Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Liu-Xiao YangJia Fan

Abstract

The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial-mesenchymal 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 in vitro and tumor progression in vivo, 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 κB/snail pathway. We found that the tumor-inhibitory effect of MAP...Continue Reading

References

Mar 10, 2001·Nature·L Chang, M Karin
Jun 8, 2001·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·T Patel
Jun 8, 2002·Molecular and Cellular Biology·Hiroaki MitaHaruo Saito
Aug 3, 2004·Nature Medicine·Bert Vogelstein, Kenneth W Kinzler
Feb 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hongbo ChiRichard A Flavell
Sep 15, 2005·The Journal of Biological Chemistry·Amy N Abell, Gary L Johnson
Oct 4, 2005·Molecular and Cellular Biology·Amy N AbellGary L Johnson
Nov 1, 2005·Biochemical and Biophysical Research Communications·Youssef AissouniPhilippe Soubeyran
Mar 10, 2007·Journal of Cellular Biochemistry·Blaine T Bettinger, David C Amberg
Aug 30, 2007·The Journal of Biological Chemistry·Amy N AbellGary L Johnson
Jun 7, 2008·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Boris Blechacz, Gregory J Gores
Oct 16, 2008·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Evisabel A CraigTodd D Camenisch
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Nov 26, 2010·Journal of Cell Science·Raffaele StrippoliMiguel Ángel Del Pozo
Feb 24, 2011·Seminars in Liver Disease·Christine SempouxSwan N Thung
Apr 14, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Hayato NakagawaShin Maeda
Jul 6, 2012·HPB : the Official Journal of the International Hepato Pancreato Biliary Association·Sarah B FisherShishir K Maithel
Jul 20, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Aug 17, 2012·Nature·Somasekar SeshagiriFrederic J de Sauvage
Mar 19, 2013·Surgery·Omar HyderTimothy M Pawlik
Sep 17, 2013·Cellular Signalling·James J SollomeRichard R Vaillancourt
Dec 12, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Basile Njei

❮ Previous
Next ❯

Citations

Dec 26, 2015·Journal of Clinical Medicine·Simone BrivioMario Strazzabosco
Mar 14, 2016·Digestive Diseases and Sciences·Zebin ZhuChaoxu Zheng
Nov 29, 2016·Expert Review of Anticancer Therapy·Shao-Bin Huang, Chao-Xu Zheng
May 12, 2018·International Journal of Oncology·Qiang KangXiao-Wen Zhang
Dec 6, 2018·Journal of Experimental & Clinical Cancer Research : CR·Yan WangLianxin Liu
Oct 12, 2019·Journal of Cellular Physiology·Lili Huang, Li Wang
Dec 31, 2019·BioMed Research International·Jie ShuFanyan Luo
Aug 26, 2019·Science China. Life Sciences
Nov 25, 2020·World Journal of Surgical Oncology·Lingyu TianXiaoying Wang
Nov 14, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Haoyang ZhouMark W Feinberg
Oct 27, 2017·Gene Expression·Simone BrivioMario Strazzabosco

❮ Previous
Next ❯

Related Concepts