Orthotopic liver transplantation (OLT) is the only curative therapy of HCC with underlying cirrhosis, but due to HCC metastasis and recurrence, its benefit is limited to a small population who meet the strict selection criteria. We previously reported that Licartin ([ 131 I]mAb HAb18G/CD147) was safe and effective in treating HCC patients, and its antigen, HAb18G/ CD147, was closely related to HCC invasion and metastasis. Here, we reported a randomized controlled trial to assess the post-OLT antirecurrence efficacy of Licartin in advanced HCC patients. We randomized 60 post-OLT patients with HCC, who were at tumor stage 3/4 and outside the Milan criteria before OLT, into 2 groups. Three weeks after OLT, the treatment group received 15.4 MBq/kg of Licartin, while the control group received placebo intravenously for 3 times with an interval of 28 days. At 1-year follow-up, the recurrence rate significantly decreased by 30.4% (P ‫؍‬ 0.0174) and the survival rate increased by 20.6% (P ‫؍‬ 0.0289) in the treatment group, compared with those in the control group. For the control group versus the treatment group, the hazard ratio for recurrence H epatocellular carcinoma is the most common type of primary liver cancer and ranks sixth among cancers as a cause of death worldwide. 1 It is a highly malignant tumor characterized by rapid progression, poor prognosis, and frequent tumor recurrence. It has an annual incidence rate of 564,000 cases, and 55% of those are in China. 2 The mean natural survival time was reported to be only 3-6 months due to the rapid progression of tumor, especially the spread and metastasis. 3,4 Surgery is the preferred treatment, but less than 20% of patients have the chance to be treated surgically Abbreviations: AFP, alpha fetoprotein; CI, confidence interval; DBIL, direct bilirubin; mAb, monoclonal antibody; OLT, orthotopic liver transplantation; TNM, tumor-nodes-metastasis. From the

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Tumor cells can move as individual cells in two interconvertible modes: mesenchymal mode and amoeboid mode. Cytoskeleton rearrangement plays an important role in the interconversion. Previously, we reported that HAb18G/CD147 and annexin II are interacting proteins involved in cytoskeleton rearrangement, yet the role of their interaction is unclear. In this study we found that the depletion of HAb18G/CD147 produced a rounded morphology, which is associated with amoeboid movement, whereas the depletion of annexin II resulted in an elongated morphology, which is associated with mesenchymal movement. The extracellular portion of HAb18G/CD147 can interact with a phosphorylation-inactive mutant of annexin II and inhibit its phosphorylation. HAb18G/CD147 inhibits Rho signaling pathways and amoeboid movement by inhibiting annexin II phosphorylation, promotes membrane localization of WAVE2 and Rac1 activation by way of the integrin-FAK-PI3K/PIP3 signaling pathway, and promotes the formation of lamellipodia and mesenchymal movement. Conclusion: These results suggest that the interaction of HAb18G/CD147 with annexin II is involved in the interconversion between mesenchymal and amoeboid movement of hepatocellular carcinoma cells.

HAb18G ⁄ CD147, a member of the immunoglobulin family enriched on the surface of tumor cells, is reported to be correlated with invasion, metastasis, growth, and survival of malignant cells. Here, we found that annexin II, a 36-kDa Ca 2+ -and phospholipid-binding protein and in vivo substrate for tyrosine kinase and PKC, is a new interaction protein of HAb18G ⁄ CD147 in human hepatocellular carcinoma (HCC) cells. In the present study, we explored the unclear role of annxin II in HCC invasion and migration and the interaction effects between HAb18G ⁄ CD147 and annexin II. Our data show that downregulation of annexin II in HCC cells significantly decreased the secretion of MMP, migration ability, and invasive potential, and affected the cytoskeleton rearrangement of tumor cells. The MMP-2 level and invasive potential of HCC cells were regulated by both annexin II and HAb18G ⁄ CD147. Also, interaction effects exist between the two molecules in tumor progression, including MMP-2 production, migration, and invasion. These results suggest that annexin II promotes the invasion and migration of HCC cells in vitro, and annexin II and HAb18G ⁄ CD147 interact with each other in the same signal transduction pathway working as a functional complex in tumor progression. (Cancer Sci 2010; 101: 387-395) I nvasion and migration are two central processes of malignant tumors that usually lead to tumor-associated death. Such migratory and invasive events are regulated by different proteolytic enzymes, including serine protease, cysteine protease, and metalloproteases.(1) These proteolytic enzymes degrade the extracellular matrix (ECM) and basement membrane surrounding blood vessels. During metastasis, cancer cells penetrate through the degraded basement membrane and ECM, become implanted in the underlying tissues, and subsequently form secondary tumors.(2) Among the proteases, MMP are mainly regulated by tumor-stroma interactions via CD147, a highly glycosylated cell surface transmembrane protein belonging to the immunoglobulin superfamily.(3) CD147 was first identified as a factor shed from the surface of tumor cells responsible for stimulating MMP-1 production by fibroblasts. One of the important and most studied functions of CD147 is its role in induction of MMP production via cell interactions -thus the derivation of its other name: extracellular matrix metalloproteinase inducer (EMMPRIN).(4) Accumulating evidence suggests a prominent role for CD147 in mediating interactions both between tumor cells themselves and between tumor cells and 'hijacked' host stromal cells to promote a number of events during cancer progression.(5) Although the detailed mechanisms through which CD147 regulates the phenomenon are not yet known, it is clear that CD147 is a major mediator of malignant cell behavior. Our team previously developed the anti-hepatocellular carcinoma (HCC) mAb HAb18 by using a cell suspension extracted from fresh human HCC tissues to immunize BALB ⁄ c mice and prepare hybridomas.(6-8) Its antigen, HAb18G, was identified ...

An increased understanding of cellular uptake mechanisms of macromolecules remains an important challenge in cell biology with implications for viral infection and macromolecular drug delivery. Here, we report a strategy based on antibody-conjugated magnetic nanoparticles for the isolation of endocytic vesicles induced by heparan sulfate proteoglycans (HSPGs), key cell-surface receptors of macromolecular delivery. We provide evidence for a role of the glucose-regulated protein (GRP)75/PBP74/mtHSP70/mortalin (hereafter termed "GRP75") in HSPG-mediated endocytosis of macromolecules. GRP75 was found to be a functional constituent of intracellular vesicles of a nonclathrin-, noncaveolin-dependent pathway that was sensitive to membrane cholesterol depletion and that showed colocalization with the membrane raft marker cholera toxin subunit B. We further demonstrate a functional role of the RhoA GTPase family member CDC42 in this transport pathway; however, the small GTPase dynamin appeared not to be involved. Interestingly, we provide evidence of a functional role of GRP75 using RNAi-mediated down-regulation of GRP75 and GRP75-blocking antibodies, both of which inhibited macromolecular endocytosis. We conclude that GRP75, a chaperone protein classically found in the endoplasmic reticulum and mitochondria, is a functional constituent of noncaveolar, membrane raft-associated endocytic vesicles. Our data provide proof of principle of a strategy that should be generally applicable in the molecular characterization of selected endocytic pathways involved in macromolecular uptake by mammalian cells.E ndocytosis is the process by which cells compartmentalize constituents of the plasma membrane and the extracellular space into intracellular vesicles for further sorting to specific cellular locations (1-4). Endocytosis regulates signaling events involved in cell motility and cell fate determination and can be exploited by microbial intruders for infection. Interestingly, the same pathways may be used for the delivery of therapeutic macromolecules (e.g., DNA, anti-sense oligonucleotides, and siRNA) in the treatment of various diseases. A more detailed understanding of endocytic mechanisms thus is a major challenge in basic cell biology with implications for viral infection, the regulation of signaling networks in cancer (3), and the development of macromolecular drugs (5).High-resolution, live-cell imaging techniques have unraveled the heterogeneity of vesicular compartments in terms of kinetic/ dynamic parameters as well as ligand specificity. In addition to the classical clathrin-dependent mechanism of endocytosis, several clathrin-independent endocytic pathways are emerging (3,4,6). Collectively, published data from several groups indicate that ligands can be taken up by multiple lipid raft-mediated pathways; however, these pathways require further definition at the molecular level. Classification schemes based on the dependence on/association with dynamin, caveolin-1, and the RhoA family GTPases Rac1, RhoA, and CDC42 have b...