{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:18:58Z","timestamp":1787663938998,"version":"build-2736575974"},"reference-count":42,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer and is frequently associated with poor clinical outcomes. Ribosome biogenesis, which is upregulated in many malignancies, plays a key role in tumor proliferation. Right open reading frame kinase 2 (RIOK2) is an atypical kinase essential for 40S ribosomal subunit maturation, but its role in ccRCC remains unexplored. We investigated the clinical and biological significance of RIOK2 in ccRCC. Immunohistochemical analysis of 166 ccRCC specimens revealed that high RIOK2 expression was significantly associated with advanced pathological stage, higher tumor grade, and shorter cancer\u2010specific and progression\u2010free survival. Public datasets confirmed the elevated RIOK2 mRNA expression in ccRCC, and its association with poor prognosis. Functional studies demonstrated that RIOK2 knockdown suppressed the proliferation, invasion, and migration of ccRCC cells. RNA sequencing, followed by gene set enrichment analysis, revealed that RIOK2 knockdown led to the downregulation of cell cycle\u2010related pathways, including E2F targets. Analyses of public datasets further highlighted suppression of the G2\/M checkpoint. Flow cytometry revealed G1 cell cycle arrest accompanied by reduced CDK2 protein expression in RIOK2\u2010knockdown cells. Furthermore, the small\u2010molecule RIOK2 inhibitor, NSC139021, suppressed ccRCC cell proliferation in a dose\u2010dependent manner, with reduced efficiency in RIOK2\u2010knockdown cells. Collectively, these findings identify RIOK2 as a clinically relevant factor associated with aggressive disease behavior and cell\u2010cycle regulation in ccRCC.<\/jats:p>","DOI":"10.1002\/cam4.72091","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T05:05:06Z","timestamp":1785992706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>RIOK2<\/scp>\n                    Promotes Clear Cell Renal Cell Carcinoma Progression Through Cell Cycle Regulation"],"prefix":"10.1002","volume":"15","author":[{"given":"Hiroyuki","family":"Shikuma","sequence":"first","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3580-1401","authenticated-orcid":false,"given":"Keisuke","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Shimo","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Hatayama","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4036-1887","authenticated-orcid":false,"given":"Kazuma","family":"Yukihiro","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyosuke","family":"Iwane","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoken","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"},{"name":"Department of Disease Models, Research Institute for Radiation Biology and Medicine Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Tasaka","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kohada","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9077-4733","authenticated-orcid":false,"given":"Kenshiro","family":"Takemoto","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2098-3916","authenticated-orcid":false,"given":"Kohei","family":"Kobatake","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1525-5463","authenticated-orcid":false,"given":"Yohei","family":"Sekino","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-2403","authenticated-orcid":false,"given":"Hiroyuki","family":"Kitano","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Goriki","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Hieda","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1211-0410","authenticated-orcid":false,"given":"Osamu","family":"Kaminuma","sequence":"additional","affiliation":[{"name":"Department of Disease Models, Research Institute for Radiation Biology and Medicine Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7014-6812","authenticated-orcid":false,"given":"Nobuyuki","family":"Hinata","sequence":"additional","affiliation":[{"name":"Department of Urology, Graduate School of Biomedical and Health Sciences Hiroshima University  Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.12848"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2018.08.036"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2024.10.019"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.104"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-4087"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003477"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070752"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2013.07.005"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.13735"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2025.03.006"},{"issue":"2","key":"e_1_2_12_12_1","first-page":"1117","article-title":"Knockdown of Ribosomal Protein S15A Inhibits Human Kidney Cancer Cell Growth In\u00a0Vitro and In\u00a0Vivo","volume":"19","author":"Liang J.","year":"2019","journal-title":"Molecular Medicine Reports"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200904048"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0193-0"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2403"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol30010031"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15107"},{"issue":"1","key":"e_1_2_12_18_1","first-page":"257","article-title":"miR\u2010145 Inhibits Human Non\u2010Small\u2010Cell Lung Cancer Growth by Dual\u2010Targeting RIOK2 and NOB1","volume":"53","author":"Liu K.","year":"2018","journal-title":"International Journal of Oncology"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2949"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9091244"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000363345"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00428\u2010025\u201004164\u20109"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.70710"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000506775"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15607"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2022.1024670"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03231-0"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1015"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1312258"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/35008660"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2016.01.001"},{"issue":"6","key":"e_1_2_12_32_1","first-page":"1593","article-title":"The cdk2 Kinase Is Required for the G1\u2010To\u2010S Transition in Mammalian Cells","volume":"8","author":"Tsai L. H.","year":"1993","journal-title":"Oncogene"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14728"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1186-3"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox14111348"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.23.8902-8912.2003"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.11.3.19002"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2022.2098110"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020105111"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14092126"},{"key":"e_1_2_12_41_1","unstructured":"GEO \u201cGSE40435: Gene Expression Profiles of Human Renal Cell Carcinoma \u201d2012 Gene Expression Omnibus https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE40435."},{"key":"e_1_2_12_42_1","unstructured":"Clinical Proteomic Tumor Analysis Consortium (CPTAC) \u201cCPTAC Clear Cell Renal Cell Carcinoma Proteome \u201d2016 National Cancer Institute https:\/\/proteomics.cancer.gov\/programs\/cptac."},{"key":"e_1_2_12_43_1","unstructured":"The Cancer Genome Atlas Research Network \u201cThe Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (KIRC) Dataset \u201d2013 cBioPortal https:\/\/www.cbioportal.org\/study\/summary?id=kirc_tcga."}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.72091","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.72091","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.72091","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:25:18Z","timestamp":1787660718000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.72091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":42,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/cam4.72091"],"URL":"https:\/\/doi.org\/10.1002\/cam4.72091","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72091"}}