{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T05:29:15Z","timestamp":1770960555306,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,15]],"date-time":"2020-03-15T00:00:00Z","timestamp":1584230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fm0208013h0003 and 19fm0208013h0203"],"award-info":[{"award-number":["19fm0208013h0003 and 19fm0208013h0203"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated.<\/jats:p>","DOI":"10.3390\/cancers12030694","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T10:01:35Z","timestamp":1584612095000},"page":"694","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Establishment and Molecular Phenotyping of Organoids from the Squamocolumnar Junction Region of the Uterine Cervix"],"prefix":"10.3390","volume":"12","author":[{"given":"Yoshiaki","family":"Maru","sequence":"first","affiliation":[{"name":"Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Kawata","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayumi","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"},{"name":"Department of Gynecology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo 113-8677, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Ishii","sequence":"additional","affiliation":[{"name":"Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0001, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayuyo","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Nagamatsu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2468-9573","authenticated-orcid":false,"given":"Katsutoshi","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9080-1642","authenticated-orcid":false,"given":"Iwao","family":"Kukimoto","sequence":"additional","affiliation":[{"name":"Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0001, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Osuga","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4975-1812","authenticated-orcid":false,"given":"Yoshitaka","family":"Hippo","sequence":"additional","affiliation":[{"name":"Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1097\/PGP.0000000000000381","article-title":"Defining the Cervical Transformation Zone and Squamocolumnar Junction: Can We Reach a Common Colposcopic and Histologic Definition?","volume":"36","author":"Reich","year":"2017","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_2","first-page":"671","article-title":"Audit of the histological definition of cervical transformation zone","volume":"58","author":"Mukonoweshuro","year":"2005","journal-title":"J. Clin. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2006.10.014","article-title":"Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix","volume":"264","author":"Delvenne","year":"2007","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_4","first-page":"444","article-title":"Original site of cervical carcinoma; topographical relationship of carcinoma of the cervix to the external os and to the squamocolumnar junction","volume":"7","author":"Marsh","year":"1956","journal-title":"Obstet. Gynecol."},{"key":"ref_5","first-page":"301","article-title":"Cervical intraepithelial neoplasia","volume":"8","author":"Richart","year":"1973","journal-title":"Pathol. Annu."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/ijc.25396","article-title":"Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication","volume":"128","author":"Li","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S0140-6736(13)60809-0","article-title":"Incidence and clearance of oral human papillomavirus infection in men: The HIM cohort study","volume":"382","author":"Kreimer","year":"2013","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.cell.2011.05.026","article-title":"Residual embryonic cells as precursors of a Barrett\u2019s-like metaplasia","volume":"145","author":"Wang","year":"2011","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10516","DOI":"10.1073\/pnas.1202684109","article-title":"A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer","volume":"109","author":"Herfs","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1002\/path.4110","article-title":"A novel blueprint for \u2018top down\u2019 differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia","volume":"229","author":"Herfs","year":"2013","journal-title":"J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/path.4533","article-title":"Carcinogenic HPV infection in the cervical squamo-columnar junction","volume":"236","author":"Mirkovic","year":"2015","journal-title":"J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.pvr.2019.04.005","article-title":"Refining our understanding of cervical neoplasia and its cellular origins","volume":"7","author":"Doorbar","year":"2019","journal-title":"Papillomavirus Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1095\/biolreprod57.4.847","article-title":"Generation of papillomavirus-immortalized cell lines from normal human ectocervical, endocervical, and vaginal epithelium that maintain expression of tissue-specific differentiation proteins","volume":"57","author":"Fichorova","year":"1997","journal-title":"Biol. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1046\/j.1523-1747.2000.00869.x","article-title":"Normal growth and differentiation in a spontaneously immortalized near-diploid human keratinocyte cell line, NIKS","volume":"114","author":"Schlosser","year":"2000","journal-title":"J. Investig. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13150","DOI":"10.1128\/JVI.79.20.13150-13165.2005","article-title":"Human papillomavirus type 16 E1circumflexE4 contributes to multiple facets of the papillomavirus life cycle","volume":"79","author":"Nakahara","year":"2005","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature07935","article-title":"Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche","volume":"459","author":"Sato","year":"2009","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1053\/j.gastro.2014.09.042","article-title":"In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection","volume":"148","author":"Bartfeld","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/ncb3510","article-title":"A three-dimensional model of human lung development and disease from pluripotent stem cells","volume":"19","author":"Chen","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1113\/jphysiol.2014.283028","article-title":"The use of murine-derived fundic organoids in studies of gastric physiology","volume":"593","author":"Schumacher","year":"2015","journal-title":"J. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11127","DOI":"10.1073\/pnas.1221926110","article-title":"Genetic reconstitution of tumorigenesis in primary intestinal cells","volume":"110","author":"Onuma","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","first-page":"6863","article-title":"Ex vivo model of non-small cell lung cancer using mouse lung epithelial cells","volume":"14","author":"Sato","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ochiai, M., Yoshihara, Y., Maru, Y., Tetsuya, M., Izumiya, M., Imai, T., and Hippo, Y. (2019). Kras-driven heterotopic tumor development from hepatobiliary organoids. Carcinogenesis.","DOI":"10.1093\/carcin\/bgz024"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Matsuura, T., Maru, Y., Izumiya, M., Hoshi, D., Kato, S., Ochiai, M., Hori, M., Yamamoto, S., Tatsuno, K., and Imai, T. (2019). Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis. Carcinogenesis.","DOI":"10.1093\/carcin\/bgz122"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-1-4939-3603-8_2","article-title":"Lentivirus-Based Stable Gene Delivery into Intestinal Organoids","volume":"1422","author":"Maru","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Naruse, M., Masui, R., Ochiai, M., Maru, Y., Hippo, Y., and Imai, T. (2020). An organoid-based carcinogenesis model induced by in vitro chemical treatment. Carcinogenesis.","DOI":"10.1093\/carcin\/bgaa011"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2014.12.021","article-title":"Organoid models of human and mouse ductal pancreatic cancer","volume":"160","author":"Boj","year":"2015","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1038\/s41467-018-05190-9","article-title":"Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics","volume":"9","author":"Li","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.stem.2018.09.016","article-title":"A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening","volume":"23","author":"Yan","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Maru, Y., and Hippo, Y. (2019). Current Status of Patient-Derived Ovarian Cancer Models. Cells, 8.","DOI":"10.3390\/cells8050505"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ygyno.2019.05.005","article-title":"Efficient use of patient-derived organoids as a preclinical model for gynecologic tumors","volume":"154","author":"Maru","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1111\/cas.13938","article-title":"Shortcuts to intestinal carcinogenesis by genetic engineering in organoids","volume":"110","author":"Maru","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2992","DOI":"10.1111\/cas.14119","article-title":"Establishment and characterization of patient-derived organoids from a young patient with cervical clear cell carcinoma","volume":"110","author":"Maru","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","article-title":"Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium","volume":"141","author":"Sato","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.jcmgh.2018.01.011","article-title":"Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine","volume":"5","author":"Whelan","year":"2018","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/modpathol.2013.166","article-title":"Keratin 17 in premalignant and malignant squamous lesions of the cervix: Proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker","volume":"27","author":"Yang","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1093\/jjco\/hyu112","article-title":"Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grade 2\/3 and invasive cervical cancer in Japanese women","volume":"44","author":"Azuma","year":"2014","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/3\/694\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:07:08Z","timestamp":1760173628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/3\/694"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,15]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cancers12030694"],"URL":"https:\/\/doi.org\/10.3390\/cancers12030694","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,15]]}}}