WNT2-Mediated FZD2 Stabilization Regulates Esophageal Cancer Metastasis via STAT3 Signaling

Abstract

Esophageal cancer micro environment factor WNT2 was critical in cancer metastasis. However, very little is known about WNT2 receptors and their role in the malignant progression of ESCC. The clinical significance and underlying molecular mechanisms of FZD2, one of the receptors of WNT2, was further investigated in ESCC. We found that FZD2 expression was positively correlated with WNT2 levels in clinical ESCC specimens through database analysis. Upregulated FZD2 expression was detected in 69% (69/100) of the primary ESCC cases examined, and increased FZD2 expression was significantly correlated with poor prognosis (P < 0.05). Mechanistically, FZD2 induced the migration and invasion of ESCC cells by regulating the FZD2/STAT3 signaling. In vivo xenograft experiments further revealed the metastasis-promoting role of FZD2 in ESCC. Moreover, we found that the WNT2 ligand could stabilize and phosphorylate the FZD2 receptor by attenuating FZD2 ubiquitination, leading to the activation of STAT3 signaling and the initiation of ESCC cell metastasis. Collectively, our data revealed that a novel non-canonical WNT2/FZD2/STAT3 signaling axis is critical for ESCC progression. Strategies targeting this specific signaling axis might be developed to treat patients with ESCC.

Analysis of the role of Frizzled 2 in different cancer types

“…As the receptors of the Wnt signaling pathway, FZDs activate downstream signaling by binding to Wnt ligands, further regulating cell proliferation, differentiation, migration, tissue polarity, and tumor development. FZDs have been found to be specifically expressed on the cell plasma membrane, and FZD2 is one of the most important receptors in the noncanonical Wnt pathway; it is highly expressed in many cancers and is a marker of poor prognosis [9,19,20].…”

“…It is one of the important receptors of the Wnt signaling pathway and is mainly involved in nonclassical pathway signal transduction [5]. It is highly expressed in a variety of malignant tumors and participates in the regulation of various tumor behaviors [6][7][8][9]. Its expression level is closely related to patient prognosis, and therefore, it is expected to become a new prognostic indicator and therapeutic target for a variety of cancers [10,11].…”

Integrated weighted gene coexpression network analysis identifies Frizzled 2 (FZD2) as a key gene in invasive malignant pleomorphic adenoma

“…FZD2 encodes a transmembrane protein with seven transmembrane domains and an extracellular cysteine-rich domain [40,41]. It can strongly bind to Wnt proteins, which subsequently activates the expression of downstream genes by the Wnt signaling pathway [40,41].…”

“…FZD2 encodes a transmembrane protein with seven transmembrane domains and an extracellular cysteine-rich domain [40,41]. It can strongly bind to Wnt proteins, which subsequently activates the expression of downstream genes by the Wnt signaling pathway [40,41]. A study performing a comprehensive analysis of FZD2 in 33 cancer types indicated that FZD2 was associated with high oncogenicity [42].…”

Non-Coding RNA and Frizzled Receptors in Cancer

“…It has also been observed that increasing miR-135b expression in chemoresistant NSCLC cell lines decreases Fzd1 expression and increases drug sensitivity ( Su et al, 2016 ). Fzd2, commonly expressed in fetal lung, brain, and kidney, as well as adult cardiac tissue, has been identified as an upregulated tumorigenic receptor in multiple cancers from primary tumors to metastatic tissues ( Sagara et al, 1998 ; Zhang et al, 2015 ; Fu et al, 2020 ). MicroRNAs that inhibit Fzd2 expression and signaling lead to inhibition of tumorigenesis.…”