• Animals
• Humans
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Drug Design
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Phosphorylation/drug effects
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Protein Kinase Inhibitors/chemistry
• Protein Kinases/metabolism
• Small Molecule Libraries/pharmacology
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/therapeutic use
• Chimerism/drug effects

• Annexin A5
• Apoptosis
• Cell cycle
• Cervical cancer
• Irradiation

• Fluorouracil/pharmacology
• Uterine Cervical Neoplasms/metabolism
• Uterine Cervical Neoplasms/pathology
• Uterine Cervical Neoplasms/drug therapy
• Uterine Cervical Neoplasms/genetics
• Humans
• Female
• Cell Line, Tumor
• Annexin A5/metabolism
• Cell Survival/drug effects
• Apoptosis/drug effects
• Antimetabolites, Antineoplastic/pharmacology
• Combined Modality Therapy
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/therapy

• ANXA2
• Bioinformatics
• Epigenetics
• Hypomethylation
• Pancreatic cancer

• Annexin A2/genetics
• Annexin A2/metabolism
• Humans
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Prognosis
• Promoter Regions, Genetic
• DNA Methylation
• Gene Expression Regulation, Neoplastic
• Up-Regulation
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism

• GSK3β
• epithelial–mesenchymal transition (EMT)
• lipid peroxidation
• mitochondrial dysfunction
• redoxins

• BFU2016-80006-P Spanish Ministry of Economy and Competitiveness
• BIO-0216 Andalusian Government (Consejería de Economía, Innovación, Ciencia y Empleo)
• ZO1-A1-000614 Intramural Research Program of the National Institute of Allergy and Infectious Diseases, Na-tional Institutes of Health

• biomarker
• cervical cancer
• human papillomavirus
• oncogenesis
• proteomics

• FRGS/1/2019/SKK13/USM/01/1 Ministry of Higher Education

• CD147
• EMMPRIN
• MMPs
• Pathological processes
• Physiological processes

• CD147
• angiogenesis
• diagnosis
• hepatocellular carcinoma
• metastasis

• Annexin A2
• Breast cancer
• HER2
• Heterogeneity
• Ki67
• Triple negative
• Triple positive

• BACH1
• invasion
• isoflurane
• microRNA-375
• migration
• proliferation
• prostate cancer cells

• Annexin A2
• FOXM1
• Glioma cells
• MMP-2
• Recombinant MeICT peptide

• ANXA2
• EpCAM
• breast cancer
• molecular pathology
• tPA

• Animals
• Annexin A2/metabolism
• Breast Neoplasms
• Cell Line, Tumor
• Epithelial Cell Adhesion Molecule/metabolism
• Estrogen Receptor alpha/metabolism
• Female
• Humans
• MCF-7 Cells
• Mice
• Tissue Plasminogen Activator/metabolism

• Cancer Society in Stockholm, Karolinska Institutet and the Stockholm County Council

• ANXA2
• GSEA
• TCGA
• biomarker
• cervical cancer
• immunohistochemistry

• Humans
• Uterine Cervical Neoplasms/diagnosis
• Uterine Cervical Neoplasms/metabolism
• Female
• Annexin A2/metabolism
• Annexin A2/genetics
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Middle Aged
• Adult
• Carcinoma, Squamous Cell/diagnosis
• Carcinoma, Squamous Cell/metabolism

• KX01860106 The International Cooperation Promotion Project of Shihezi University
• 81560053, 81760386 National Natural Science Foundation of China

• Annexin A2
• Dual-luciferase reporter assay
• Microarray
• RNA-sequencing
• Thyroid carcinoma

• Annexin A2/genetics
• Gene Ontology
• Humans
• MicroRNAs
• Sequence Analysis, RNA
• Thyroid Gland/metabolism
• Thyroid Gland/pathology
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/pathology
• Up-Regulation

• CD147
• Glucose metabolism
• Hepatocellular carcinoma
• Immunosuppression

Interaction between cancer cells and fibroblasts mediated by extracellular matrix metalloproteinase inducer (emmprin, CD147) is important in the invasion and proliferation of cancer cells. However, the exact mechanism of emmprin mediated stimulation of matrix metalloprotease-2 (MMP-2) production from fibroblasts has not been elucidated. Our previous studies using an inhibitory peptide against emmprin suggested the presence of a molecule on the cell membrane which forms a complex with emmprin. Here we show that CD73 expressed on fibroblasts interacts with emmprin and is a required factor for MMP-2 production in co-cultures of sarcoma cells with fibroblasts.

CD73 along with CD99 was identified by mass spectrometry analysis as an emmprin interacting molecule from a co-culture of cancer cells (epithelioid sarcoma cell line FU-EPS-1) and fibroblasts (immortalized fibroblasts cell line ST353i). MMP-2 production was measured by immunoblot and ELISA. The formation of complexes of CD73 with emmprin was confirmed by immunoprecipitation, and their co-localization in tumor cells and fibroblasts was shown by fluorescent immunostaining and proximity ligation assays.

Stimulated MMP-2 production in co-culture of cancer cells and fibroblasts was completely suppressed by siRNA knockdown of CD73, but not by CD99 knockdown. MMP-2 production was not suppressed by CD73-specific enzyme inhibitor (APCP). However, MMP-2 production was decreased by CD73 neutralizing antibodies, suggesting that CD73-mediated suppression of MMP-2 production is non-enzymatic. In human epithelioid sarcoma tissues, emmprin was immunohistochemically detected to be mainly expressed in tumor cells, and CD73 was expressed in fibroblasts and tumor cells: emmprin and CD73 were co-localized predominantly on tumor cells.

This study provides a novel insight into the role of CD73 in emmprin-mediated regulation of MMP-2 production.

• CD73
• Emmprin
• Fibroblasts
• MMP-2
• Sarcoma

An increased surface level of CIE (clathrin-independent endocytosis) proteins is a new feature of malignant neoplasms. CD147 is a CIE glycoprotein highly up-regulated in hepatocellular carcinoma (HCC). The ability to sort out the early endosome and directly target the recycling pathway confers on CD147 a prolonged surface half-life. However, current knowledge on CD147 trafficking to and from the cell-surface is limited. In this study, an MSP (membrane and secreted protein)-cDNA library was screened against EpoR/LR-F3/CD147EP-expressed cells by MAPPIT (mammalian protein–protein interaction trap). CD147 co-expressing with the new binder was investigated by GEPIA (gene expression profiling interactive analysis). The endocytosis, ER-Golgi trafficking and recycling of CD147 were measured by confocal imaging, flow cytometry, and biotin-labeled chase assays, respectively. Rab GTPase activation was checked by GST-RBD pull-down and MMP activity was measured by gelatin zymography. HCC malignant phenotypes were determined by cell adhesion, proliferation, migration, Transwell motility, and invasion assays. An ER-Golgi-resident transmembrane protein YIPF2 was identified as an intracellular binder to CD147. YIPF2 correlated and co-expressed with CD147, which is a survival predictor for HCC patients. YIPF2 is critical for CD147 glycosylation and trafficking functions in HCC cells. YIPF2 acts as a Rab-GDF (GDI-displacement factor) regulating three independent trafficking steps. First, YIPF2 recruits and activates Rab5 and Rab22a GTPases to the endomembrane structures. Second, YIPF2 modulates the endocytic recycling of CD147 through distinctive regulation on Rab5 and Rab22a. Third, YIPF2 mediates the mature processing of CD147 via the ER-Golgi trafficking route. Decreased YIPF2 expression induced a CD147 efficient delivery to the cell-surface, promoted MMP secretion, and enhanced the adhesion, motility, migration, and invasion behaviors of HCC cells. Thus, YIPF2 is a new trafficking determinant essential for CD147 glycosylation and transport. Our findings revealed a novel YIPF2-controlled ER-Golgi trafficking signature that promotes CD147-medated malignant phenotypes in HCC.

Long non‐coding RNAs (lncRNAs) play essential roles in diverse biological processes; however, current understanding of the mechanism underlying the regulation of tumour proliferation and metastasis is limited. Lung cancer‐associated transcript 1 (LUCAT1) has been reported in a variety of human cancers, while its role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to determine the biological role and underlying mechanism of LUCAT1 on progression and metastasis in HCC cells and clinical specimens. Our results demonstrated that LUCAT1 was up‐regulated in HCC tissues and cells. Loss‐ and gain‐of‐function studies revealed that LUCAT1 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Furthermore, RNA pulldown and Western blot assays indicated that LUCAT1 inhibited the phosphorylation of Annexin A2 (ANXA2) to reduce the degradation of ANXA2‐S100A10 heterotetramer (AIIt), which in turn accelerated the secretion of plasminogen into plasmin, thereby resulting in the activation of metalloprotease proteins. In conclusion, we propose that LUCAT1 serves as a novel diagnostic and therapeutic target for HCC.

• Annexin A2
• hepatocellular carcinoma
• long non-coding RNA
• phosphorylation
• tumour progression and metastasis

• ANX A2
• ECM
• cancer
• metastasis
• neoangiogenesis

• Cancer
• Chemotherapy
• Metastasis
• Resistance

The interaction between cancer cells and stromal components contributes to cancer invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC). The present study investigated the role of the correlation between annexin II (ANX2) and stromal tenascin C (TNC) with the progression of PDAC. The functions of the expression ANX2 and TNC were assessed in in vitro experiments using mouse and human PDAC cells, and the clinical effect was analyzed using immunohistochemistry with surgically resected PDAC tissues. The effects on epithelial to mesenchymal transition (EMT), invasion, putative cancer stemness, and anoikis resistance were examined in vitro using murine precancerous pancreatic intraepithelial neoplasia (PanIN) cells and murine and human invasive PDAC cells with ANX2 knockdown using specific small interfering RNA (siRNA)s and recombinant TNC (rTNC). ANX2 was expressed at a high level in primary PanIN cells and invasive PDAC cells, compared with the levels in liver metastatic PDAC cells. In the ANX2-knockdown cells, there were fewer cells with a morphological mesenchymal appearance in three-dimensional culture and invasion was reduced compared with that in the control cells. Morphological change into the mesenchymal phenotype and invasion were enhanced by rTNC treatment in the control PDAC cells but not in the ANX2-knockdown cells. Pancreatosphere formation assays showed that ANX2 and TNC facilitated the maintenance of stem-like characters in PDAC cells. Furthermore, anoikis assays indicated that the interaction of ANX2-TNC contributed to anoikis resistance in PDAC cells. In the immunohistochemistry analyses, the group with a high expression of ANX2 and high stromal TNC was significantly correlated with distant metastasis, and was associated with hematogenous/peritoneal recurrence and poor outcomes following surgery in resected human primary PDAC tissues. In conclusion, the results demonstrated that ANX2 and stromal TNC regulated invasion in addition to stemness and anoikis resistance, which are crucial for metastasis in the progression of PDAC. These results indicate the potential of the ANX2-TNC axis as a therapeutic target for PDAC metastasis.

Recurrence and metastasis are common in hepatocellular carcinoma (HCC) and correlate with poor prognosis. We investigated the role of fibronectin type III domain containing 3B (FNDC3B) in HCC metastasis. Overexpression of FNDC3B in HCC cell lines enhanced cell migration and invasion. On the other hand, knockdown of FNDC3B using short-hairpin RNA reduced tumor nodule formation in both intra- and extra-hepatic metastasis. High levels of FNDC3B were observed in metastatic HCCs and correlated with poor patient survival and shorter recurrence time. Mutagenesis and LC-MS/MS analyses showed that FNDC3B promotes cell migration by cooperating with annexin A2 (ANXA2). Furthermore, FNDC3B and ANXA2 expression correlated negatively with patient survival. Our results indicate that FNDC3B behaves like an oncogene by promoting cell migration. This suggests FNDC3B could serve as a biomarker and therapeutic target for HCC metastasis.

• FNDC3B
• hepatocellular carcinoma
• metastasis

The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to disease progression by mediating cytokine or chemokine release, the activation of platelets and monocytes, as well as the formation of monocyte-platelet aggregates (MPAs). EMMPRIN is also involved in atherosclerosis by mediating the infiltration of pro-inflammatory cells. There is also evidence that EMMPRIN controls energy metabolism of cells and that EMMPRIN binding partners modulate intracellular glycosylation and trafficking of EMMPRIN towards the cell membrane. In this review, we systematically discuss these multifaceted roles of EMMPRIN and its interaction partners, such as Cyclophilins, in cardiovascular disease.

• cardiovascular disease
• immunoglobulin superfamily
• inflammation
• monocyte-platelet aggregates
• platelets

Extracellular matrix metalloproteinase inducer, also knowns as cluster of differentiation 147 (CD147) or basigin, is a widely distributed cell surface glycoprotein that is involved in numerous physiological and pathological functions, especially in tumor invasion and metastasis. Monocarboxylate transporters (MCTs) catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane to preserve the intracellular pH and maintain cell homeostasis. As a chaperone to some MCT isoforms, CD147 overexpression significantly contributes to the metabolic transformation of tumor. This overexpression is characterized by accelerated aerobic glycolysis and lactate efflux, and it eventually provides the tumor cells with a metabolic advantage and an invasive phenotype in the acidic tumor microenvironment. This review highlights the roles of CD147 and MCTs in tumor cell metabolism and the associated molecular mechanisms. The regulation of CD147 and MCTs may prove to be with a therapeutic potential for tumors through the metabolic modification of the tumor microenvironment.

• extracellular matrix metalloproteinase inducer
• glycolysis
• monocarboxylate transporters
• p53
• tumor acidic microenvironment

Glioblastoma (GBM) is the most devastating tumor of the brain, characterized by an almost inevitable tendency to recur after intensive treatments and a fatal prognosis. Indeed, despite recent technical improvements in GBM surgery, the complete eradication of cancer cell disseminated outside the tumor mass still remains a crucial issue for glioma patients management. In this context, Annexin 2A (ANXA2) is a phospholipid-binding protein expressed in a variety of cell types, whose expression has been recently associated with cell dissemination and metastasis in many cancer types, thus making ANXA2 an attractive putative regulator of cell invasion also in GBM.

Here we show that ANXA2 is over-expressed in GBM and positively correlates with tumor aggressiveness and patient survival. In particular, we associate the expression of ANXA2 to a mesenchymal and metastatic phenotype of GBM tumors. Moreover, we functionally characterized the effects exerted by ANXA2 inhibition in primary GBM cultures, demonstrating its ability to sustain cell migration, matrix invasion, cytoskeletal remodeling and proliferation. Finally, we were able to generate an ANXA2-dependent gene signature with a significant prognostic potential in different cohorts of solid tumor patients, including GBM.

In conclusion, we demonstrate that ANXA2 acts at multiple levels in determining the disseminating and aggressive behaviour of GBM cells, thus proving its potential as a possible target and strong prognostic factor in the future management of GBM patients.

• annexin 2A
• cell cycle
• cytoskeletal remodeling
• glioblastoma
• invasion

The potential effects of adipose tissue-derived mesenchymal stem cells (AT-MSCs) on the growth and invasion of canine tumours including hepatocellular carcinoma (HCC) are not yet understood. Moreover in humans, the functional contribution of AT-MSCs to malignancies remains controversial. The purpose of this study was to investigate the effects of AT-MSCs on the proliferation and invasion of canine HCC cells in vitro. The effect of AT-MSCs on mRNA levels of factors related to HCC progression were also evaluated. Conditioned medium from AT-MSCs (AT-MSC-CM) significantly enhanced canine HCC cell proliferation and invasion. Moreover, mRNA expression levels of transforming growth factor-beta 1, epidermal growth factor A, hepatocyte growth factor, platelet-derived growth factor-beta, vascular endothelial growth factor, and insulin-like growth factor 2 were 2.3 ± 0.4, 2.0 ± 0.5, 5.7 ± 1.9, 1.7 ± 0.2, 2.1 ± 0.4, and 1.4 ± 0.3 times higher, respectively (P < 0.05). The mRNA expression level of MMP-2 also increased (to 4.0 ± 1.2 times control levels) in canine HCC cells co-cultured with AT-MSCs, but MMP-9 mRNA significantly decreased (to 0.5 ± 0.1 times control levels). These findings suggest that soluble factors from AT-MSCs promote the proliferation and invasion of canine HCC cells.

Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy.

Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition.

No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K_D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences.

The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

The online version of this article (10.1186/s12985-017-0904-4) contains supplementary material, which is available to authorized users.

• Annexin A2
• Hepatitis C virus
• Hepatocellular carcinoma
• NS5B
• RNA, allosteric inhibition, filibuvir, surface plasmon resonance

Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protein kinase B (Akt). Likewise, tumor cells pretreated with LGRFYAASG-pen exhibited an impaired capacity to colonize the lungs in vivo in several mouse models. Together, our findings demonstrate an unrecognized functional link between intracellular annexin A2 and tumor cell adhesion, migration and in vivo grafting. Moreover, this work uncovers a new peptide motif that binds to and inhibits intracellular annexin A2 as a candidate therapeutic lead for potential translation into clinical applications.

β1, 3-N-acetylglucosminyltransferase 8(β3GnT8) synthesizes a unique cabohydrate structure known as polylactosamine, and plays a vital role in progression of various human cancer types. However, its involvement in gastric cancer remains unclear. In this study, we analyzed the expression and clinical significance of β3GnT8 by Western blot in 6 paired fresh gastric cancer tissues, noncancerous tissues and immunohistochemistry on 110 paraffin-embedded slices. β3GnT8 was found to be over-expressed in gastric cancer tissues, which correlated with lymph node metastasis and TNM stage. Forced the expression of β3GnT8 promoted migration and invasion of gastric cancer cells, whereas β3GnT8 knockdown led to the opposite results. Further studies showed that the regulated β3GnT8 could convert the heterogeneous N-glycosylated forms of CD147 and change the polylactosamine structures carried on CD147. In addition, our data suggested the annexin A2 (ANXA2) to be an essential interaction partner of β3GnT8 during the process of CD147 glycosylation. Collectively, these results provide a novel molecular mechanism for β3GnT8 in promotion of gastric cancer invasion and metastasis. Targeting β3GnT8 could serve as a new strategy for future gastric cancer therapy.

• CD147
• gastric cancer
• glycosylation
• invasion
• β3GnT8

• Annexin A2
• CD147
• DOCK3
• WAVE2
• cell movement

• Annexin A2
• cell proliferation
• epidermal growth factor receptor signaling
• epithelial-mesenchymal transition

• annexin A2
• extracellular matrix
• ovarian cancer
• plasmin
• tumour microenvironment

• Animals
• Cell Adhesion
• Cell Communication/physiology
• Extracellular Matrix/metabolism
• Extracellular Matrix/pathology
• Female
• Humans
• Neoplasm Invasiveness
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Peritoneal Neoplasms/metabolism
• Peritoneal Neoplasms/secondary
• Peritoneum/metabolism
• Peritoneum/pathology
• Protein Processing, Post-Translational
• Proteomics

• ANXA2
• ANXA4
• Prognosis
• Survival
• Uterine cervical neoplasms

• Annexin A4
• Early recurrences/metastasis
• Epithelial–mesenchymal transition (EMT)
• Hepatocellular Carcinoma (HCC)
• Prognostic biomarker

• Annexin A4/genetics
• Annexin A4/metabolism
• Apoptosis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Blotting, Western
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/secondary
• Cell Movement
• Cell Proliferation
• Female
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/metabolism
• Neoplasm Recurrence, Local/pathology
• Neoplasm Staging
• Prognosis
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tumor Cells, Cultured

• Annexin A2
• hepatocellular carcinoma
• invasion
• ubiquitin associated protein 2
• ubiquitination

• Annexin A2/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carrier Proteins/metabolism
• Cell Line, Tumor
• Cell Proliferation/physiology
• Female
• Hep G2 Cells
• Humans
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Invasiveness
• Prognosis
• Ubiquitination

• Breast cancer
• Neoangiogenesis
• Plasmin
• Tumor microenvironment

• Animals
• Annexin A2/antagonists & inhibitors
• Annexin A2/immunology
• Annexin A2/metabolism
• Antibodies, Monoclonal/pharmacology
• Antineoplastic Agents/pharmacology
• Breast Neoplasms/drug therapy
• Breast Neoplasms/immunology
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Enzyme Activation
• Female
• Fibrinolysin/metabolism
• Humans
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Mice, Nude
• Signal Transduction/drug effects
• Time Factors
• Tissue Plasminogen Activator/metabolism
• Tumor Burden
• Tumor Microenvironment
• Xenograft Model Antitumor Assays

• Annexin A2
• Hepatocellular carcinoma
• Prognosis
• Up-regulation

• Adult
• Aged
• Aged, 80 and over
• Annexin A2/blood
• Annexin A2/genetics
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/blood
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms/blood
• Neoplasms/genetics
• Prognosis
• Transcriptional Activation

Matrix metalloproteinases (MMPs) comprise a family of 23 zinc-dependent enzymes involved in various pathologic and physiologic processes. In cancer, MMPs contribute to processes from tumour initiation to establishment of distant metastases. Complex signalling and protein transport networks regulate MMP synthesis, cell surface presentation and release. Earlier attempts to disrupt MMP activity in patients have proven to be intolerable and with underwhelming clinical efficacy; thus targeting ancillary proteins that regulate MMP activity may be a useful therapeutic approach. Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally characterized as a factor present on lung cancer cells, which stimulated collagenase (MMP-1) production in fibroblasts. Subsequent studies demonstrated that EMMPRIN was identical with several other protein factors, including basigin (Bsg), all of which are now commonly termed CD147. CD147 modulates the synthesis and activity of soluble and membrane-bound [membrane-type MMPs (MT-MMPs)] in various contexts via homophilic/heterophilic cell interactions, vesicular shedding or cell-autonomous processes. CD147 also participates in inflammation, nutrient and drug transporter activity, microbial pathology and developmental processes. Despite the hundreds of manuscripts demonstrating CD147-mediated MMP regulation, the molecular underpinnings governing this process have not been fully elucidated. The present review summarizes our present knowledge of the complex regulatory systems influencing CD147 biology and provides a framework to understand how CD147 may influence MMP activity.

• CD147
• EMMPRIN
• basigin
• cancer
• matrix metalloproteinase
• protein oligomerization

Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs.

We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry.

A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018).

We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.

• AFP
• Annexin A2
• Follistatin
• Hepatocellular carcinoma

• CD147
• CD98
• Chemotaxis
• Homotypic cell aggregation
• Jurkat T cells

• Animals
• Basigin/chemistry
• Basigin/genetics
• Basigin/metabolism
• Cells, Cultured
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/metabolism
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Humans
• Hydrocarbons, Brominated/toxicity
• Immunohistochemistry
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinases/genetics
• Matrix Metalloproteinases/metabolism
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Polymerase Chain Reaction
• RNA Interference
• RNA, Small Interfering/metabolism
• Tissue Inhibitor of Metalloproteinases/metabolism

Focal adhesions (FAs), integrin-mediated macromolecular complexes located at the cell membrane extracellular interface, have been shown to regulate cell adhesion and migration. Our previous studies have indicated that HAb18G/CD147 (CD147) is involved in cytoskeleton reorganization and FA formation in human hepatocellular carcinoma (HCC) cells. However, the precise mechanisms underlying these processes remain unclear. In the current study, we determined that CD147 was involved in vinculin-mediated FA focal adhesion formation in HCC cells. We also found that deletion of CD147 led to reduced vinculin-mediated FA areas (P<0.0001), length/width ratios (P<0.0001), and mean intensities (P<0.0001). CD147 promoted lamellipodia formation by localizing Arp2/3 to the leading edge of the cell. Deletion of CD147 significantly reduced the fluorescence (t_1/2) recovery times (22.7±3.3 s) of vinculin-mediated focal adhesions (P<0.0001). In cell-spreading assays, CD147 was found to be essential for dynamic focal adhesion enlargement and disassembly. Furthermore, the current data showed that CD147 reduced tyrosine phosphorylation in vinculin-mediated focal adhesions, and enhanced the accumulation of the acidic phospholipid phosphatidylinositol-4, 5-bisphosphate (PIP2). Together, these results revealed that CD147 is involved in vinculin-mediated focal adhesion formation, which subsequently promotes cytoskeleton reorganization to facilitate invasion and migration of human HCC cells.

• Actin-Related Protein 2-3 Complex/biosynthesis
• Actin-Related Protein 2-3 Complex/metabolism
• Basigin/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Adhesion/genetics
• Cell Adhesion/physiology
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Movement/physiology
• Cytoskeleton/physiology
• Focal Adhesions/genetics
• Focal Adhesions/physiology
• Humans
• Liver Neoplasms/pathology
• Neoplasm Invasiveness/pathology
• Phosphatidylinositol 4,5-Diphosphate/metabolism
• Pseudopodia/physiology
• RNA Interference
• RNA, Small Interfering
• Vinculin/biosynthesis
• Vinculin/metabolism

Upper tract urothelial carcinoma (UTUC) is a tumor with sizable metastases and local recurrence. It has a worse prognosis than bladder cancer. This study was designed to investigate the urinary potential tumor markers of UTUC.

Between January 2008 and January 2009, urine was sampled from 13 patients with UTUC and 20 healthy adults. The current study identified biomarkers for UTUC using non-fixed volume stepwise weak anion exchange chromatography for fractionation of urine protein prior to two-dimensional gel electrophoresis.

Fifty five differential proteins have been determined by comparing with the 2-DE maps of the urine of UTUC patients and those of healthy people. Western blotting analysis and immunohistochemistry of tumor tissues and normal tissues from patients with UTUC were carried out to further verify five possible UTUC biomarkers, including zinc-alpha-2-glycoprotein, calreticulin, annexin A2, annexin A3 and haptoglobin. The data of western blot and immunohistochemical analysis are consistent with the 2-DE data. Combined the experimental data in the urine and in tumor tissues collected from patients with UTUC, the crucial over-expressed proteins are calreticulin, annexin A2, and annexin A3.

Calreticulin, annexin A2, and annexin A3 are very likely a panel of biomarkers with potential value for UTUC diagnosis.

• CD147
• CFTR
• NYD-SP8
• STK31
• Spermatogenesis
• YWK-II