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.
Highlights
Esophageal carcinoma (EC) is the sixth leading cause of cancer-related death worldwide due to its high risk of metastasis and recurrence [1]
Our previous study showed that CAF-secreted WNT2 is a critical tumor microenvironment factor that can enhance esophageal squamous cell carcinoma (ESCC) cell motility and invasiveness [22]
We found that the FZD2 level increased in whole cell lysates (WCLs) and immunoprecipitated samples with the Flag antibody were treated with WNT2
Summary
Esophageal carcinoma (EC) is the sixth leading cause of cancer-related death worldwide due to its high risk of metastasis and recurrence [1]. The most prevalent histological subtype of EC in eastern Asia ( in China) and in eastern and southern Africa is esophageal squamous cell carcinoma (ESCC) [2, 3]. The 5-year post-operative survival rate of ESCC patients remains. WNT2/FZD2/STAT3 Regulates ESCC Metastasis below 30% because a large proportion of these patients are diagnosed at an advanced stage with distant metastasis [4]. Lymph node (LN) metastasis is an indicator of distant metastasis and poor prognosis for patients with ESCC [5]. Aberrant WNT signaling, one of the key signaling cascades that regulates the tumourigenesis and metastasis in many types of cancers, is observed in ESCC [6, 7]. The mechanisms by which the WNT pathway is activated during ESCC metastasis remain to be further explored
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