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Angiogenesis, Metastasis, and the Cellular Microenvironment

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

¹ Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology and ² Department of Clinical Immunology in Xijing Hospital, Fourth Military Medical University, Xi'an, China

Requests for reprints: Zhi-Nan Chen, Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 17 West Changle Street, Xi'an 710032, China. Phone: 86-29-84774547; Fax: 86-29-83226349. E-mail: znchen{at}fmmu.edu.cn or Ping Zhu, Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, 17 West Changle Street, Xi'an 710032, China. Phone: 86-29-84774545; Fax: 86-29-83293906. E-mail: zhuping{at}fmmu.edu.cn

CD147 molecule is reported to be correlated with the malignancy of some cancers; however, it remains unclear whether it is involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the function of HAb18G/CD147, a member of CD147 family, and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis. We observed that HAb18G/CD147 gene silence in HCC cells significantly decreased the secretion of matrix metalloproteinase (MMP) and the invasive potential of HCC cells (P < 0.001). MMP silence in HCC cells also significantly suppressed the invasion of the cells when cocultured with fibroblasts; however, its inhibitory effect was significantly weaker than that of both HAb18G/CD147 silence in HCC cells and that of MMP silence in fibroblasts (P < 0.001). Blocking theHAb18G/CD147 molecule on HCC cells with HAb18 monoclonal antibody resulted in a similar suppressive effect on MMP secretion and cell invasion, but with no significant effects on the cell growth. ¹³¹I-labeled HAb18 F(ab')₂ (LICARTIN), however, significantly inhibited the in vitro growth of HCC cells (P < 0.001). In an orthotopic model of HCC in nude mice, HAb18 and LICARTIN treatment effectively reduced the tumor growth and metastasis as well as the expression of three major factors in the HCC microenviroment (MMPs, vascular endothelial growth factor, and fibroblast surface protein) in the paracancer tissues. Overall, these results suggest that HAb18G/CD147 plays an important role in HCC invasion and metastasis mainly via modulating fibroblasts, as well as HCC cells themselves to disrupt the HCC microenviroment. LICARTIN can be used as a drug targeting to HAb18G/CD147 in antimetastasis and recurrence therapy of HCC. (Mol Cancer Res 2007;5(6):605–14)