{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T10:36:26Z","timestamp":1770892586727,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["#20H03523"],"award-info":[{"award-number":["#20H03523"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["#20K07605"],"award-info":[{"award-number":["#20K07605"]}]},{"name":"MEXT of Japan","award":["#20H03523"],"award-info":[{"award-number":["#20H03523"]}]},{"name":"MEXT of Japan","award":["#20K07605"],"award-info":[{"award-number":["#20K07605"]}]},{"name":"P-Direct","award":["#20H03523"],"award-info":[{"award-number":["#20H03523"]}]},{"name":"P-Direct","award":["#20K07605"],"award-info":[{"award-number":["#20K07605"]}]},{"name":"P-Create from AMED of Japan","award":["#20H03523"],"award-info":[{"award-number":["#20H03523"]}]},{"name":"P-Create from AMED of Japan","award":["#20K07605"],"award-info":[{"award-number":["#20K07605"]}]},{"name":"Life Science Foundation of Japan","award":["#20H03523"],"award-info":[{"award-number":["#20H03523"]}]},{"name":"Life Science Foundation of Japan","award":["#20K07605"],"award-info":[{"award-number":["#20K07605"]}]},{"name":"Takeda Science Foundation","award":["#20H03523"],"award-info":[{"award-number":["#20H03523"]}]},{"name":"Takeda Science Foundation","award":["#20K07605"],"award-info":[{"award-number":["#20K07605"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objective: Ovarian cancer (OC) is one of the most lethal gynecological cancers, having a worldwide mortality rate of 66% in 2020. The overall 5-year relative survival rate is only 21% for distant stages, due to the lack of early diagnosis. Epithelial OC, the most common high-grade serous carcinoma, carries p53 mutations in most cases. However, we found that the immediate early response 5 gene (IER5), a p53 target gene, is overexpressed in ovarian cancer cells. The molecular mechanism underlying the role of IER5 in OC has not been well studied. We previously reported that IER5 promotes the dephosphorylation and activation of heat shock factor-1 (HSF1), the master regulator of proteostasis, which induces heat shock protein (HSP) expression. Methods\/Results: Here we show that Ier5 mRNA expression is higher in ovarian cancer cells (MOV, ID8G, and HM-1) compared to normal ovarian cells. We also show that OC cells floating in the ascites have higher Ier5 expression than the parental strain. Knockdown of Ier5 suppressed HSP upregulation and proliferation of OC, while overexpression of IER5 promoted HSP upregulation. Knockdown of Hsf1 showed results similar to Ier5 knockdown. Conclusions: These results indicate that the IER5-HSF1 pathway contributes to the proliferation and peritoneal dissemination of OC cells. We also found that higher expression of IER5 family genes is related to poorer prognosis of OC patients, suggesting the potential of the IER5 gene family as diagnostic markers for OC, as well as potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/cancers17040610","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T08:05:42Z","timestamp":1739347542000},"page":"610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["IER5 Promotes Ovarian Cancer Cell Proliferation and Peritoneal Dissemination"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0116-0546","authenticated-orcid":false,"given":"Jayaraman","family":"Krishnaraj","sequence":"first","affiliation":[{"name":"Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-5631","authenticated-orcid":false,"given":"Sayaka","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, Fujita Health University, Toyoake 470-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moe","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan"},{"name":"Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Tabata","sequence":"additional","affiliation":[{"name":"Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan"},{"name":"Department of Molecular Diagnosis, Chiba University School of Medicine, Chiba 260-0856, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Asano","sequence":"additional","affiliation":[{"name":"Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9761-1750","authenticated-orcid":false,"given":"Tomoaki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnosis, Chiba University School of Medicine, Chiba 260-0856, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7221-5858","authenticated-orcid":false,"given":"Tomohisa","family":"Kuzuyama","sequence":"additional","affiliation":[{"name":"Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6610-1902","authenticated-orcid":false,"given":"Hideyuki","family":"Saya","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, Fujita Health University, Toyoake 470-1192, Japan"},{"name":"Graduate School of Medicine, Keio University, Tokyo 160-0016, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7775-6653","authenticated-orcid":false,"given":"Rieko","family":"Ohki","sequence":"additional","affiliation":[{"name":"Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1002\/ijc.30676","article-title":"International patterns and trends in ovarian cancer incidence, overall and by histologic subtype","volume":"140","author":"Coburn","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1055\/a-1545-4279","article-title":"2020 WHO Classification of Female Genital Tumors","volume":"81","author":"Brambs","year":"2021","journal-title":"Geburtshilfe Und Frauenheilkd."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e62","DOI":"10.3802\/jgo.2023.34.e62","article-title":"An attempt to establish real-world databases of poly(ADP-ribose) polymerase inhibitors for advanced or recurrent epithelial ovarian cancer: The Japanese Gynecologic Oncology Group","volume":"34","author":"Shimada","year":"2023","journal-title":"J. Gynecol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Spagnol, G., Sensi, F., De Tommasi, O., Marchetti, M., Bonaldo, G., Xhindoli, L., Noventa, M., Agostini, M., Tozzi, R., and Saccardi, C. (2023). Patient Derived Organoids (PDOs), Extracellular Matrix (ECM), Tumor Microenvironment (TME) and Drug Screening: State of the Art and Clinical Implications of Ovarian Cancer Organoids in the Era of Precision Medicine. Cancers, 15.","DOI":"10.3390\/cancers15072059"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.tcb.2015.10.011","article-title":"HSF1: Guardian of Proteostasis in Cancer","volume":"26","author":"Dai","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"515","DOI":"10.2174\/1568009618666181018162117","article-title":"HSF1 as a Cancer Biomarker and Therapeutic Target","volume":"19","author":"Carpenter","year":"2019","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cyran, A.M., and Zhitkovich, A. (2022). Heat Shock Proteins and HSF1 in Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.860320"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wang, G., Cao, P., Fan, Y., and Tan, K. (2020). Emerging roles of HSF1 in cancer: Cellular and molecular episodes. Biochim. Biophys. Acta (BBA) Rev. Cancer, 1874.","DOI":"10.1016\/j.bbcan.2020.188390"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dai, C. (2018). The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: From proteomic stability to oncogenesis. Philos. Trans. R. Soc. B Biol. Sci., 373.","DOI":"10.1098\/rstb.2016.0525"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Powell, C.D., Paullin, T.R., Aoisa, C., Menzie, C.J., Ubaldini, A., and Westerheide, S.D. (2016). The Heat Shock Transcription Factor HSF1 Induces Ovarian Cancer Epithelial-Mesenchymal Transition in a 3D Spheroid Growth Model. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168389"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.3892\/ijmm.2017.2978","article-title":"Targeting HSF1 leads to an antitumor effect in human epithelial ovarian cancer","volume":"39","author":"Chen","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Asano, Y., Kawase, T., Okabe, A., Tsutsumi, S., Ichikawa, H., Tatebe, S., Kitabayashi, I., Tashiro, F., Namiki, H., and Kondo, T. (2016). IER5 generates a novel hypo-phosphorylated active form of HSF1 and contributes to tumorigenesis. Sci. Rep., 6.","DOI":"10.1038\/srep19174"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111686","DOI":"10.1016\/j.yexcr.2019.111686","article-title":"Nuclear import of IER5 is mediated by a classical bipartite nuclear localization signal and is required for HSF1 full activation","volume":"386","author":"Yamano","year":"2020","journal-title":"Exp. Cell Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wu, Z., Wang, D., Zeng, F., Zhang, Y., Zhu, G., Ma, Y., Song, B., Lui, S., and Wu, M. (2021). High IER5 Gene Expression Is Associated with Poor Prognosis in Glioma Patients. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.679684"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ueno, S., Sudo, T., Saya, H., and Sugihara, E. (2022). Pigment epithelium-derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03837-4"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/febs.16612","article-title":"PP2A-B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle-related genes","volume":"290","author":"Doi","year":"2023","journal-title":"FEBS J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5889","DOI":"10.2147\/IJGM.S439190","article-title":"IER5L is a Prognostic Biomarker in Pan-Cancer Analysis and Correlates with Immune Infiltration and Immune Molecules in Non-Small Cell Lung Cancer","volume":"16","author":"Chen","year":"2023","journal-title":"Int. J. Gen. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/s41419-024-06907-z","article-title":"The PP2A regulator IER5L supports prostate cancer progression","volume":"15","author":"Crespo","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6494","DOI":"10.1038\/s41388-021-02027-6","article-title":"IER2-induced senescence drives melanoma invasion through osteopontin","volume":"40","author":"Kyjacova","year":"2021","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1038\/onc.2011.535","article-title":"The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients","volume":"31","author":"Neeb","year":"2012","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.cellsig.2018.12.012","article-title":"IER family proteins are regulators of protein phosphatase PP2A and modulate the phosphorylation status of CDC25A","volume":"55","author":"Ueda","year":"2019","journal-title":"Cell. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1038\/s41467-019-13116-2","article-title":"Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1093\/carcin\/bgr183","article-title":"Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells","volume":"32","author":"Motohara","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1093\/carcin\/21.4.585","article-title":"Development of a syngeneic mouse model for events related to ovarian cancer","volume":"21","author":"Roby","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/j.1349-7006.1989.tb02336.x","article-title":"Unstable expression of E-cadherin adhesion molecules in metastatic ovarian tumor cells","volume":"80","author":"Hashimoto","year":"1989","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/febs.13134","article-title":"Heat-induced expression of the immediate-early gene IER5 and its involvement in the proliferation of heat-shocked cells","volume":"282","author":"Ishikawa","year":"2015","journal-title":"FEBS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1016\/j.febslet.2015.10.013","article-title":"Immediate-early response 5 (IER5) interacts with protein phosphatase 2A and regulates the phosphorylation of ribosomal protein S6 kinase and heat shock factor 1","volume":"589","author":"Kawabata","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e87","DOI":"10.3802\/jgo.2024.35.e87","article-title":"Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT)","volume":"35","author":"Kobayashi","year":"2024","journal-title":"J. Gynecol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.cell.2012.06.031","article-title":"HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers","volume":"150","author":"Mendillo","year":"2012","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Krishnaraj, J., Yamamoto, T., and Ohki, R. (2023). p53-Dependent Cytoprotective Mechanisms behind Resistance to Chemo-Radiotherapeutic Agents Used in Cancer Treatment. Cancers, 15.","DOI":"10.3390\/cancers15133399"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/4\/610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:31:15Z","timestamp":1760027475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/4\/610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,11]]},"references-count":32,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cancers17040610"],"URL":"https:\/\/doi.org\/10.3390\/cancers17040610","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,11]]}}}