Follistatin-Like 3 Enhances Invasion and Metastasis via β-Catenin-Mediated EMT and Aerobic Glycolysis in Colorectal Cancer.

Yuqiang Li,Qian Pei,Dan Wang,Mengxiang Tian,Cenap Güngör,Fengbo Tan,Wenxue Liu,Zhongyi Zhou,Yan Huang

doi:10.3389/fcell.2021.660159

Abstract

Previous studies reported that Follistatin-like 3 (FSTL3) is abundantly expressed in several solid tumors and participate in the regulation of cell metabolism. However, the clinico-pathological significance, biological role and molecular mechanism of FSTL3 in colorectal cancer (CRC) is still unclear. Here we report that the expression level of FSTL3 in colon cancer specimens was significantly higher, compared to normal tissue and interestingly, the expression of FSTL3 was related to lymph node metastasis, tumor stage, tumor size, and intravascular emboli (IVE). As an upstream molecular event, we found that transcriptional regulation of FSTL3 was highly dependent on YAP1 de-phosphorylation events and that increased FSTL3 expression readily activated the β-Catenin pathway, which is a well-known signaling hub that promotes EMT processes and aerobic glycolysis in cancer cells. We found that elevated FSTL3 expression strongly promotes migration, invasion and metastatic formation of CRC cells by directly activating β-Catenin -mediated EMT and aerobic glycolysis. In the xenograft mouse model, FSTL3 expression was linked to increased metastatic formation of CRC cells. Together, the activation of YAP1 induces FSTL3 expression. FSTL3-mediated β-Catenin pathway activation promotes EMT and aerobic glycolysis and therefore affecting the invasive and metastatic capacity of CRC cells. The abundant FSTL3 expression is a poor prognostic factor and pharmacological targeting of YAP1 can counteract FSTL3 expression, suggesting a promising therapeutic target for anti-metastatic strategies in patients suffering from CRC.

Highlights

Colorectal cancer (CRC) is the third most frequent cancer which results in the 2nd cancer-related mortality worldwide (Siegel et al, 2020)
Because nuclear translocation of Yes-associated protein-1 (YAP1) is modulated by the Wnt/β-Catenin pathway in melanomaassociated fibroblasts (Liu et al, 2019) and YAP1 is necessary to transactivate Follistatin-like 3 (FSTL3) gene expression (Figure 3F), we hypothesized that elevated FSTL3 expression modulates β-Catenin signaling in CRC
Because of the fact that β-Catenin can induce YAP1, and YAP1 is able to transactivate FSTL3, we curiously investigated a possible impact of abundant FSTL3 on β-Catenin signaling in CRC and found elevated β-Catenin expression levels, and increased β-Catenin nuclear translocation in FSTL3 overexpressed cells, suggesting a positive feedback loop

Summary

Introduction

Colorectal cancer (CRC) is the third most frequent cancer which results in the 2nd cancer-related mortality worldwide (Siegel et al, 2020). Treatment modalities for CRC includes surgical resection, chemotherapy, and/or radiation therapy. Invasion and metastatic formation of tumor cells are still the main causes of death in patients suffering from CRC (Siegel et al, 2020). The exploration of key molecules and their related molecular mechanisms regulating invasion and metastasis can provide prognostic markers and potentially new therapeutic targets for the treatment course of CRC in future settings. Increasing evidences demonstrate that EMT can initiate the metastatic progression of CRC (Thiery et al, 2009; Sleeman and Thiery, 2011; Dongre and Weinberg, 2019). Exploration of the role and molecular mechanism of key genes that regulate EMT can provide a basis for controlling the invasion and metastatic formation of CRC cells

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