{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:07:24Z","timestamp":1778285244158,"version":"3.51.4"},"reference-count":44,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["130157\u2010RSG\u201016\u2010216\u201001\u2010TBG"],"award-info":[{"award-number":["130157\u2010RSG\u201016\u2010216\u201001\u2010TBG"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K24CA172123"],"award-info":[{"award-number":["K24CA172123"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA204002"],"award-info":[{"award-number":["R01CA204002"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA216846"],"award-info":[{"award-number":["R01CA216846"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005190","name":"Melanoma Research Alliance","doi-asserted-by":"publisher","award":["308721"],"award-info":[{"award-number":["308721"]}],"id":[{"id":"10.13039\/100005190","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002192","name":"LUNGevity Foundation","doi-asserted-by":"publisher","award":["308721"],"award-info":[{"award-number":["308721"]}],"id":[{"id":"10.13039\/100002192","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["TR000140"],"award-info":[{"award-number":["TR000140"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["TR000140"],"award-info":[{"award-number":["TR000140"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>PLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain\u2010tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss\u2010 and gain\u2010of\u2010function studies were used to explore the underlying mechanisms of PLEKHA5\u2010mediated tumor growth and the crosstalk between PLEKHA5 and PI3K\/AKT\/mTOR or MAPK\/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G<jats:sub>1<\/jats:sub>\u2010to\u2010S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K\/AKT\/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.32611","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T08:45:51Z","timestamp":1574757951000},"page":"1016-1030","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["PLEKHA5 regulates tumor growth in metastatic melanoma"],"prefix":"10.1002","volume":"126","author":[{"given":"Hongyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"},{"name":"Department of Microbiology and Immunology, School of Basic Medicine Jinan University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huifang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"},{"name":"Molecular Medicine and Cancer Research Center Chongqing Medical University Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yale University School of Medicine New Haven Connecticut"},{"name":"Department of Neurosurgery Renmin Hospital, Wuhan University Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher R.","family":"Zito","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"},{"name":"Department of Biology, School of Arts, Sciences, Business, and Education University of Saint Joseph West Hartford Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor O.","family":"Oria","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chetan K.","family":"Rane","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2939-6312","authenticated-orcid":false,"given":"Shenqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yale University School of Medicine New Haven Connecticut"},{"name":"Department of Neurosurgery Renmin Hospital, Wuhan University Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-7575","authenticated-orcid":false,"given":"Thuy","family":"Tran","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adebowale","family":"Adeniran","sequence":"additional","affiliation":[{"name":"Department of Pathology Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanfan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangbing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuval","family":"Kluger","sequence":"additional","affiliation":[{"name":"Department of Pathology Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus W.","family":"Bosenberg","sequence":"additional","affiliation":[{"name":"Department of Dermatology Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harriet M.","family":"Kluger","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia B.","family":"Jilaveanu","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Medicine Yale University School of Medicine New Haven Connecticut"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JOP.2016.011882"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clindermatol.2012.08.008"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.35.15_suppl.9508"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30429-1"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.35.15_suppl.9507"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30139-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30053-5"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1429"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2674"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.112748"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2194"},{"key":"e_1_2_8_13_1","first-page":"932","article-title":"A microRNA\u2010based signature predicts melanoma brain metastasis at the time of diagnosis","volume":"26","author":"Hanniford D","year":"2013","journal-title":"Pigment Cell Melanoma Res"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0861"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31624"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17091468"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30594"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2011.10.018"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3510019"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.32604\/biocell.2012.36.127","article-title":"A likely role for a novel PH\u2010domain containing protein, PEPP2, in connecting membrane and cytoskeleton","volume":"36","author":"Zou Y","year":"2012","journal-title":"Biocell"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1985"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-3003"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0064"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0142"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2359"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3361"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130276"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030311"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1405601111"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2009.09.001"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2014.06.022"},{"key":"e_1_2_8_32_1","first-page":"83","article-title":"MicroRNA in melanoma","volume":"10","author":"Howell PM","year":"2010","journal-title":"Ochsner J"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-1719"},{"key":"e_1_2_8_34_1","first-page":"2315","article-title":"Expression of Pdcd4 tumor suppressor in human melanoma cells","volume":"34","author":"Vikhreva PN","year":"2014","journal-title":"Anticancer Res"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8375"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2011.142"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-9-163"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399408000744"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1042\/BC20080191"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-015-3446-8"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1378"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-011-1121-y"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-8-70"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2008.00497.x"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.32611","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cncr.32611","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.32611","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T16:39:16Z","timestamp":1760287156000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.32611"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,26]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,3]]}},"alternative-id":["10.1002\/cncr.32611"],"URL":"https:\/\/doi.org\/10.1002\/cncr.32611","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,26]]},"assertion":[{"value":"2018-11-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}