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SFRP5 inhibits gastric epithelial cell migration induced by macrophage-derived Wnt5a
Chenghai Zhao1, Haiying Ma, Xianmin Bu
1Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, 110001, China. zhaochenghai2005@yahoo.com.cn
Abstract:
Secreted frizzled-related protein 5 (SFRP5) is frequently found downregulated in gastric cancer due to SFRP5 gene hypermethylation, and there is a great necessity to elucidate the role of its downregulation in gastric cancer. By binding Wnt molecules, SFRP5 is generally supposed to exert negative effects on Wnt signal pathways widely linked to human cancers. This study found that macrophages over-produced Wnt5a under the stimulation of Lipopolysaccharide (LPS) or Helicobacter pylori, the most common infectious agent in human stomach. Wnt5a-conditioned medium from macrophages enhanced cell migration and CXCR4 expression in either SFRP5-negative gastric epithelial cells (GEC) harboring SFRP5 methylation or SFRP5-positive cells treated with SFRP5 small interfering RNA (siRNA). However, such induced effect was remarkably eliminated by either Wnt5a siRNA in macrophages or treatment with recombinant SFRP5. We also found that Wnt5a-conditioned medium stimulated phosphorylation of c-jun N-terminal kinase (JNK) and c-Jun, and JNK inhibitor SP600125 blocked Wnt5a-induced CXCR4 expression and cell migration in SFRP5-negative cells. Taken together, these findings suggest that epithelium-derived SFRP5 may play a probable defensive role in impeding gastric cancer progression, characteristically by inhibiting GEC migration induced by macrophage-derived Wnt5a via JNK signaling activation.
Insights
Secreted frizzled-related protein 5 (SFRP5) downregulation in gastric cancer promotes cell migration. Macrophage-derived Wnt5a activates JNK signaling, enhancing gastric cancer progression, but SFRP5 may offer protection.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Gastric cancer frequently exhibits downregulated Secreted frizzled-related protein 5 (SFRP5) due to gene hypermethylation.
- SFRP5 typically inhibits Wnt signaling pathways implicated in various cancers.
- The precise role of SFRP5 downregulation in gastric cancer progression requires further elucidation.
Purpose of the Study:
- To investigate the functional role of SFRP5 downregulation in gastric cancer.
- To explore the interaction between macrophage-derived Wnt5a and SFRP5 in gastric epithelial cells (GEC).
- To elucidate the signaling pathways involved in SFRP5-mediated regulation of GEC migration and CXCR4 expression.
Main Methods:
- Utilized lipopolysaccharide (LPS) or Helicobacter pylori to stimulate macrophages, generating Wnt5a-conditioned medium.
- Assessed the effects of conditioned medium on SFRP5-negative GEC and SFRP5-positive GEC treated with SFRP5 small interfering RNA (siRNA).
- Employed Wnt5a siRNA in macrophages and recombinant SFRP5 for intervention, alongside JNK inhibitor SP600125 to study signaling pathways.
Main Results:
- Macrophage-derived Wnt5a enhanced GEC migration and CXCR4 expression, effects abrogated by Wnt5a inhibition or SFRP5 addition.
- SFRP5-negative GEC or GEC with SFRP5 knockdown showed increased migration and CXCR4 expression upon Wnt5a stimulation.
- Wnt5a-conditioned medium induced JNK and c-Jun phosphorylation; JNK inhibition blocked Wnt5a-induced effects.
Conclusions:
- Epithelium-derived SFRP5 likely acts as a tumor suppressor in gastric cancer.
- SFRP5 impedes gastric cancer progression by inhibiting macrophage-induced GEC migration via the JNK signaling pathway.
- SFRP5 downregulation, driven by macrophage-derived Wnt5a, contributes to gastric cancer advancement.
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