":"10.1038\/nrdp.2016.18","article-title":"Hepatocellular Carcinoma","volume":"2","author":"Llovet J. 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R.","year":"2020","journal-title":"Journal of Experimental & Clinical Cancer Research"},{"issue":"11","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","DOI":"10.1172\/JCI159839","article-title":"Hypoxia\u2010Inducible Factors: Cancer Progression and Clinical Translation","volume":"132","author":"Wicks E. 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D.","year":"2010","journal-title":"American Journal of Roentgenology"},{"key":"e_1_2_11_37_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3389\/fphys.2012.00097","article-title":"Nerve\u2010Cancer Interactions in the Stromal Biology of Pancreatic Cancer","volume":"3","author":"Demir I. E.","year":"2012","journal-title":"Frontiers in Physiology"},{"issue":"1","key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0360-3016(03)01433-0","article-title":"Perineural Invasion Is Associated With Increased Relapse After External Beam Radiotherapy for Men With Low\u2010Risk Prostate Cancer and May Be a Marker for Occult, High\u2010Grade Cancer","volume":"58","author":"Beard C. 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