4615

MYD88

myeloid differentiation primary response 88;MYD88;myeloid differentiation primary response 88

myeloid differentiation primary response gene (88)|myeloid differentiation primary response protein MyD88

3p22

protein-coding

PURPOSE: To investigate the expression of myeloid differentiation factor 88 (MyD88) in hepatocellular carcinoma (HCC) and its prognostic value in patients with HCC. EXPERIMENTAL DESIGN: expression of MyD88 was detected by immunohistochemistry in surgical HCC specimens (n = 110). The correlation of MyD88 expression to clinicopathologic characteristics was analyzed. The involvement of MyD88 in tumor growth and invasion was investigated. RESULTS: The expression of MyD88 was significantly higher in HCC tumors than that in adjacent nontumor tissues. Particularly, high expression of MyD88 was found in HCCs with late tumor stage (P = 0.029). Patients with high MyD88 staining revealed a higher recurrence rate (65% vs. 40%; P = 0.008). Kaplan-Meier analysis showed that recurrence-free survival (RFS; P = 0.011) and overall survival (OS; P = 0.022) were significantly worse among patients with high MyD88 staining. Univariate and multivariate analyses revealed that MyD88 was an independent predictor for OS and RFS. Ectopic expression of MyD88 promoted HCC cell proliferation and invasion in vitro. Suppression of MyD88 expression with lentivirus encoding short hairpin RNA reduced tumor growth and invasion, as well as lung metastasis. Finally, silencing of MyD88 inhibited the activation of NF-kappaB and AKT in HCC cells, whereas forced expression of MyD88 was able to enhance the activation of NF-kappaB and p38/extracellular signal-regulated kinase without Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. CONCLUSION: Elevated expression of MyD88 may promote tumor growth and metastasis via both TLR/IL-1R-dependent and -independent signaling and may serve as a biomarker for prognosis of patients with HCC.

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-3beta 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.