Reduced expression of CD109 in tumor-associated endothelial cells promotes tumor progression by paracrine interleukin-8 in hepatocellular carcinoma
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Bo-Gen Ye1,2,*, Hui-Chuan Sun1,2,*, Xiao-Dong Zhu1,2,*, Zong-Tao Chai3,*, Yuan-Yuan Zhang1,2, Jian-Yang Ao4, Hao Cai1,2, De-Ning Ma1,2, Cheng-Hao Wang1,2, Cheng-Dong Qin1,2, Dong-Mei Gao1,2, Zhao-You Tang1,2
1Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China
2Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
3General Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
4The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
*These authors contributed equally to this work
Zhao-You Tang, e-mail: mail:[email protected].
Keywords: CD109, hepatocellular carcinoma, interleukin-8, TGF-β, tumor-associated endothelial cells
Received: November 23, 2015 Accepted: March 28, 2016 Published: April 18, 2016
Tumor-associated endothelial cells (TEC) directly facilitate tumor progression, but little is known about the mechanisms. We investigated the function of CD109 in TEC and its clinical significance in hepatocellular carcinoma (HCC). The correlation between CD109 expressed on tumor vessels and the prognosis after surgical resection of HCC was studied. The effect of human umbilical vein endothelial cells (HUVEC) with different CD109 expression on hepatoma cell proliferation, migration, and invasion was compared in co-culture assay. Associated key factors were screened by human cytokine antibody array and validated thereafter. HUVEC with different CD109 expression were co-implanted with HCCLM3 or HepG2 cells in nude mice to investigate the effect of CD109 expression on tumor growth and metastasis. Reduced expression of CD109 on tumor vessels was associated with large tumor size, microvascular invasion, and advanced tumor stage. CD109 was an independent risk factor for disease-free survival (P = 0.001) after curative resection of HCC. CD109 knockdown in HUVEC promoted hepatoma cell proliferation, migration, and invasion. Interleukin-8 (IL-8) was a key tumor-promoting factor secreted from CD109 knockdown HUVEC. CD109 knockdown upregulated IL-8 expression through activation of TGF-β/Akt/NF-κB pathway in HUVEC. Co-implantation with CD109 knockdown HUVEC accelerated tumor growth and metastasis in mice models. In conclusion, CD109 expression on tumor vessels is a potential prognostic marker for HCC, and its reduced expression on TEC promoted tumor progression by paracrine IL-8.
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