CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma.
Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3beta (GSK-3beta)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels in vitro and reduced their in vivo metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151(high)/MMP9(high)/MVD(high) were significantly lower than those of the CD151(low)/MMP9(low)/MVD(low) group or groups in which only one or two of CD151, MMP9, and MVD were highly expressed. Cumulative recurrence rates were also highest in HCC patients with CD151(high)/MMP9(high)/MVD(high) in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC.


CONCLUSIONS
Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3beta/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC.
Shi
Guo-Ming
GM
Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, People's Republic of China.
Ke
Ai-Wu
AW
Zhou
Jian
J
Wang
Xiao-Ying
XY
Xu
Yang
Y
Ding
Zhen-Bin
ZB
Devbhandari
Ranjan Prasad
RP
Huang
Xiao-Yong
XY
Qiu
Shuang-Jian
SJ
Shi
Ying-Hong
YH
Dai
Zhi
Z
Yang
Xin-Rong
XR
Yang
Guo-Huan
GH
Fan
Jia
J
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000401:mortality / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D060185:Tetraspanin 24; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
D015703:Antigens, CD; D014408:Biomarkers, Tumor; D038362:Glycogen Synthase Kinase 3; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000071250:Snail Family Transcription Factors; D060185:Tetraspanin 24; D014157:Transcription Factors; C554715:CD151 protein, human; C554716:Cd151 protein, mouse