title: Enhanced myeloid differentiation factor 88 promotes tumor metastasis via induction of epithelial-mesenchymal transition in human hepatocellular carcinoma.
abstract: Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) after curative resection. Therefore, it is critical to understand the mechanisms underlying tumor metastasis in HCC. We have previously shown that elevated expression of myeloid differentiation factor 88 (MyD88) may promote tumor growth and metastasis in HCC. In this study, we reported that enhanced expression of MyD88 promoted epithelial-mesenchymal transition (EMT) properties and tumor-initiating capabilities in HCC cells. MyD88 was found to be able to interact with p85, a regulatory subunit of phosphoinositide 3-kinase (PI3-K), independent of TLR/IL-1R-mediated response and caused PI3-K/v-akt murine thymoma viral oncogene homolog (Akt) activation, which resulted in subsequent phosphorylation of glycogen synthase kinase-3β and stabilization of Snail, a critical EMT mediator. Consistently, we observed a significant correlation between MyD88 expression and p-Akt levels in a cohort of HCC patients, and found that the combination of these two parameters have better prognostic value for HCC patients. Taken together, these results suggest that elevated MyD88 may facilitate HCC metastasis by promoting EMT properties and tumor-initiating capabilities via PI3-K/Akt pathway.
authors.affiliation: 1] International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China [2] School of Pharmacy, Liaocheng University, 1 Hunan Road, Liaocheng 252059, People's Republic of China.
authors.forename: R-J
authors.initials: RJ
authors.lastname: Jia
authors.affiliation: 1] International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China [2] School of Medicine, Shanghai Jiao Tong University, 227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Jing
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: M-H
authors.initials: MH
authors.lastname: Zhu
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: S-W
authors.initials: SW
authors.lastname: Guo
authors.affiliation: Guangxi Cancer Hospital, Guangxi Medical University, Nanning 530021, People's Republic of China.
authors.forename: G-B
authors.initials: GB
authors.lastname: Wu
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Fan
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Medicine, Shanghai Jiao Tong University, 227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: 1] International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China [2] School of Pharmacy, Liaocheng University, 1 Hunan Road, Liaocheng 252059, People's Republic of China [3] PLA General Hospital Cancer Center, PLA postgraduate School of Medicine, 28 Fuxing Road, Beijing 100853, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 1] International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China [2] School of Pharmacy, Liaocheng University, 1 Hunan Road, Liaocheng 252059, People's Republic of China [3] PLA General Hospital Cancer Center, PLA postgraduate School of Medicine, 28 Fuxing Road, Beijing 100853, People's Republic of China [4] National Engineering Research Center of Antibody Medicine and State Key Laboratory of Antibody Medicine and Targeting Therapy, 99 Libing Road, Shanghai 201203, People's Republic of China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Guo
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D058543:Class Ia Phosphatidylinositol 3-Kinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3