The Involvement of HAb18G/CD147 in Regulation of Store-operated Calcium Entry and Metastasis of Human Hepatoma Cells

Jiang, Jian; Zhou, Quan; Yu, Man; Ho, Lok Sze; Chen, Zhi‐Nan; Chan, Hsiao Chang

doi:10.1074/jbc.m108291200

Cited by 119 publications

(115 citation statements)

References 44 publications

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“…These results suggest that HAb18G/ CD147 plays a role in HCC invasion via regulation of MMP production by both tumor cells and surrounding fibroblasts, thus influencing the balance of tumor microenvironment, and the modulation of that by fibroblasts was more critical in the process. Our previous study also showed that HAb18G/ CD147 was involved in tumor metastasis and invasion as a signal transduction molecule by regulating Ca 2+ inflow (25,27). All these findings show that HAb18G/CD147 may play some important roles in HCC progression, including adhesion, migration, and enzymes degradation.…”

Section: Discussionmentioning

confidence: 92%

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HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

Xu¹,

Xu²,

Zhang³

et al. 2007

Molecular Cancer Research

144

134

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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 the HAb18G/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. 131 I-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.

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Section: Discussionmentioning

confidence: 92%

“…Our previous reports suggested that HAb18G/CD147 was an HCC-associated antigen and was possibly related to HCC invasion in vitro (25)(26)(27). In the present study, we examined the role of HAb18G/CD147 in HCC invasion and metastasis in vitro, and in an orthotopic model of HCC in nude mice.…”

Section: Discussionmentioning

confidence: 99%

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

Xu¹,

Xu²,

Zhang³

et al. 2007

Molecular Cancer Research

144

134

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“…On the other side, NO-releasing agents have been shown to suppress the metastatic tumor cell behavior in various in vitro and in vivo tumor models by decreasing angiogenesis and, therefore, tumor cell invasion. [9][10][11][12][13] The anti-invasiveness and anti-metastatic properties of NO have been attributed either to inhibition of angiogenic factors such as β-FGF and TGFβ1, [9][10][11] or induction of TIMP-2 production and inhibition of p38. 13 Alternatively, NO has been proposed to interfere with the storeoperated calcium mobilization through regulation of the NO/ cGMP-mediated mechanism, 10 or it can prevent the excessive formation of oxygen radicals and peroxynitrate (ONOO -), which cause cell damage and facilitate tumor metastasis.…”

Section: Resultsmentioning

confidence: 99%

“…These findings are in agreement with other studies showing the inhibitory effects of NO-releasing agents in metastatic tumor cell behavior both in vitro and in vivo. [9][10][11][12][13] The challenge regarding NO donors as therapeutic agents is to deliver NO in a sustained and controlled manner. NO donors that spontaneously generate large amounts of NO, independent of iNOS induction, are activated at physiological pH.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

Baritaki¹,

Huerta-Yépez²,

Sahakyan³

et al. 2010

Cell Cycle

100

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“…HAb18G/CD147, which belongs to the CD147 family, is a transmembrane glycoprotein that was cloned by screening a human HCC cDNA library using a monoclonal HAb18 antibody in our laboratory (Jiang et al, 2001). The molecular weight of CD147 is variable, ranging between 35 and 65/kDa depending on the degree of glycosylation.…”

Section: Introductionmentioning

confidence: 99%

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

et al. 2011

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Epithelial-mesenchymal transition (EMT) induced by transforming growth factor-b (TGF-b) is implicated in hepatocarcinogenesis and hepatocellular carcinoma (HCC) metastasis. HAb18G/CD147, which belongs to the CD147 family, is an HCC-associated antigen that has a crucial role in tumor invasion and metastasis. The goal of this study was to investigate the role of HAb18G/ CD147 during EMT in hepatocarcinogenesis. Human normal hepatic cell lines QZG and L02, primary mouse hepatocytes and nude mouse models were used to determine the role of HAb18G/CD147 in EMT, and the involvement of the TGF-b-driven pathway. A dualluciferase reporter assay and ChIP were used to investigate the transcriptional regulation of the CD147 gene. Samples from patients with liver disease were assessed to determine the relationship between HAb18G/CD147 and typical markers for EMT. Our results show that upregulation of HAb18G/CD147 is induced by TGF-b coupled with downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The expression of HAb18G/CD147 is controlled by the cell survival PI3K/ Akt/GSK3b signaling pathway, and is directly regulated by the transcription factor Slug. Transfection of CD147 also induces an elevated expression of TGF-b. CD147-transfected hepatocytes have mesenchymal phenotypes that accelerate tumor formation and tumor metastasis in vivo. Immunohistochemistry analysis shows a negative correlation between HAb18G/CD147 and E-cadherin expression (r s ¼ À0.3622, P ¼ 0.0105), and a positive correlation between HAb18G/CD147 and Slug expression (r s ¼ 0.3064, P ¼ 0.0323) in human HCC tissues. Our study uncovers a novel role of HAb18G/CD147 in mediating EMT in the process of HCC progression and showed that CD147 is a Slug target gene in the signaling cascade TGF-b-PI3K/Akt-GSK3b-Snail-Slug-CD147. Our results suggest that CD147 may be a potential target for the treatment and prevention of HCC.

show abstract

The Involvement of HAb18G/CD147 in Regulation of Store-operated Calcium Entry and Metastasis of Human Hepatoma Cells

Abstract: The present study examined the effect of hepatomaassociated antigen HAb18G (homologous to CD147) expression on the NO/cGMP-regulated Ca 2؉ mobilization and metastatic process of human hepatoma cells.

Cited by 119 publications

References 44 publications

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

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