Cancer-associated fibroblast-derived WNT5A promotes cell proliferation, metastasis, stemness and glycolysis in gastric cancer via regulating HK2.

Background: Gastric cancer (GC) is one of the most common cancers worldwide. Tumor microenvironment plays an important role in tumor progression. This study aims to explore the role of cancer-associated fibroblasts (CAFs) in GC and the underlying mechanism.

Methods: Cell viability, proliferation, invasion and migration were assessed by MTT, EdU, transwell and wound healing assays, respectively. Sphere formation assay was used to evaluate cell stemness. Glucose consumption, lactate production and ATP consumption were measured to assess glycolysis. In addition, The RNA and protein expression were detected by qRT-PCR and western blot. The interaction between wingless Type MMTV Integration Site Family, Member 5 A (WNT5A) and hexokinase 2 (HK2) was verified by Co-immunoprecipitation. The xenograft model was established to explore the function of CAFs on GC tumor growth in vivo.

Results: CAFs promoted the proliferation, metastasis, stemness and glycolysis of GC cells. WNT5A was upregulated in CAFs, and CAFs enhanced WNT5A expression in GC cells. Knockdown of WNT5A in either GC cells or CAFs repressed the progression of GC cells. In addition, WNT5A promoted HK2 expression, and overexpression of HK2 reversed the effect of WNT5A knockdown in CAFs on GC cells. Besides, knockdown of WNT5A in CAFs inhibits tumor growth in vivo.

Conclusion: CAF-derived WNT5A facilitates the progression of GC via regulating HK2 expression.