High expression of endothelial progenitor cell-induced angiogenic markers is associated with bile acid levels in HCC

Jiang-Long Chen; Long Wang; Rong Li; Ying-Fu Jiao; Wei-Feng Yu

doi:10.3892/ol.2020.11815

High expression of endothelial progenitor cell-induced angiogenic markers is associated with bile acid levels in HCC

Oncol Lett. 2020 Sep;20(3):2729-2738. doi: 10.3892/ol.2020.11815. Epub 2020 Jul 6.

Authors

Jiang-Long Chen¹, Long Wang², Rong Li³, Ying-Fu Jiao⁴, Wei-Feng Yu⁴

Affiliations

¹ Department of General Surgery, Children's Hospital of Shanghai, Shanghai Jiao Tong University, Shanghai 200062, P.R. China.
² Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, P.R. China.
³ Department of Pathology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200433, P.R. China.
⁴ Department of Anesthesiology, Ren Ji Hospital, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.

Abstract

Endothelial progenitor cell (EPC)-induced angiogenesis activity is enhanced in hepatocellular carcinoma (HCC); however, the contributing factors remain unknown. The present study aimed to investigate the factors influencing the number of EPCs and circulating progenitor cells (CPCs), as well as the expression levels of vascular endothelial growth factor receptor 2 (VEGFR-2) and CD34, in patients with HCC. The expression levels of VEGFR-2 and CD34 were assessed in 72 HCC tumor and matched adjacent tissue microarrays by immunohistochemistry. The associations between VEGFR-2 or CD34 expression in tumors, clinicopathological characteristics and overall survival rates were analyzed. The number of EPCs and CPCs were analyzed in the peripheral blood of patients with HCC. In this study, high expression levels of VEGFR-2 and CD34 were detected in the tumor tissues of 41 (56.9%) and 44 (61.1%) patients, respectively. VEGFR-2 expression was significantly associated with tumor size (P<0.001), bile acid level (P=0.014) and α-fetoprotein level (P=0.011). However, CD34 expression was associated with tumor size (P=0.009), recrudescence (P<0.001) and bile acid (P=0.009). Next, the expression levels of VEGFR-2 and CD34 in tumor and adjacent tissues were compared according to the bile acid level. VEGFR-2 and CD34 expression levels were both higher in the high bile acid group, whereas expression levels of the markers were higher in adjacent tissues compared with tumor tissues. Kaplan-Meier curve analysis identified that patients with low CD34 expression had a longer overall survival compared with patients with high CD34 expression (P=0.029). Multivariate analysis also indicated that both VEGFR-2 (P=0.020) and CD34 (P=0.035) were independent prognostic risk factors. Moreover, flow cytometry demonstrated that the number of EPCs and CPCs was negatively related with the bile acid levels in patients with HCC. In conclusion, in patients with HCC, bile acid promotes EPC-induced angiogenesis. Furthermore, EPCs and CPCs may be activated by bile acid in tumors but are more so in adjacent tissues.

Keywords: CD34; bile acid; endothelial progenitor cells; hepatocellular carcinoma; vascular endothelial growth factor receptor-2.