Reduced expression of CD109 in tumor-associated endothelial cells promotes tumor progression by paracrine interleukin-8 in hepatocellular carcinoma.
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.
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Bo-Gen
BG
Ye
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Hui-Chuan
HC
Sun
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Xiao-Dong
XD
Zhu
General Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Zong-Tao
ZT
Chai
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Yuan-Yuan
YY
Zhang
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Jian-Yang
JY
Ao
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Hao
H
Cai
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
De-Ning
DN
Ma
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Cheng-Hao
CH
Wang
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Cheng-Dong
CD
Qin
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Dong-Mei
DM
Gao
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
Zhao-You
ZY
Tang
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018450:Disease Progression; D018572:Disease-Free Survival; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins / Q000032:analysis / Q000096:biosynthesis; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis*; D019899:Paracrine Communication / Q000502:physiology
D015703:Antigens, CD; D014408:Biomarkers, Tumor; C120523:CD109 protein, human; C508606:CXCL8 protein, human; D058851:GPI-Linked Proteins; D016209:Interleukin-8; D009363:Neoplasm Proteins
CD109; TGF-β; hepatocellular carcinoma; interleukin-8; tumor-associated endothelial cells