{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:24:08Z","timestamp":1774355048847,"version":"3.50.1"},"reference-count":63,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":82,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005054","name":"Nantong University","doi-asserted-by":"publisher","award":["XNBHCX31773"],"award-info":[{"award-number":["XNBHCX31773"]}],"id":[{"id":"10.13039\/501100005054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy, and the molecular drivers of its progression are not fully defined. Dickkopf\u20103 (DKK3), a context\u2010dependent modulator of oncogenic signaling, has been implicated in several solid tumors, but its role in ESCC is unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated Mendelian randomization based on cis\u2010expression quantitative trait loci (cis\u2010eQTLs) from 31,684 individuals with The Cancer Genome Atlas (TCGA) ESCC transcriptomic data (|log\n                      <jats:sup>2<\/jats:sup>\n                      FC| &gt; 1 and\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.05) , single\u2010cell RNA sequencing, and in vitro\/in vivo functional assays to identify causal ESCC\u2010associated genes. DKK3 expression was validated by Western blotting, its effects on ESCC cell proliferation, migration, and clonogenicity were tested experimentally, and DKK3\u2010related pathways were explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Integrative differential expression and MR analyses identified 22 ESCC\u2010associated genes. Single\u2010cell epithelial profiling further prioritized three candidates (DKK3, NINJ2, and SAPCD2), among which only DKK3 showed high and progressively increasing expression along the malignant epithelial trajectory and was therefore selected for mechanistic validation. DKK3 knockdown significantly inhibited ESCC cell proliferation, migration, and clonogenic capacity in vitro and suppressed tumor growth in nude mice. DKK3 silencing reduced p\u2010PI3K and p\u2010AKT levels, and enrichment analyses supported that DKK3 promotes ESCC progression at least partly through activation of the PI3K\u2013AKT signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>By linking germline regulatory variation with single\u2010cell tumor profiling and functional validation, this study identifies DKK3 as a causally relevant oncogenic regulator in ESCC that drives epithelial tumor growth and migration via PI3K\u2013AKT pathway activation, supporting DKK3 as a potential biomarker and therapeutic targe<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/6777692","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T11:10:00Z","timestamp":1774350600000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Mendelian Randomization and Single\u2010Cell Pseudotime Analysis Reveal DKK3 as a PI3K\u2013AKT\u2010Modulated Driver of Esophageal Squamous Cell Carcinoma"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3223-8625","authenticated-orcid":false,"given":"Zhanghao","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4616-2718","authenticated-orcid":false,"given":"Tiegang","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1688-8548","authenticated-orcid":false,"given":"You Lang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8635-5376","authenticated-orcid":false,"given":"Jiahai","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"e_1_2_14_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.662774"},{"key":"e_1_2_14_2_2","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.21037\/tlcr-20-618","article-title":"Alternative Splicing of HER2: a Novel Mediator of EGFR TKI Resistance","volume":"9","author":"Yochum Z. 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