Enhanced myeloid differentiation factor 88 promotes tumor metastasis via induction of epithelial-mesenchymal transition in human hepatocellular carcinoma

R-J Jia; L Cao; L Zhang; W Jing; R Chen; M-H Zhu; S-W Guo; G-B Wu; X-Y Fan; H Wang; Y-Y Zhang; X-Y Zhou; J Zhao; Y-J Guo

doi:10.1038/cddis.2014.71

Enhanced myeloid differentiation factor 88 promotes tumor metastasis via induction of epithelial-mesenchymal transition in human hepatocellular carcinoma

Cell Death Dis. 2014 Mar 6;5(3):e1103. doi: 10.1038/cddis.2014.71.

Authors

R-J Jia¹, L Cao², L Zhang³, W Jing⁴, R Chen³, M-H Zhu⁴, S-W Guo⁴, G-B Wu⁵, X-Y Fan³, H Wang³, Y-Y Zhang⁶, X-Y Zhou⁴, J Zhao⁷, Y-J Guo⁸

Affiliations

¹ 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.
² 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.
³ International Joint Cancer Institute, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
⁴ Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China.
⁵ Guangxi Cancer Hospital, Guangxi Medical University, Nanning 530021, People's Republic of China.
⁶ School of Medicine, Shanghai Jiao Tong University, 227 South Chongqing Road, Shanghai 200025, People's Republic of China.
⁷ 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.
⁸ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / mortality
Carcinoma, Hepatocellular / secondary
Class Ia Phosphatidylinositol 3-Kinase / genetics
Class Ia Phosphatidylinositol 3-Kinase / metabolism
Enzyme Activation
Epithelial-Mesenchymal Transition*
Glycogen Synthase Kinase 3 / genetics
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Hep G2 Cells
Humans
Kaplan-Meier Estimate
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / mortality
Liver Neoplasms / pathology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, SCID
Myeloid Differentiation Factor 88 / genetics
Myeloid Differentiation Factor 88 / metabolism*
Phosphorylation
Prognosis
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Signal Transduction
Snail Family Transcription Factors
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism
Transfection
Up-Regulation

Substances

Biomarkers, Tumor
MYD88 protein, human
Myeloid Differentiation Factor 88
Snail Family Transcription Factors
Transcription Factors
Class Ia Phosphatidylinositol 3-Kinase
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3