{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T18:12:47Z","timestamp":1760983967021,"version":"3.40.4"},"reference-count":10,"publisher":"S. Karger AG","issue":"3-4","license":[{"start":{"date-parts":[[2010,1,1]],"date-time":"2010-01-01T00:00:00Z","timestamp":1262304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2010,1,1]],"date-time":"2010-01-01T00:00:00Z","timestamp":1262304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Oncology"],"published-print":{"date-parts":[[2010]]},"abstract":"<i>Objective:<\/i> In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase-4 (MKK4) expression to the development of endometrial cancer. <i>Methods:<\/i> MKK4 expression in endometrial cancer was assessed by immunohistochemistry using 87 paraffin-embedded tissue specimens, and clinical data was collected via a retrospective chart review. <i>MKK4<\/i> gene knockdown using silencing RNA and an <i>MKK4 <\/i>gene transfection system was used to assess <i>MKK4<\/i> function in tissue samples of endometrial cancer. <i>Results:<\/i> Lower expression of MKK4 immunointensity was observed in 63.2% (55\/87) of the analyzed tumors. High-grade endometrioid adenocarcinoma (G2 and G3) (p = 0.024), postmenopausal status (p = 0.018), and patient age (\u226760) (p = 0.012) were significantly correlated with lower MKK4 expression. Patients with lower MKK4 expression in endometrial cancer tissues tended to have a shorter overall survival (p = 0.197). Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected HEC1B cells, a line with a low endogenous expression of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in HEC1B cells resulted in reduced cell migration activity in a simulated wound healing assay. To confirm that MKK4 expression is related to tumor suppressor function, we used 2 independent but complementary approaches. MKK4 gene knockdown in JHEM1 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in Ishikawa cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of HEC1B. Similar results were produced in tumor xenografts in nude mice. <i>Conclusion:<\/i> These results indicate that MKK4 acts as a tumor suppressor, and reduced expression of MKK4 may contribute to the development of endometrial cancer.<\/jats:p>","DOI":"10.1159\/000322644","type":"journal-article","created":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T13:42:30Z","timestamp":1299591750000},"page":"238-246","source":"Crossref","is-referenced-by-count":10,"title":["Functional and Clinicopathological Analysis of Loss of MKK4 Expression in Endometrial Cancer"],"prefix":"10.1159","volume":"79","author":[{"given":"Masako","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed Tanjimur","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Munmun","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuko","family":"Katagiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouji","family":"Iida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohji","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2011,3,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1002%2Fijc.1571"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1007%2Fs10147-005-0546-1"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1053%2Fhupa.2001.25929"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1007%2Fs00428-003-0947-3"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1002%2Fijc.25332"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1158%2F1078-0432.CCR-04-0885"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016%2FS0002-9440%2810%2965073-0"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.3892%2For_00000576"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1007%2Fs10495-009-0354-6"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1158%2F0008-5472.CAN-05-3676"}],"container-title":["Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/322644","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/322644","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/322644","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T19:13:11Z","timestamp":1745435591000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000322644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010]]},"references-count":10,"journal-issue":{"issue":"3-4","published-online":{"date-parts":[[2011,3,1]]},"published-print":{"date-parts":[[2011,3,29]]}},"URL":"https:\/\/doi.org\/10.1159\/000322644","archive":["Portico"],"relation":{},"ISSN":["0030-2414","1423-0232"],"issn-type":[{"type":"print","value":"0030-2414"},{"type":"electronic","value":"1423-0232"}],"subject":[],"published":{"date-parts":[[2010]]}}}