{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:43:26Z","timestamp":1760402606259,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T00:00:00Z","timestamp":1587340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["1072314-B-182A-158MY3"],"award-info":[{"award-number":["1072314-B-182A-158MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005795","name":"Chang Gung Memorial Hospital, Linkou","doi-asserted-by":"publisher","award":["CMRPG3J1411, CMRPG3J1412 and CMRPG3J1413"],"award-info":[{"award-number":["CMRPG3J1411, CMRPG3J1412 and CMRPG3J1413"]}],"id":[{"id":"10.13039\/501100005795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked (DDX3X) is a member of the DEAD-box family of RNA helicases whose function has been revealed to be involved in RNA metabolism. Recent studies further indicate the abnormal expression in pan-cancers and the relevant biological effects on modulating cancer progression. However, DDX3X\u2019s role in renal cell carcinoma (RCC) progression remains largely unknown. In this study, a medical informatics-based analysis using The Cancer Genome Atlas (TCGA) dataset was performed to evaluate clinical prognoses related to DDX3X. The results suggest that DDX3X is epigenetically repressed in tumor tissue and that lower DDX3X is correlated with the poor overall survival of RCC patients and high tumor size, lymph node metastasis, and distant metastasis (TNM staging system). Furthermore, knowledge-based transcriptomic analysis by Ingenuity Pathway Analysis (IPA) revealed that the SPINK1-metallothionein pathway is a top 1-repressed canonical signaling pathway by DDX3X. Furthermore, SPINK1 and the metallothionein gene family all serve as poor prognostic indicators, and the expression levels of those genes are inversely correlated with DDX3X in RCC. Furthermore, digoxin was identified via Connectivity Map analysis (L1000) for its capability to reverse gene signatures in patients with low DDX3X. Importantly, cancer cell proliferation and migration were decreased upon digoxin treatment in RCC cells. The results of this study indicate the significance of the DDX3Xlow\/SPINK1high\/metallothioneinhigh axis for predicting poor survival outcome in RCC patients and suggest digoxin as a precise and personalized compound for curing those patients with low DDX3X expression levels.<\/jats:p>","DOI":"10.3390\/ijms21082881","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T04:49:38Z","timestamp":1587444578000},"page":"2881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["DDX3X is Epigenetically Repressed in Renal Cell Carcinoma and Serves as a Prognostic Indicator and Therapeutic Target in Cancer Progression"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-3580","authenticated-orcid":false,"given":"Tsung-Chieh","family":"Lin","sequence":"first","affiliation":[{"name":"Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou 333, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature01031","article-title":"Comprehensive proteomic analysis of the human spliceosome","volume":"419","author":"Zhou","year":"2002","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6579","DOI":"10.1158\/0008-5472.CAN-05-2415","article-title":"DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1\/cip1 promoter, is a candidate tumor suppressor","volume":"66","author":"Chao","year":"2006","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2004.09.029","article-title":"Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function","volume":"119","author":"Yedavalli","year":"2004","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1126\/science.275.5305.1468","article-title":"Requirement of the DEAD-Box protein ded1p for messenger RNA translation","volume":"275","author":"Chuang","year":"1997","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/sj.onc.1210687","article-title":"Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein","volume":"27","author":"Shih","year":"2008","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4708","DOI":"10.1093\/nar\/gkn454","article-title":"Human DDX3 functions in translation and interacts with the translation initiation factor eIF3","volume":"36","author":"Lee","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lin, T.C. 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