{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:55:50Z","timestamp":1792119350051,"version":"4.4.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,10,17]],"date-time":"2015-10-17T00:00:00Z","timestamp":1445040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2015,10,17]],"date-time":"2015-10-17T00:00:00Z","timestamp":1445040000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:p>The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen\u2010activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial\u2010mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. MAP3K4 has somatic mutation in iCCA so we sequenced all exons of MAP3K4 in 124 iCCA patients. We identified nine somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that messenger RNA and protein levels of MAP3K4 were significantly reduced in iCCA versus paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and tumor progression <jats:italic toggle=\"yes\">in vivo<\/jats:italic>, accompanied by a typical EMT process. In contrast, overexpression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of the p38\/nuclear factor \u03baB\/snail pathway. We found that the tumor\u2010inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. <jats:italic toggle=\"yes\">Conclusions:<\/jats:italic> MAP3K4, significantly down\u2010regulated, frequently mutated, and potently regulating the EMT process in iCCA, was a putative tumor suppressor of iCCA. (H<jats:sc>epatology<\/jats:sc> 2015;62:1804\u20101816)<\/jats:p>","DOI":"10.1002\/hep.28149","type":"journal-article","created":{"date-parts":[[2015,9,4]],"date-time":"2015-09-04T15:51:39Z","timestamp":1441381899000},"page":"1804-1816","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":37,"title":["Mitogen\u2010activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial\u2010mesenchymal transition"],"prefix":"10.1097","volume":"62","author":[{"given":"Liu\u2010Xiao","family":"Yang","sequence":"first","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie\u2010Yi","family":"Shi","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi\u2010Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Hong","family":"Shi","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai\u2010Wu","family":"Ke","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Ming","family":"Shi","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Bin","family":"Cai","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Ren","family":"Liu","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Duan","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Jun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College,Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Pathology, Zhongshan Hospital,Fudan University,Shanghai,P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Mei","family":"Gao","sequence":"additional","affiliation":[{"name":"Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education),Fudan University,Shanghai,P.R. 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