{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T18:47:06Z","timestamp":1740163626482,"version":"3.37.3"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The role of Ras-related associated with diabetes (RRAD) in gastric cancer (GC) or colorectal cancer (CRC) has not been investigated. We aimed to investigate the biological and clinical roles of RRAD in GC and CRC and to assess RRAD as a therapeutic target. A total of 31 cancer cell lines (17 GC cell lines, 14 CRC cell lines), 59 patient-derived cells (PDCs from 48 GC patients and 11 CRC patients), and 84 matched pairs of primary cancer tissue and non-tumor tissue were used to evaluate the role of RRAD <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. RRAD expression was frequently increased in GC and CRC cell lines, and siRNA\/shRNA-mediated RRAD inhibition induced significant decline of tumor cell proliferation both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. A synergistic effect of RRAD inhibition was generated by combined treatment with chemotherapy. Notably, RRAD expression was markedly increased in PDCs, and RRAD inhibition suppressed PDC proliferation. RRAD inhibition also resulted in reduced cell invasion, decreased expression of EMT markers, and decreased angiogenesis and levels of associated proteins including VEGF and ANGP2. Our study suggests that RRAD could be a novel therapeutic target for treatment of GC and CRC, especially in patients with peritoneal seeding.<\/jats:p>","DOI":"10.1038\/s41598-019-55767-7","type":"journal-article","created":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T11:02:52Z","timestamp":1576753372000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["RRAD expression in gastric and colorectal cancer with peritoneal carcinomatosis"],"prefix":"10.1038","volume":"9","author":[{"given":"Hee Kyung","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inkyoung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung Tae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4911-6165","authenticated-orcid":false,"given":"Jeeyun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoung-Mee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joon Oh","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Won Ki","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,12,19]]},"reference":[{"key":"55767_CR1","doi-asserted-by":"publisher","first-page":"E359","DOI":"10.1002\/ijc.29210","volume":"136","author":"J Ferlay","year":"2015","unstructured":"Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer 136, E359\u2013386 (2015).","journal-title":"International journal of cancer"},{"key":"55767_CR2","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1200\/JCO.2005.05.2308","volume":"24","author":"F Kamangar","year":"2006","unstructured":"Kamangar, F., Dores, G. M. & Anderson, W. F. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 24, 2137\u20132150 (2006).","journal-title":"Journal of clinical oncology: official journal of the American Society of Clinical Oncology"},{"key":"55767_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0895-4356(02)00534-6","volume":"56","author":"JR Kelley","year":"2003","unstructured":"Kelley, J. R. & Duggan, J. M. Gastric cancer epidemiology and risk factors. Journal of clinical epidemiology 56, 1\u20139 (2003).","journal-title":"Journal of clinical epidemiology"},{"key":"55767_CR4","first-page":"104","volume":"64","author":"R Siegel","year":"2014","unstructured":"Siegel, R., Desantis, C. & Jemal, A. Colorectal cancer statistics, 2014. CA: a cancer journal for clinicians 64, 104\u2013117 (2014).","journal-title":"CA: a cancer journal for clinicians"},{"key":"55767_CR5","doi-asserted-by":"crossref","unstructured":"Cristescu, R. et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. 21, 449\u2013456 (2015).","DOI":"10.1038\/nm.3850"},{"key":"55767_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8002","volume":"6","author":"E Medico","year":"2015","unstructured":"Medico, E. et al. The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nat Commun 6, 7002 (2015).","journal-title":"Nat Commun"},{"key":"55767_CR7","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1053\/j.gastro.2015.05.059","volume":"149","author":"P Tan","year":"2015","unstructured":"Tan, P. & Yeoh, K. G. Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma. Gastroenterology 149, 1153\u20131162 e1153 (2015).","journal-title":"Gastroenterology"},{"key":"55767_CR8","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nrd3504","volume":"10","author":"MG Vander Heiden","year":"2011","unstructured":"Vander Heiden, M. G. Targeting cancer metabolism: a therapeutic window opens. Nature reviews. Drug discovery 10, 671\u2013684 (2011).","journal-title":"Nature reviews. Drug discovery"},{"key":"55767_CR9","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1126\/science.8248782","volume":"262","author":"C Reynet","year":"1993","unstructured":"Reynet, C. & Kahn, C. R. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans. Science 262, 1441\u20131444 (1993).","journal-title":"Science"},{"key":"55767_CR10","doi-asserted-by":"publisher","first-page":"23111","DOI":"10.1074\/jbc.271.38.23111","volume":"271","author":"JS Moyers","year":"1996","unstructured":"Moyers, J. S., Bilan, P. J., Reynet, C. & Kahn, C. R. Overexpression of Rad inhibits glucose uptake in cultured muscle and fat cells. The Journal of biological chemistry 271, 23111\u201323116 (1996).","journal-title":"The Journal of biological chemistry"},{"key":"55767_CR11","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/bies.950140308","volume":"14","author":"J Downward","year":"1992","unstructured":"Downward, J. Regulatory mechanisms for ras proteins. BioEssays: news and reviews in molecular, cellular and developmental biology 14, 177\u2013184 (1992).","journal-title":"BioEssays: news and reviews in molecular, cellular and developmental biology"},{"key":"55767_CR12","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1016\/j.leukres.2012.05.004","volume":"36","author":"SY Yeom","year":"2012","unstructured":"Yeom, S. Y., Lee, S. J., Kim, W. S. & Park, C. Rad knockdown induces mitochondrial apoptosis in bortezomib resistant leukemia and lymphoma cells. Leukemia research 36, 1172\u20131178 (2012).","journal-title":"Leukemia research"},{"key":"55767_CR13","first-page":"2071","volume":"61","author":"YH Tseng","year":"2001","unstructured":"Tseng, Y. H. et al. Regulation of growth and tumorigenicity of breast cancer cells by the low molecular weight GTPase Rad and nm23. Cancer research 61, 2071\u20132079 (2001).","journal-title":"Cancer research"},{"key":"55767_CR14","doi-asserted-by":"publisher","first-page":"3049","DOI":"10.1158\/1535-7163.MCT-14-0244","volume":"13","author":"SY Yeom","year":"2014","unstructured":"Yeom, S. Y., Nam, D. H. & Park, C. RRAD promotes EGFR-mediated STAT3 activation and induces temozolomide resistance of malignant glioblastoma. Molecular cancer therapeutics 13, 3049\u20133061 (2014).","journal-title":"Molecular cancer therapeutics"},{"key":"55767_CR15","doi-asserted-by":"publisher","first-page":"4357","DOI":"10.1158\/0008-5472.CAN-09-3791","volume":"70","author":"I Lee","year":"2010","unstructured":"Lee, I., Yeom, S. Y., Lee, S. J., Kang, W. K. & Park, C. A novel senescence-evasion mechanism involving Grap2 and Cyclin D interacting protein inactivation by Ras associated with diabetes in cancer cells under doxorubicin treatment. Cancer research 70, 4357\u20134365 (2010).","journal-title":"Cancer research"},{"key":"55767_CR16","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/nrm3758","volume":"15","author":"S Lamouille","year":"2014","unstructured":"Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nature reviews. Molecular cell biology 15, 178\u2013196 (2014).","journal-title":"Nature reviews. Molecular cell biology"},{"key":"55767_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s40169-015-0048-3","volume":"4","author":"S Heerboth","year":"2015","unstructured":"Heerboth, S. et al. EMT and tumor metastasis. Clinical and translational medicine 4, 6 (2015).","journal-title":"Clinical and translational medicine"},{"key":"55767_CR18","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.mrrev.2011.05.002","volume":"728","author":"F van Zijl","year":"2011","unstructured":"van Zijl, F., Krupitza, G. & Mikulits, W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutation research 728, 23\u201334 (2011).","journal-title":"Mutation research"},{"key":"55767_CR19","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1245\/s10434-006-9089-6","volume":"14","author":"M Suzuki","year":"2007","unstructured":"Suzuki, M. et al. Methylation and gene silencing of the Ras-related GTPase gene in lung and breast cancers. Annals of surgical oncology 14, 1397\u20131404 (2007).","journal-title":"Annals of surgical oncology"},{"key":"55767_CR20","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.canlet.2012.03.042","volume":"323","author":"Y Mo","year":"2012","unstructured":"Mo, Y. et al. Promoter hypermethylation of Ras-related GTPase gene RRAD inactivates a tumor suppressor function in nasopharyngeal carcinoma. Cancer letters 323, 147\u2013154 (2012).","journal-title":"Cancer letters"},{"key":"55767_CR21","doi-asserted-by":"publisher","first-page":"14225","DOI":"10.1074\/jbc.M113.527671","volume":"289","author":"Y Wang","year":"2014","unstructured":"Wang, Y. et al. Ras-induced epigenetic inactivation of the RRAD (Ras-related associated with diabetes) gene promotes glucose uptake in a human ovarian cancer model. The Journal of biological chemistry 289, 14225\u201314238 (2014).","journal-title":"The Journal of biological chemistry"},{"key":"55767_CR22","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.ccr.2008.05.005","volume":"13","author":"G Kroemer","year":"2008","unstructured":"Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancer\u2019s Achilles\u2019 heel. Cancer cell 13, 472\u2013482 (2008).","journal-title":"Cancer cell"},{"key":"55767_CR23","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/nrc3579","volume":"13","author":"SK Parks","year":"2013","unstructured":"Parks, S. K., Chiche, J. & Pouyssegur, J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nature reviews. Cancer 13, 611\u2013623 (2013).","journal-title":"Nature reviews. Cancer"},{"key":"55767_CR24","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1126\/science.123.3191.309","volume":"123","author":"O Warburg","year":"1956","unstructured":"Warburg, O. On the origin of cancer cells. Science (New York, N.Y.) 123, 309\u2013314 (1956).","journal-title":"Science (New York, N.Y.)"},{"key":"55767_CR25","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","volume":"324","author":"MG Vander Heiden","year":"2009","unstructured":"Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029\u20131033 (2009).","journal-title":"Science"},{"key":"55767_CR26","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1126\/science.1193494","volume":"330","author":"AJ Levine","year":"2010","unstructured":"Levine, A. J. & Puzio-Kuter, A. M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330, 1340\u20131344 (2010).","journal-title":"Science"},{"key":"55767_CR27","doi-asserted-by":"crossref","first-page":"14982","DOI":"10.18632\/oncotarget.3719","volume":"6","author":"J Liu","year":"2015","unstructured":"Liu, J. et al. RRAD inhibits the Warburg effect through negative regulation of the NF-kappaB signaling. Oncotarget 6, 14982\u201314992 (2015).","journal-title":"Oncotarget"},{"key":"55767_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/srep17940","volume":"5","author":"XB Lv","year":"2015","unstructured":"Lv, X. B. et al. SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer. Scientific reports 5, 17940 (2015).","journal-title":"Scientific reports"},{"key":"55767_CR29","doi-asserted-by":"publisher","first-page":"5097","DOI":"10.1007\/s13277-015-4329-7","volume":"37","author":"R Shang","year":"2016","unstructured":"Shang, R. et al. RRAD inhibits aerobic glycolysis, invasion, and migration and is associated with poor prognosis in hepatocellular carcinoma. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 37, 5097\u20135105 (2016).","journal-title":"Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine"},{"key":"55767_CR30","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s10147-017-1156-4","volume":"22","author":"K Kawada","year":"2017","unstructured":"Kawada, K., Toda, K. & Sakai, Y. Targeting metabolic reprogramming in KRAS-driven cancers. International journal of clinical oncology 22, 651\u2013659 (2017).","journal-title":"International journal of clinical oncology"},{"key":"55767_CR31","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1038\/nrc822","volume":"2","author":"JP Thiery","year":"2002","unstructured":"Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nature reviews. Cancer 2, 442\u2013454 (2002).","journal-title":"Nature reviews. Cancer"},{"key":"55767_CR32","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/nrc2868","volume":"10","author":"AS Chung","year":"2010","unstructured":"Chung, A. S., Lee, J. & Ferrara, N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nature reviews. Cancer 10, 505\u2013514 (2010).","journal-title":"Nature reviews. Cancer"},{"key":"55767_CR33","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.celrep.2014.06.059","volume":"8","author":"N Rigamonti","year":"2014","unstructured":"Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell reports 8, 696\u2013706 (2014).","journal-title":"Cell reports"},{"key":"55767_CR34","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/(SICI)1097-0142(20000115)88:2<358::AID-CNCR16>3.0.CO;2-O","volume":"88","author":"B Sadeghi","year":"2000","unstructured":"Sadeghi, B. et al. Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 88, 358\u2013363 (2000).","journal-title":"Cancer"},{"key":"55767_CR35","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1046\/j.1365-2168.2002.02274.x","volume":"89","author":"DG Jayne","year":"2002","unstructured":"Jayne, D. G., Fook, S., Loi, C. & Seow-Choen, F. Peritoneal carcinomatosis from colorectal cancer. The British journal of surgery 89, 1545\u20131550 (2002).","journal-title":"The British journal of surgery"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55767-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55767-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55767-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T17:43:48Z","timestamp":1671299028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-55767-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,19]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["55767"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-55767-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2019,12,19]]},"assertion":[{"value":"5 July 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19439"}}