{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T22:50:09Z","timestamp":1782255009006,"version":"3.54.5"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,10,12]],"date-time":"2015-10-12T00:00:00Z","timestamp":1444608000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81472335"],"award-info":[{"award-number":["81472335"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec><jats:label\/><jats:p>The RAS\u2010association domain family (RASSF) consists of 10 members, and several members act as tumor suppressor genes and epigenetically inactivated in different tumor types. The present study investigated the role and methylation status of RASSF2, RASSF3, RASSF4, and RASSF6 in the pathogenesis and prognosis of GCA. Quantitative real\u2010time RT\u2010PCR, Western blot, and immunohistochemistry (IHC) methods were used respectively to detect the expression of RASSF2, RASSF3, RASSF4, and RASSF6 in 135 GCA cases and BS\u2013MSP method was used to clarify the methylation status of these four genes. Decreased mRNA and protein expression of RASSF2, RASSF3, RASSF4, and RASSF6 were detected in GCA tumor tissues. Aberrant CpG island methylation of RASSF2, RASSF4, and RASSF6 were detected in GCA tumor tissues and were inversely correlated with the expression levels of these genes. Both of RASSF2 and RASSF6 expression and methylation were associated with TNM stage, depth of invasion, LN metastasis, distant metastasis or recurrence, and UGIC family history. GCA patients with simultaneous negative protein expression of RASSF2 and RASSF6 or with simultaneous methylation of both genes demonstrated poor patient survival. These results suggest that down\u2010regulation of RASSF2, RASSF3, RASSF4, and RASSF6 is a tumor\u2010specific phenomenon and the inactivation of RASSF2 and RASSF6 may be associated with tumor progression. Inactivation of RASSF2, RASSF4, and RASSF6 through CpG island methylation may play important roles in GCA carcinogenesis. A combination of RASSF2 and RASSF6 expression or hypermethylation may serve as useful prognostic biomarker for GCA. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mc.22416","type":"journal-article","created":{"date-parts":[[2015,10,13]],"date-time":"2015-10-13T04:27:35Z","timestamp":1444710455000},"page":"1655-1666","source":"Crossref","is-referenced-by-count":34,"title":["Decreased expression and frequent promoter hypermethylation of RASSF2 and RASSF6 correlate with malignant progression and poor prognosis of gastric cardia adenocarcinoma"],"prefix":"10.1002","volume":"55","author":[{"given":"Wei","family":"Guo","sequence":"first","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Dong","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Guo","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Guo","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Kuang","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Hebei Cancer Institute the Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,10,12]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2004.04.021"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/25.5.941"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1055-3207(02)00002-9"},{"key":"e_1_2_6_5_1","first-page":"76","article-title":"Sub\u2010site specific time trends of carcinoma stomach in North Kerala\u2010a retrospective analysis","volume":"26","author":"Harikumar R","year":"2005","journal-title":"Trop Gastroenterol"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i1.17"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-9-269"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(96)30038-8"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2009.03.004"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.010389"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206191"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/07357900802620828"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-014-9646-5"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22245"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-015-9693-6"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2929"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00769.x"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22185"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-11-40"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208566"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210805"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2014.15.3.1171"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2013.32"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602854"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-9-264"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205365"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2013.10.014"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0059024"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207407"},{"key":"e_1_2_6_30_1","first-page":"781","article-title":"Aberrant methylation of RASSF4\/AD037 in nasopharyngeal carcinoma","volume":"12","author":"Chow LS","year":"2004","journal-title":"Oncol Rep"},{"key":"e_1_2_6_31_1","first-page":"1519","article-title":"Frequent promoter hypermethylation of tumor\u2010related genes in head and neck squamous cell carcinoma","volume":"22","author":"Steinmann K","year":"2009","journal-title":"Oncol Rep"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-2065"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.02.013"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210440"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-8-42"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.4161\/15592294.2014.983361"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2168.1998.00940.x"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.2034"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.08.005"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/18.11.1427"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-0572"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2013.11.009"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kve022"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/959461"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706550"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-011-1668-5"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmc.22416","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmc.22416","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.22416","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T03:54:06Z","timestamp":1695009246000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.22416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,12]]},"references-count":46,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2016,11]]}},"alternative-id":["10.1002\/mc.22416"],"URL":"https:\/\/doi.org\/10.1002\/mc.22416","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,12]]}}}