WAVE2 Enhanced Hepatic Stellate Cells Activity in Colorectal Liver Metastases

BACKGROUND: Cancer cell migration, tumor angiogenesis, and activated hepatic stellate cells (a-HSCs) promote the development of colorectal liver metastases (CLM). Wiskott–Aldrich syndrome protein family verprolin-homologous protein 2 (WAVE2) has been associated with CLM, although the underlying molecular mechanisms remain unclear. METHODS: In the current study, we evaluated the relationship between WAVE2 and CLM in 103 CLM patients who underwent liver resection. Immunohistochemistry (IHC) staining was performed to determine the association between WAVE2 protein expression and hepatic micro-metastasis in human CLM tissues. WAVE2 knockout was performed in hepatic stellate cells (HSC) to explore the function and signaling pathways of WAVE2 in colorectal cancer progression. RESULTS: Significantly higher levels of WAVE2 were detected in portal-associated relative to sinusoid-associated micro-metastasis. A strong correlation was identified between WAVE2 levels and microvessel density (MVD) in hepatic metastasis. Similarly, expression of WAVE2 was closely associated with activation of HSCs. Mechanistically, WAVE2 regulated the progression of human CLM acts by regulating the growth factor β (TGF-β) and Hippo pathways via effector yes-associated protein (YAP1). CONCLUSION: Overall, our results demonstrated that WAVE2 participates in CLM tumor microenvironment, and can be a potential latent therapeutic target for CLM.