title: 14-3-3ζ and aPKC-ι synergistically facilitate epithelial-mesenchymal transition of cholangiocarcinoma via GSK-3β/Snail signaling pathway.
abstract: Cholangiocarcinoma (CCA) invasion and metastasis are the primary causes of poor survival rates in patients. The epithelial-mesenchymal transition (EMT) is a crucial step in cancer invasion and metastasis. However, it is still unclear of the molecular mechanism. In this study, the expression of 14-3-3ζ and atypical protein kinase C-ι (aPKC-ι) was further detected in CCA tissues and cell lines. Meanwhile, we established the EMT model of CCA cells and investigated 14-3-3ζ and aPKC-ι co-regulatory effect on the EMT in vitro and in vivo. Further, we identified the downstream molecular glycogen synthase kinase 3 beta (GSK-3β)/Snail signalling pathway that contribute to regulating the EMT. Our data showed that the expression of 14-3-3ζ and aPKC-ι was synergistically increased in CCA tissues compared with adjacent noncancerous tissues and was intimately associated with differentiation and the tumour-node-metastasis (TNM) stage. Multivariate Cox regression analysis indicated that high 14-3-3ζ and aPKC-ι expression separately predicted a poor prognosis and were independent prognostic indicators in patients with CCA. The CO-IP experiment confirmed that the mutual binding relationship between 14-3-3ζ and aPKC-ι. Small interfering RNAs and siRNA rescue experiment demonstrated that 14-3-3ζ and aPKC-ι regulated each other. In addition, 14-3-3ζ and aPKC-ι pretreatment by si-RNA inhibit the phosphorylated GSK-3β and Snail expression during EMT. Meanwhile, silence of 14-3-3ζ or aPKC-ι suppressed CCA cells migration, metastasis and proliferation in vitro and in vivo. Our study demonstrates that 14-3-3ζ and aPKC-ι synergistically facilitate EMT of CCA via GSK-3β/Snail signalling pathway, and may be potential therapeutic target for CCA.
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Jun-Chuang
authors.initials: JC
authors.lastname: He
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Wang
authors.affiliation: Department of General and Transplant Surgery, University Hospital Heidelberg, Heidelberg 69120, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Chao-Qun
authors.initials: CQ
authors.lastname: Ma
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Ya-Wei
authors.initials: YW
authors.lastname: Qian
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Qi
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
mesh_terms: D048948:14-3-3 Proteins / Q000502:physiology*; D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors / Q000502:physiology*; D000099293:Protein Kinase C-lambda
chemical_list: D048948:14-3-3 Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D007527:Isoenzymes; D011493:Protein Kinase C; D000071250:Snail Family Transcription Factors; D000099293:Protein Kinase C-lambda
keywords: cholangiocarcinoma; epithelial-mesenchymal transition; silencing; synergy; transfection