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Ephrin receptor B2 (EPHB2) promotes malignant phenotypes in multiple tumor types; however, its functional role and mechanistic basis in cervical cancer, particularly in VM-associated plasticity, remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>EPHB2 dysregulation was screened in public transcriptomic cohorts (GSE168244, tumor vs. normal; GSE138080, precancer vs. normal) and validated at the protein level in an institutional immunohistochemistry (IHC) cohort. Its clinical relevance was assessed in TCGA-CESC with GTEx normal cervix controls for tumor\u2013normal comparison and survival analysis. Single-cell RNA-seq data (GSE168652) were used to map EPHB2 expression and characterize epithelial functional states. Gain- and loss-of-function assays in HeLa and SiHa cells evaluated proliferation, clonogenicity, migration, apoptosis, EMT marker expression, and Matrigel-based capillary-like network formation. In vivo validation was performed in SiHa xenografts with stable EPHB2 knockdown. Mechanistic analyses integrated two independent RNA-seq comparisons after EPHB2 silencing with pathway enrichment, qRT\u2013PCR and Western blot validation, and functional interrogation of ETV4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EPHB2 was consistently upregulated in cervical cancer across multiple cohorts, including precancerous lesions, and showed increased protein abundance in tumor tissues. In TCGA-CESC, high EPHB2 expression was associated with poorer overall survival and enhanced EMT activity. Single-cell analysis linked EPHB2-positive\/high epithelial cells to EMT\/VM-related epithelial states. Functionally, EPHB2 silencing inhibited proliferation, colony formation, migration, and capillary-like network formation, increased apoptosis, and shifted EMT markers toward an epithelial phenotype, whereas EPHB2 overexpression produced reciprocal effects. Stable EPHB2 knockdown further suppressed xenograft growth and altered angiogenesis\/VM- and EMT-related features in vivo. Mechanistically, two independent RNA-seq datasets converged on \u201cTranscriptional misregulation in cancer\u201d as the only shared tumor-relevant enriched pathway. Subsequent validation supported an EPHB2\u2013ERK\u2013ETV4 module accompanied by coordinated changes in DUSP6 and CXCL8. ETV4 depletion impaired proliferation and VM-like network formation and attenuated the growth advantage conferred by EPHB2 overexpression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>EPHB2 promotes cervical cancer progression by sustaining EMT-linked plasticity and VM-like behavior, at least in part through an ERK\u2013ETV4-centered transcriptional program. These findings identify EPHB2 as a candidate biomarker of aggressive cervical cancer and a potential therapeutic entry point for further investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08300-0","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T09:54:33Z","timestamp":1778925273000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EPHB2 drives EMT-linked vasculogenic mimicry and cervical cancer progression via an ERK\u2013ETV4 transcriptional program"],"prefix":"10.1186","volume":"24","author":[{"given":"Wenzhi","family":"Jiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyang","family":"Huai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyuan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minmin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,16]]},"reference":[{"issue":"3","key":"8300_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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The use of publicly available datasets, including TCGA, GTEx, and published single-cell RNA-seq datasets, did not require additional ethical approval. Animal experiments were performed in accordance with institutional guidelines for the care and use of laboratory animals and were approved by the Animal Ethics Committee. The use of archived human cervical tissue specimens was approved by the Ethics Committee of the Second Hospital of Nanjing (Approval No. 2026-LS-ky012), and informed consent was obtained from all patients or waived by the Ethics Committee, as appropriate.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"774"}}