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

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

doi:10.1038/cddis.2014.71

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.

Highlights

Several studies have demonstrated the role of myeloid differentiation factor 88 (MyD88) in the protumorigenic inflammatory response.[5,6,7] In addition to its role in inflammation-associated tumorigenesis, MyD88 may act intrinsically in epithelial cells to promote carcinogenesis via non-inflammatory functions
We demonstrated that elevated MyD88 is able to induce properties of Epithelial–mesenchymal transition (EMT) and tumor-initiating cells via PI3K/akt murine thymoma viral oncogene homolog (Akt)/glycogen synthase kinase-3b (GSK-3b)/Snail pathway to facilitate tumor metastasis in hepatocellular carcinoma (HCC)
Knockdown of Snail by small interfering RNA targeting Snail greatly attenuated MyD88-triggered enhanced invasive ability in PLC/PRF/5 cells (Figures 5d and e). All these results suggest that Akt/GSK-3b/Snail pathway is critical in MyD88-mediated EMT and metastasis in HCC cells

Summary

Introduction

Several studies have demonstrated the role of MyD88 in the protumorigenic inflammatory response.[5,6,7] In addition to its role in inflammation-associated tumorigenesis, MyD88 may act intrinsically in epithelial cells to promote carcinogenesis via non-inflammatory functions. Epithelial–mesenchymal transition (EMT) is defined as the process in which epithelial cells lose their epithelial signatures while acquiring the characteristics of mesenchymal cells including morphology, cellular structure, and biological function.[14] EMT usually occurs in the critical phases of embryonic development. This developmental program has an important role in tumor metastasis. The EMT cells acquire stem cell-like properties, including the ability of self-renewal and the ability to resist apoptotic stimulations, which is critical for the survival and metastasis of disseminated cancer cells.[15,16,17] Induction of EMT in immortalized human mammary epithelial cells was reported to result in the expression of stem cell markers and increased ability associated with stemness. These findings illustrate a direct link between the EMT and the acquisition of epithelial stem cell properties

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Results

Conclusion