HAb18G/CD147-mediated calcium mobilization and hepatoma metastasis require both C-terminal and N-terminal domains

Jiang, Jian‐Li; Chan, Hsiao Chang; Zhou, Quan; Yu, Man; Yao, Xi-ying; Lam, S.Y.; Zhu, Han; Ho, Lok Sze; Leung, Ka Man; Chen, Z N

doi:10.1007/s00018-004-4146-4

Cited by 48 publications

(29 citation statements)

References 21 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: 67%

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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: 67%

“…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: 83%

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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“…The CD147 expression vector (CD147-pcDNA3.1) was developed in our laboratory. 36 After cells were grown to 60-80% confluency, transfection was performed using the LipofectAMINE 2000 reagent (Invitrogen) according to the manufacturer's instructions. The pcDNA3.1 empty vector was used as a negative control under similar conditions.…”

Section: Methodsmentioning

confidence: 99%

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Tang

Zhang

et al. 2012

Cell Death Differ

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The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) ( À 82/ À 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment. The uncontrolled growth and insufficient vascularization of a tumor mass lead to a stressed state in the tumor microenvironment, which includes low oxygen supply, nutrient deprivation and pH changes. Microenvironment stresses directly impinge on the luminal milieu of the endoplasmic reticulum (ER) and might be sufficiently severe to cause ER stress (ERS). 1 These ERS conditions activate a range of cellular stress response pathways, including the unfolded protein response (UPR). 2,3 UPR activation has profound consequences for tumor growth and resistance to radiotherapy and chemotherapy. [4][5][6] Therefore, the UPR might be responsible for the failure of some patients to respond to treatment and is associated with a poor prognosis. 7 Given the observation that UPR is correlated with certain types of aggressive tumors, drug resistance, recurrence and poor survival, 8-11 the inhibition of the UPR pathway may yield more efficient treatments for cancer.Although there is sufficient evidence to indicate that the UPR is generally activated in solid tumors, the UPR remains poorly characterized in cancers. The three major UPR transducers are inositol-requiring enzyme 1 (IRE1), pancreatic kinase-like ER kinase (PERK) and the UPR-specific transcription factor, activating transcription factor 6 (ATF6).These factors all sense the presence of unfolded proteins in the ER lumen and transduce signals to the nucleus that activate the transcription of UPR target genes, such as Bip (also called glucose-regulated protein 78). 12-14 The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been...

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“…Accordingly, we recently developed a CD147 mAb, metuzumab, an antibody-dependent cellular cytotoxicity (ADCC)-optimized recombinant human and mouse chimeric with a glycoengineered IgG1 isotype and developed by humanizing and affinity optimizing of the HAb18 mAb (25). Metuzumab is expressed in a fucosyltransferase-deficient CHO cell line, which generates a homogenously afucosylated mAb with increased affinity for FcgIIIA and enhanced ADCC activity.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody

Zhang

Sun³

et al. 2015

Molecular Cancer Therapeutics

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Metuzumab is an affinity-optimized and nonfucosylated anti-CD147 human-mouse chimeric IgG1 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC). The purpose of this study was to characterize the pharmacokinetics, safety, and antitumor activities of metuzumab in mouse, rat, and monkey. The ADCC activity was assessed by a lactate dehydrogenase release assay. The pharmacokinetics of metuzumab were determined in Sprague-Dawley rats and in cynomolgus monkeys. Single-and repeat-dose toxicology studies of the i.v. administration of high-dose metuzumab were conducted in cynomolgus monkeys. Mice bearing human tumor xenografts were used to evaluate the antitumor efficacy of metuzumab. The ADCC potency of metuzumab was enhanced compared with the nonglycoengineered parental antibody. Metuzumab also effectively inhibited tumor growth in A549 and NCI-H520 xenograft models. In the monkey model, the total clearance of metuzumab decreased with increasing dose. The nonspecific clearance in monkeys was estimated to be 0.53 to 0.92 mL/h/kg. In single-and repeat-dose toxicology studies in cynomolgus monkeys, metuzumab did not induce any distinct or novel adverse findings and was well tolerated at all tested doses. These preclinical safety data facilitated the initiation of an ongoing clinical trial of metuzumab for the treatment of non-small cell lung cancer

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HAb18G/CD147-mediated calcium mobilization and hepatoma metastasis require both C-terminal and N-terminal domains

Cited by 48 publications

References 21 publications

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody

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