Clinical implication of Frizzled 2 expression and its association with epithelial-to-mesenchymal transition in hepatocellular carcinoma

Abstract

The epithelial-to-mesenchymal transition (EMT) is an initial, critical step in hepatocellular carcinoma (HCC) tumor invasion and metastasis. Frizzled 2 (Fzd2) expression might drive EMT through the non-canonical Wnt pathway, one of the various EMT signaling pathways. The expression of epithelial (E-cadherin) and mesenchymal (vimentin) markers, as well as that of Wnt5b, Stat3, IL-6, Jak2 and Fzd2, were measured in 15 HCC cell lines. The EMT status (vimentin to E-cadherin mRNA expression ratio), Fzd2 mRNA expression, and pSTAT3 protein expression were assessed by immunostaining in 100 HCC patients, and correlations of their expression with clinicopathological factors and prognosis were analyzed. Cell proliferation, migration, and invasiveness were assessed after Fzd2 knockdown. Fzd2 expression was significantly correlated with a mesenchymal phenotype in the HCC cell lines. Treatment of the cell lines with Fzd2 siRNA resulted in significantly reduced migration and invasiveness but did not affect proliferation. A significant correlation was detected between the EMT status and Fzd2 expression in the HCC patients. Multivariate analysis revealed that Fzd2 expression was an independent predictor of recurrence (P=0.034). Patients with high Fzd2 expression had significantly poorer recurrence‑free survival than those with low expression (P=0.03). Finally, pSTAT3 expression was significantly correlated with the EMT and Fzd2 status (P=0.0028, and P=0.0066, respectively). Fzd2 expression induced EMT and enhanced cell migration and invasiveness, and it might be a novel predictor of HCC recurrence. Furthermore, Stat3 might be controlled by both the Wnt5/Fzd2 and IL-6/Jak2 signaling pathways and play an important role in EMT.

Frizzled 2‐induced epithelial‐mesenchymal transition correlates with vasculogenic mimicry, stemness, and Hippo signaling in hepatocellular carcinoma

“…Among them, a study has revealed that FZD2 drives EMT and cell metastasis through a previously unrecognized, noncanonical pathway that involves molecules such as the tyrosine kinase (FYN) and STAT3 . Another study confirmed that FZD2 upregulation was significantly correlated with EMT status in HCC …”

“…9 Another study confirmed that FZD2 upregulation was significantly correlated with EMT status in HCC. 10 Epithelial-mesenchymal transition has been associated with CSC properties and VM in several tumors. [11][12][13] Cancer stem cells are a small subgroup within tumors that are capable of selfrenewal and maintain tumor-initiating capacity through differentiation into the heterogeneous nature of tumor cells that comprise the primary tumor.…”

Wnt receptor Frizzled 8 is a target of ERG in prostate cancer

“…Earlier studies have demonstrated the involvement of several Frizzled receptors, including FZD8, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, and FZD10 in different cancers. Though Frizzled receptors function as key components of the Wnt signaling pathway, the specific link with the ETS‐related transcription factor ERG is unknown.…”

Caveolin‐1 down‐regulation is required for Wnt5a‐Frizzled 2 signalling in Ha‐RasV12‐induced cell transformation

“…Currently, a number of Wnt5a receptors were reported, including Fzd2, Fzd3, Fzd4, Fzd5, Fzd6, Fzd7, Fzd8, RYK, ROR2 and CD146 . Results from several independent studies indicated that Fzd2 expression might drive EMT through the non‐canonical Wnt pathway in different cancer cells . Gujral et al reported that Wnt5a and its ligand Fzd2 are overexpressed in several metastatic cancer cell lines and tumours.…”