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 ß (TGF-ß) 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.

Prognostic Value of PLXND1 and TGF-ß1 Coexpression and Its Correlation With Immune Infiltrates in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with no curative treatments. Plexin D1 (PLXND1) is a cellular receptor whose functions have been explored in several human cancers; however, the critical roles of PLXND1 in HCC have rarely been probed. Therefore, the present study attempted to elucidate the expression pattern, prognostic significance, and potential roles of PLXND1 in HCC. We found that PLXND1 expression in HCC tissues was significantly higher compared with normal liver tissue from Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB) databases. This result was further validated by immunohistochemistry staining (IHC) using tissue microarrays, which contained 216 HCC cases collected from our hospital. Additionally, PLXND1 expression showed a significant correlation with several clinical characteristics, including tumor grade and tumor hemorrhage (TH). Moreover, TISIDB and GEPIA databases were used to investigate the roles of PLXND1 in tumor-immune system interactions in HCC. As an immunoinhibitor, transforming growth factor-beta (TGF-ß1) displayed the greatest correlations with PLXND1 in HCC. Finally, Kaplan-Meier curves and Cox analysis were conducted to further examine the potential clinical value of PLXND1 in HCC. We described a subclassification of HCC based on PLXND1 and TGF-ß1 expression, which could be used to predict clinical outcomes and patient prognosis. Taken together, the results of this study indicate that PLXND1 might be a promising prognostic biomarker and potential therapeutic target in HCC.