Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.
Humans ; Integrins/metabolism* ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Cell Adhesion ; Carcinogenesis ; Cell Transformation, Neoplastic ; Tumor Microenvironment

Integrin is a large family of cell adhesion molecules (CAMs) which involves in the interaction of cells/cells and cells/ extracellular matrix (ECM) to mediate cell proliferation, differentiation, adhesion, migration, etc. In recent years, aberrant expression of integrin has been clearly found in many tumor studies, indicating that integrin is closely related to tumor formation and development. Meanwhile, it has effects on tumor cell differentiation, cell migration, proliferation and tumor neovascularization. The study of drugs targeting integrins is of great significance for the clinical treatment of tumors. Because of its important role in tumorigenesis and development, integrin has become a promising target for the treatment of cancer. This review summarizes the role of integrin in tumor development and the current state of integrin inhibitors to provide a valuable reference for subsequent research.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Biological Products ; pharmacology ; therapeutic use ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Extracellular Matrix ; metabolism ; Humans ; Integrins ; antagonists & inhibitors ; classification ; genetics ; metabolism ; Neoplasms ; drug therapy ; pathology ; Neovascularization, Pathologic ; drug therapy ; pathology ; Signal Transduction ; drug effects

OBJECTIVETo study the effect of nadroparin in the migration of breast cancer cells MDA-MB-231 and its action mechanism.

METHODThe MTT test was adopted to observe the effect of different concentrations of naringenin on the growth capacity of breast cancer cells MDA-MB-231. Wound healing and transwell experiment analysis were conducted to detect the effect of naringenin on the migration of breast cancer cells MDA-MB-231. Western blotting was adopted to investigate the effect of naringenin on protein expressions of MDA-MB-231 cell Integrin β3, β1 and matrix metalloproteinase MMP-2 and MMP-9. The computer virtual docking technique was used to evaluate the combining capacity of naringenin and Integrin β3 in vitro.

RESULTNaringenin inhibited the migration of MDA-MB-231 cells in a dose-dependent manner. In wound healing and transwell experiments, with the increase in the concentration of naringenin, the number of migrant MDA-MB-231 cells and the invasion capacity of breast cancer cells decreased. Naringenin could inhibit the protein expression of Integrin β3 in a dose-dependent manner, but with unobvious effect on expression of Integrin β1. Besides, naringenin could significantly inhibit the protein expressions of MMP-2 and MMP-9. The results of the computer virtual docking showed a negative value in the combining capacity between naringenin and Integrin β3, indicating the high affinity between them.

CONCLUSIONNaringenin can inhibit the growth capacity of breast cancer cells MDA-MB-231 and block the migration and invasion of breast cancer cells MDA-MB-231. Its mechanism is to down-regulate MMP-2 and MMP-9 expressions after combining with Integrin β3.

Breast Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cell Movement ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Female ; Flavanones ; pharmacology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Integrins ; genetics ; metabolism ; Matrix Metalloproteinase 2 ; genetics ; metabolism ; Matrix Metalloproteinase 9 ; genetics ; metabolism ; Neoplasm Invasiveness

Celastrol is a type of quinone methyl triterpene isolated from traditional Chinese medicine Tripterygium wilfordii, with pharmacological activities, like anti-inflammatory, immunosuppression and anti-tumor. This study focused on the effects of celastrol on adhesion, migration and invasion of lung cancer cells. The migration inhibition of lung cancer cells induced by celastrol was detected by the scratch test. The invasion inhibition of lung cancer cells induced by celastrol was measured by the transwell experiment. RT-PCR and Western blot were used to determine the effect of different concentrations of celastrol in integrin family and Akt signaling pathway in lung cancer cells. The results showed that celastrol inhibited adhesion, migration and invasion of lung cancer cells and expressions of integrins β3, β4, αv and phosphorylated Akt, GSK-3β, c-Raf, PDK1 in Akt signal pathway in a dose-dependent manner. Therefore, the study implies that Celastrol could inhibit the metastasis of lung cancer cells by suppressing Akt signaling pathway and expression of integrins.
Apoptosis ; drug effects ; Cell Line, Tumor ; Drugs, Chinese Herbal ; pharmacology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Integrins ; genetics ; metabolism ; Lung Neoplasms ; genetics ; metabolism ; pathology ; physiopathology ; Neoplasm Metastasis ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Signal Transduction ; drug effects ; Triterpenes ; pharmacology

BACKGROUNDThe initial osteoblastic adhesion to materials characterizes the first phase of cell-material interactions and influences all the events leading to the formation of new bone. In a previous work, we developed a novel amorphous calcium phosphate (ACP)/poly(L-lactic acid) (PLLA) material that demonstrated morphologic variations in its microstructure. The aim of this study was to investigate the initial interaction between this material and osteoblastic cells. Cellular attachment and the corresponding signal transduction pathways were investigated.

METHODSA porous ACP/PLLA composite and PLLA scaffold (as a control) were incubated in fetal bovine serum (FBS) containing phosphate-buffered saline (PBS), and the protein adsorption was determined. Osteoblastic MG63 cells were seeded on the materials and cultured for 1, 4, 8, or 24 hours. Cell attachment was evaluated using the MTS method. Cell morphology was examined using scanning electron microscopy (SEM). The expression levels of the genes encoding integrin subunits α1, α5, αv, β1, focal adhesion kinase (FAK), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were determined using real-time reverse transcription polymerase chain reaction (RT-PCR).

RESULTSThe ACP/PLLA material significantly increased the protein adsorption by 6.4-fold at 1 hour and 2.4-fold at 24 hours, compared with the pure PLLA scaffold. The attachment of osteoblastic cells to the ACP/PLLA was significantly higher than that on the PLLA scaffold. The SEM observation revealed a polygonal spread shape of cells on the ACP/ PLLA, with the filopodia adhered to the scaffold surface. In contrast, the cells on the PLLA scaffold exhibited a spherical or polygonal morphology. Additionally, real-time RT-PCR showed that the genes encoding the integrin subunits α1, αv, β1, and FAK were expressed at higher levels on the ACP/PLLA composite.

CONCLUSIONSThe ACP/PLLA composite promoted protein adsorption and osteoblastic adhesion. The enhanced cell adhesion may be mediated by the binding of integrin subunits α1, αv, and β1, and subsequently may be regulated through the FAK signal transduction pathways.

Biocompatible Materials ; chemistry ; Calcium Phosphates ; chemistry ; Cell Adhesion ; physiology ; Cells, Cultured ; Focal Adhesion Protein-Tyrosine Kinases ; metabolism ; Humans ; Integrin alpha1 ; metabolism ; Integrin alpha5 ; metabolism ; Integrin alphaV ; metabolism ; Integrin beta1 ; metabolism ; Integrins ; genetics ; metabolism ; Lactic Acid ; chemistry ; Osteoblasts ; cytology ; Porosity ; Tissue Engineering ; methods

The purpose of this study was to investigate the growth characteristics and the expression level of integrin mRNA of the cultured bone marrow mesenchymal stem cells (BMMSCs) from patients with chronic myeloid leukemia (CML) in myeloid crisis (MC), and explore the role of BMMSCs in pathogenesis of CML. Five CML patients were enrolled in experimental group, five healthy persons were used as control. BMMSCs were cultured in vitro. The morphology of BMMSCs was observed every day and the growth curve were portrayed, and the ability of cell proliferation were detected according to the daily results of cell counting. Total RNA was extracted from third and fourth passages of BMMSCs, The expression of integrins mRNA of BMMSCs were measured by real-time PCR. The results showed that the BMMSCs of experimental and control groups had no difference in growth characterisctics, but the expression of integrins mRNA of the BMMSCs was higher in CML patients than in normal control group (p < 0.05). It is concluded that the abnormally high expression of integrins of BMMSC from the CML patients take part in pathogenesis of CML.
Adult ; Blast Crisis ; metabolism ; Bone Marrow Cells ; metabolism ; pathology ; Cell Proliferation ; Female ; Humans ; Integrins ; genetics ; metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; metabolism ; pathology ; Male ; Mesenchymal Stromal Cells ; metabolism ; pathology ; Middle Aged ; RNA, Messenger ; genetics ; metabolism ; Tumor Cells, Cultured

OBJECTIVETo search novel genes or pathways involved in the recovery process after restraint stress in rats.

METHODSWe compared the hypothalamus transcriptional profiles of two different recovery patterns (fast recovery vs slow recovery) from restraint stress in rats using oligonucleotide microarray, the recovery pattern was determined by the decrement of plasma adrenocorticotropic-hormone (ACTH) and corticosterone levels during one hour recovery period after stress. A real-time quantitative RT-PCR was applied to validate the differential expressed genes.

RESULTSAnalysis of the microarray data showed that most of genes were not differentially expressed between fast recovery group and slow recovery group. Among the differentially expressed genes we found that talin, together with serine/threonine protein phosphatase PP1-beta catalytic subunit (PP-1B) and integrin alpha-6 precursor (VLA-6) genes, were at least 1.5 fold up-regulated in the fast recovery group, while junctional adhesion molecule 1 (F11r) was 1.5 fold down-regulated in the fast recovery group.

CONCLUSIONThe results implied that integrin signaling pathway may be involved in the recovery from restraint stress in rats. The present study provided a global overview of hypothalamus transcriptional profiles during the process of recovery from the restraint stress in rats. The integrin signaling pathway seems to be involved in the recovery process, which deserves further study to clarify the integrin-mediated recovery mechanism after restraint stress.

Adrenocorticotropic Hormone ; blood ; Animals ; Corticosterone ; blood ; Disease Models, Animal ; Gene Expression Regulation ; physiology ; Integrins ; genetics ; metabolism ; Male ; Oligonucleotide Array Sequence Analysis ; methods ; RNA, Messenger ; biosynthesis ; Rats ; Rats, Sprague-Dawley ; Recovery of Function ; physiology ; Restraint, Physical ; methods ; Reverse Transcriptase Polymerase Chain Reaction ; methods ; Signal Transduction ; physiology ; Stress, Psychological ; metabolism ; physiopathology ; Time Factors

OBJECTIVETo analyze the phenotypic and functional characteristics of endothelial (T3A) cells derived from human hepatocellular cell carcinoma.

METHODSEndothelial cells were isolated from human hepatocellular carcinoma specimens. The identification of T3A cells was performed by checking von Willebrand Factor (vWF), CD31, CD34 and Dil-Ac-LDL uptake. The cell surface fenestrations, a specific morphological feature of tumor derived EC, were investigated by scanning and transmission electron microscopy. The phenotypic characteristics of T3A cells were analyzed by fluorescence-activated cell sorter (FACS) and were further conformed by real-time PCR at transcription level. Furthermore, tumor necrosis factor alpha (TNFalpha)-induced cytotoxicity was evaluated by 3-(4, 5-dimethythiazolyl) -2, -diphenyl-2H-tetrazolium-bromide (MTT) assay; Matrix metalloproteinase secretion was detected by zymography; Angiogenic ability in vitro was analyzed by culturing T3A cells in three-dimensional Matrigel plug. Coagulant and fibrinolytic activities were detected by enzyme-linked immunosorbent assay (ELISA).

RESULTSThe isolated T3A cells exhibited classic "spindle-shape" morphology and monolayer growth and contact inhibition properties. Immunofluorescent staining showed that T3A cells expressed vWF, CD31, CD34, and uptake of Dil-Ac-LDL at a high level. The cell surface fenestrations were observed on T3A cells by scanning and transmission electron microscopy. By FACS and real-time PCR, T3A cells were found to express alphav3, alphavbeta5 and TNF receptor p75 at high levels, and TNF receptor p55 and ICAM-1 at low levels, as compared with those in human liver sinusoidal endothelial cells (LSEC). In response to TNFalpha, LSEC exhibited a dose-dependent cytotoxicity, while T3A cells were resistant. Gelatin zymography showed that MMP-2 activity was higher in T3A cells than that in LSEC. In a three-dimensional plug of Matrigel, T3A cells exhibited stronger angiogenic ability as compared with LSEC. In addition, T3A cells released more tissue factor (TF), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) and urine plasminogen activator (u-PA) than LSEC in response to TNFalpha.

CONCLUSIONTumor-derived endothelial cells are phenotypically and functionally different from those derived from normal liver tissue.

Antigens, CD34 ; metabolism ; Carcinoma, Hepatocellular ; genetics ; metabolism ; pathology ; Cell Proliferation ; drug effects ; Cell Shape ; Cells, Cultured ; Endothelial Cells ; metabolism ; pathology ; ultrastructure ; Gene Expression ; Humans ; Integrin alphaVbeta3 ; metabolism ; Integrins ; metabolism ; Intercellular Adhesion Molecule-1 ; metabolism ; Lipoproteins, LDL ; metabolism ; Liver Neoplasms ; genetics ; metabolism ; pathology ; Lung ; blood supply ; metabolism ; pathology ; Matrix Metalloproteinase 2 ; metabolism ; Microscopy, Electron, Scanning ; Neovascularization, Pathologic ; metabolism ; pathology ; Phenotype ; Plasminogen Activator Inhibitor 1 ; metabolism ; Platelet Endothelial Cell Adhesion Molecule-1 ; metabolism ; Receptors, Tumor Necrosis Factor, Type I ; metabolism ; Receptors, Vitronectin ; metabolism ; Tissue Plasminogen Activator ; metabolism ; Tumor Cells, Cultured ; Tumor Necrosis Factor Decoy Receptors ; metabolism ; Tumor Necrosis Factor-alpha ; pharmacology ; von Willebrand Factor ; metabolism

Adhesion and migration of vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of atherosclerosis. These processes involve the interaction of VSMCs with extracellular matrix proteins. Here, we investigated integrin isoforms and signaling pathways mediating the adhesion and migration of VSMCs on betaig-h3, a transforming growth factor (TGF)-beta-inducible extracellular matrix protein that is elevated in atherosclerotic plaques. Adhesion assays showed that the alphavbeta5 integrin is a functional receptor for the adhesion of aortic VSMCs to betaig-h3. An YH18 motif containing amino acids between 563 and 580 of betaig-h3 was an essential motif for the adhesion and growth of VSMCs. Interaction between the YH18 motif and the alphavbeta5 integrin was responsible for the migration of VSMCs on betaig-h3. Inhibitors of phosphatidylinositide 3-kinase, extracellular signal-regulated kinase (ERK), and Src kinase reduced the adhesion and migration of VSMCs on betaig-h3. betaig-h3 triggered phosphorylation and activation of AKT, ERK, focal adhesion kinase, and paxillin mediating the adhesion and migration of VSMCs. Taken together, these results suggest that betaig-h3 and alphavbeta5 integrin play a role in the adhesion and migration of VSMCs during the pathogenesis of atherosclerosis.
src-Family Kinases/antagonists & inhibitors ; Transforming Growth Factor beta/genetics/*physiology ; Signal Transduction/*physiology ; Receptors, Vitronectin/genetics/*physiology ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Paxillin/metabolism ; Myocytes, Smooth Muscle/drug effects/metabolism ; Muscle, Smooth, Vascular/cytology/drug effects/*metabolism ; Morpholines/pharmacology ; Molecular Sequence Data ; Integrins/genetics/*physiology ; Humans ; Flavonoids/pharmacology ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Matrix Proteins/genetics/*physiology ; Enzyme Inhibitors/pharmacology ; Chromones/pharmacology ; Cells, Cultured ; Cell Movement/*physiology ; Cell Adhesion/physiology ; Animals ; Amino Acid Sequence ; Amino Acid Motifs/genetics ; 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors

AIMTo construct an efficient recombinant viral vector for gene therapy.

METHODSFirst-generation adenovirus (Ad) vector was modified with the RGD peptide inserted into the fiber. Both in vitro and in vivo experiments of gene expression in different tumor cells with conventional and recombinant vectors were conducted. RT-PCR was used for detecting the expression of coxackievirus and adenovirus receptor and integrin at the surface of Meth-A cells.

RESULTSFiber-mutant adenovirus vector showed a notably enhanced gene expression in A2058, B16BL6, OV-HM, and Meth-A tumor cells compared with that of conventional ones. In vivo study carried out using Meth-A tumor-bearing mice also demonstrated that the intra-tumoral injection of recombinant adenovirus induced strong gene expression in these CAR-deficient tumor cells.

CONCLUSIONThe recombinant vector can be a promising one for effective cancer gene therapy.

Adenoviridae ; genetics ; Amino Acid Sequence ; Animals ; Base Sequence ; Cell Line ; Cell Line, Tumor ; Enterovirus ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Therapy ; methods ; Genetic Vectors ; Green Fluorescent Proteins ; genetics ; metabolism ; Humans ; Integrins ; genetics ; metabolism ; Luciferases ; genetics ; metabolism ; Mice ; Mice, Inbred BALB C ; Microscopy, Fluorescence ; Mutation ; Neoplasm Transplantation ; Neoplasms, Experimental ; genetics ; pathology ; therapy ; Oligopeptides ; genetics ; Receptors, Virus ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection