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

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.

LncRNA LINC00924 upregulates NDRG2 to inhibit epithelial‐mesenchymal transition via sponging miR‐6755‐5p in hepatitis B virus‐related hepatocellular carcinoma

“…22 Epithelial-mesenchymal transition (EMT) exerts crucial functions in the process of tumor metastasis and invasion, including breast cancer, thyroid cancer, and colon cancer. [23][24][25] EMT refers to the process of cell remodeling characterized by migratory and invasive abilities through epithelial cells upon multiple physiological and pathological stimuli. 26 The promoting effects of EMT on HBV-related HCC progression have been suggested.…”

“…Moreover, LINC01352 dysregulation enhances HBV‐related HCC by targeting miR‐135b 22 . Epithelial‐mesenchymal transition (EMT) exerts crucial functions in the process of tumor metastasis and invasion, including breast cancer, thyroid cancer, and colon cancer 23–25 . EMT refers to the process of cell remodeling characterized by migratory and invasive abilities through epithelial cells upon multiple physiological and pathological stimuli 26 .…”

Elevation of ADAM12 facilitates tumor progression by enhancing metastasis and immune infiltration in gastric cancer

“…5A , most of the molecules in this signaling pathway have a significant relationship with the EMT phenotype. The analysis of the interaction network indicated that ADAM12 may interact with FSTL3 to potentially promote the metastasis and EMT phenotype of tumors ( 41 , 42 ). Therefore, we constructed stable ADAM12 overexpression AGS cells and knockdown HGC27 cells ( Fig.…”

“…Interestingly, the protein-protein interaction network revealed that follistatin like 3 (FSTL3) may be a potential partner of ADAM12. Previous studies have emphasized that FSTL3 can enhance tumor cell metastasis ( 41 , 42 ) and the polarization of macrophages and fibroblasts by forming an inhibitory immune microenvironment ( 47 ). Therefore, it is clear that ADAM12 and FSTL3 perform similar functions, which may imply a mutual adjustment relationship between them.…”

ENO3 Inhibits Growth and Metastasis of Hepatocellular Carcinoma via Wnt/β-Catenin Signaling Pathway

“…Metabolic reprogramming, known as the Warburg effect, is characterized by enhanced glycolytic activity and lactate fermentation in cancer ( Warburg, 1956 ; Li et al, 2021 ). Tumor cells rewire metabolic pathways to supply energy and increase tolerance to an oxygen-deficient environment ( Li et al, 2021 ). The connections between aerobic glycolysis and EMT are not well-understood.…”