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

UNLABELLED: AbstractObjective: To investigate the effect of the axon guidance factor Netrin-1 on the expression of VEGFA in T cell acute lymphoblastic leukemia(T-ALL) and its related mechanism. METHODS: ELISA assays were applied to detect the levels of Netrin-1 and VEGFA in the bone marrow (BM) samples from children in the T-ALL and control group. The level of Netrin-1 and VEGFA were compared between control children and patients, and the liner correlation between Netrin-1 and VEGFA was analyzed. The T-ALL cells Jurkat and Molt-4 were culture in vitro, and the cells were treated with different concentration of Netrin-1 (0, 25, 50, 100 ng/ml) for 24 h, quantitative RT-PCR (qRT-PCR) and Western blot were used to detect the VEGFA expression in Jurkat, Molt-4 cells. The expression of Netrin-1 receptors in T-ALL cells was detected by qRT-PCR and the interaction between Netrin-1 and receptor in each cells was detected by co-IP. Furthermore, Western blot was used to detect the phosphorylation level of key prateins of AKT signal transduction pathway including Akt and mTOR in T-ALL cells treated with Netrin-1 (100 ng/ml). The expression of VEGFA and phosphorylation of AKT pathway transducers were detected by Western blot, after T-ALL cells treated with Netrin-1 (100 ng/ml) combined with inhibitors specific to Akt or mTOR. RESULTS: The expression level of Netrin-1 and VEGFA in T-ALL patients BM samples were both signi-ficantly higher than that of control group. And the expression level of Netrin-1 was positively correlated with that of VEGFA（r2=0974). With the increase of Netrin-1 concentration, the expression level of VEGFA also increased(P<0.05）. Netrin-1 interacted with its receptor, integrin-β4 at the Netrin-1 concentration of 100 ng/ml. Further, the treatment of Netrin-1 could increase the phosphorylation of Akt and mTOR, which were the key transducers of AKT pathway. After treatment of T-ALL cells with Netrin-1 (100 ng/mL) and Akt inhibitor, the expression of VEGFA and phosphorylation of Akt or mTOR decreased. When the cells were treated with Netrin-1(100 ng/ml) and mTOR inbititor, the phosphorylation level of mTOR and the expression of VEGFA decreased, the phosphorylation level of Akt increased. CONCLUSION The expression of Netrin-1 and VEGFA in bone marrow of childred with T-ALL were abnormal, and there was a linear relationship between them. Netrin-1 can interact with its receptor, integrin-β4 and activate AKT transduction pathway to elevate the expression of VEGFA in T-ALL cells.
Child ; Humans ; Integrins ; Netrin-1/metabolism* ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Proto-Oncogene Proteins c-akt/metabolism* ; T-Lymphocytes ; TOR Serine-Threonine Kinases/metabolism* ; Vascular Endothelial Growth Factor A

Recent studies have showed that thrombosis is closely related to leucocytes involved in immunity. Interfering with the binding of leukocyte integrin Mac-1 and platelet GPIbα can inhibit thrombosis without affecting physiological coagulation. Mac-1-GPIbα is proposed as a potential safety target for antithrombotic agents. Guanxinning tablet (GXNT) is an oral Chinese patent medicine used for the treatment of angina pectoris, which contains phenolic acid active ingredients, such as salvianolic acids, ferulic acid, chlorogenic acid, caffeic acid, rosmarinic acid, tanshinol, and protocatechualdehyde. Our previous studies demonstrated that GXN exhibited significant antithrombotic effects, and clinical studies suggested that it did not increase bleeding risk. In addition, GXN exerted a significantly regulatory effect on immune inflammation. In the current study, we intended to evaluate the effects of GXN on bleeding events and explore the safety antithrombotic mechanism of GXN based on leukocyte-platelet interaction. First, we established a gastric ulcer model induced by acetic acid in rats and found that GXN not only did not increase the degree of gastrointestinal bleeding when gastric ulcer occurred, but also had a certain promoting effect on the healing of gastric ulcer. Second, in vitroexperiments showed that after pretreatment with GXN and activation by phorbol 12-myristate-13-acetate (PMA), the adhesion and aggregation of leukocytes with human platelets were reduced. It was also found that GXN reduced the expression and activation of Mac-1 in leucocytes, and inhibited platelet activation due to leukocyte engagement via Mac-1. Overall, the results suggest that GXN may be a safe antithrombotic agent, and its low bleeding risk mechanism is probably related to inhibited leukocyte-platelet aggregation and its interaction target Mac-1-GPIbα.
Animals ; Fibrinolytic Agents ; Humans ; Integrins ; Leukocytes ; Macrophage-1 Antigen ; Rats ; Stomach Ulcer ; Tablets ; Thrombosis

Neutrophil extracellular traps (NETs) play an important role in the formation of immunothrombosis. However, how vascular endothelial cells mediate the formation of NETs has not been fully understood. We stimulated neutrophils firmly attached on the endothelial cell surface intercellular adhesion molecule-1 (ICAM-1) with lipopolysaccharide (LPS) or phorbol-12-myristate-13-acetate (PMA) for 4 h, then labeled NETs-DNA with Sytox green dye and the formation of NETs was observed by fluorescent microscopy. The area and fluorescence intensity of NETs-DNA were analyzed to quantify the formation of NETs. The results showed that both PMA and LPS were able to induce firmly adhered neutrophils on ICAM-1 to produce NETs. NETs induced by PMA were independent of neither β2 integrin lymphocyte function-associated antigen-1 (LFA-1) nor macrophage antigen complex-1 (Mac-1). In contrast, LPS-stimulated NETs were mediated by Mac-1 integrin, but not by LFA-1. After inhibition of actin filaments or Talin-1, the formation of NETs irrespective of the stimulus was significantly reduced. This study reveals the mechanism of the direct interaction between neutrophils and endothelial cells to produce NETs under inflammatory conditions, providing a new theoretical basis for the treatment of related diseases and the development of new drugs.
Cytoskeletal Proteins ; Endothelial Cells ; Extracellular Traps ; Integrins ; Intercellular Adhesion Molecule-1 ; Lipopolysaccharides/pharmacology* ; Macrophages ; Neutrophils

Integrins are a large family of heterodimeric cell adhesion molecules composed of α and β subunits. Through interaction with their specific ligands, integrins mediate cell-cell and cell-extracellular matrix interactions. Via outside-in signaling, integrins can recruit cytoplasmic proteins to their intracellular domains and then cluster into supramolecular structures and trigger downstream signaling. Integrin activation is associated with a global conformation rearrangement from bent to extended in ectodomains and the separation of α and β subunit cytoplasmic domains. During cell migration, integrins regulate the focal adhesion dynamics and transmit forces between the extracellular matrix and the cell cytoskeleton. In tumor microenvironment, integrins on multiple kinds of cells could be activated, which modulates cell migration into tumor and contributes to angiogenesis and tumor metastasis. Here, we review the mechanism of integrin activation, dynamics of focal adhesions during cell migration and tumor metastasis.
Cell Adhesion ; Cell Adhesion Molecules ; Focal Adhesions ; Integrins ; Signal Transduction

OBJECTIVE: To investigate the damaging of human umbilical vein endothelial cells (HUVEC) induced by antiplatelet integrin β3 antibodies in vitro. METHODS: The serum from 36 chronic ITP patients were collected, flow cytometry and monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay were used to collect antiplatelet integrin β3 antibodies from the serum of the patients. After HUVEC were treated by ITP patient serum (PS) containing anti-integrin β3 antibodies, the cell damage was detected by Lactate dehydrogenase (LDH) assay, cell apoptosis was detected by flow cytometry, the expression of apoptosis-related gene Bax was detected by Reverse transcription-Quantitative real-time PCR (RT-qPCR), and expression of Apoptosis-related signaling pathway protein Akt and related protein Bax were detected by Western blot. HUVEC were treated by PS combined with Akt activator SC79, the cells damage were detected by LDH assay, apoptosis of the cells were detected by flow cytometry, the expression of apoptosis-related gene Bax was detected by RT-qPCR. RESULTS: Among 36 cases of serum from the chronic ITP patients, 5 patients' serum containing anti-integrin β3 antibodies were collected. After HUVEC was treated by PS, the viability of LDH was significant increased（P<0.05）, so as for the apoptosis of the cells（P<0.05）, the expression of gene and protein of Bax was increased up-regulated（P<0.05）, the protein expression of pAkt was down-regulated（P<0.05）. Comparing with HUVEC cultured with PS alone, the viability of LDH of HUVEC treated by PS combined with SC79 was significantly reduced（P<0.05）, so as for the apoptosis of the cells（P<0.05）, and gene expression of Bax was significantly decreased（P<0.05）. CONCLUSION Anti-integrin β3 serum can cause the damage and apoptosis of HUVEC through Akt signaling pathway，the apoptotic effects of anti-integrin β3 antibodies to HUVEC was effectively reversed by SC79.
Apoptosis ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells ; Humans ; Integrin beta3 ; Signal Transduction

Humans with chronic psychological stress are prone to develop multiple disorders of body function including impairment of immune system. Chronic psychological stress has been reported to have negative effects on body immune system. However, the underlying mechanisms have not been clearly demonstrated. All immune cells are derived from hematopoietic stem cells (HSC) in the bone marrow, including myeloid cells which comprise the innate immunity as a pivotal component. In this study, to explore the effects of chronic psychological stress on HSC and myeloid cells, different repeated restraint sessions were applied, including long-term mild restraint in which mice were individually subjected to a 2 h restraint session twice daily (morning and afternoon/between 9:00 and 17:00) for 4 weeks, and short-term vigorous restraint in which mice were individually subjected to a 16 h restraint session (from 17:00 to 9:00 next day) for 5 days. At the end of restraint, mice were sacrificed and the total cell numbers in the bone marrow and peripheral blood were measured by cell counting. The proportions and absolute numbers of HSC (LinCD117Sca1CD150CD48) and myeloid cells (CD11bLy6C) were detected by fluorescence activated cell sorting (FACS) analysis. Proliferation of HSC was measured by BrdU incorporation assay. The results indicated that the absolute number of HSC was increased upon long-term mild restraint, but was decreased upon short-term vigorous restraint with impaired proliferation. Both long-term mild restraint and short-term vigorous restraint led to the accumulation of CD11bLy6C cells in the bone marrow as well as in the peripheral blood, as indicated by the absolute cell numbers. Taken together, long-term chronic stress led to increased ratio and absolute number of HSC in mice, while short-term stress had opposite effects, which suggests that stress-induced accumulation of CD11bLy6C myeloid cells might not result from increased number of HSC.
Animals ; Antigens, Ly ; metabolism ; Bone Marrow Cells ; cytology ; CD11b Antigen ; metabolism ; Cell Proliferation ; Hematopoietic Stem Cells ; cytology ; Mice ; Mice, Inbred C57BL ; Restraint, Physical ; Stress, Psychological

OBJECTIVE: To analyze the association of integrinα5 (ITGA5) with grading of liver cancer and the overall patient survival and investigate the effects of integrin α5 (ITGA5) silencing on the proliferation, invasion and migration abilities of human liver cancer Bel-7404 cells. METHODS: UALCAN was used to analyze the expression of ITGA5 in liver cancer tissues and normal tissues, and expression in different grades of liver cancer tissues. GEPIA was used to analyze the relationship between ITGA5 expression and the survival of liver cancer patients through.The ITGA5 shRNA lentiviral vector was used to infect Bel-7404 cells to establish a cell line with stable ITGA5 silencing verified by Western blotting. Plate clone formation assay and Transwell assay were used to detect the proliferation, invasion and migration of Bel-7404 cells. The correlation between ITGA5 and PI3K in liver cancer tissues and control tissues was analyzed using Oncomine cancer specimen database. RESULTS: The expression of ITGA5 was significantly higher in liver cancer than in normal tissues ( < 0.05). The expression of ITGA5 was significantly lower in grade 1 than in grade 2 liver cancer, and also lower in grade 2 than in grade 3 liver cancer ( < 0.05). The patients with high ITGA5 expression had a significantly lower overall survival rate than those with low ITGA5 expression ( < 0.05). Plate clone formation assay showed that the clone formation rate was significantly lowered in Bel-7404 cells with ITGA5 silencing compared with the blank and negative control cells ( < 0.05). ITGA5 silencing significantly attenuated the migration of Bel-7404 cells as shown by Transwell assay ( < 0.05). ITGA5 and PI3K were both highly expressed and showed a positive correlation in liver cancer tissues ( < 0.05). CONCLUSIONS ITGA5 is closely related to the progression of liver cancer and the patients' prognosis. ITGA5 silencing inhibits the proliferation, invasion and migration of liver cancer cells. ITGA5 promotes the liver cancer growth and metastasis possibly by regulating the PI3K signaling pathway.
Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Integrin alpha5 ; Liver Neoplasms ; Neoplasm Invasiveness ; Phosphatidylinositol 3-Kinases

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

OBJECTIVE: To establish 293T cell lines stably expressing Calpain-cleavage related α3 cytoplasmic tail mutants, and to explore the effect of amino acid motifs in integrin β3 cytoplasmic tail on αⅡbβ3-mediated cell function. METHODS: 293T cell lines stably co-expressing human wild type integrin αⅡb and full length β3 or mutant β3, including β3-ΔNITY (β3 cytoplasmic tail NITY motif deleted), β3-Δ754 (β3 cytoplasmic tail TNITYRGT motif deleted) and β3-Δ759 (β3 cytoplasmic tail RGT motif deleted) were established. Spreading and adhesion of these stable cell lines on immobilized fibrinogen were tested. RESULTS: 293T-αⅡbβ3ΔNITY, 293T-αⅡbβ3Δ754, 293T-αⅡbβ3Δ759 and 293T-αⅡbβ3 cell lines were successfully established. Compared with the 293T cells, 293T-αⅡbβ3 cells which expressed full β3, possessed well adhesion and spread ability on immobilized fibrinogen, suggesting it can be as a surrogate for platelet. Compared with 293T-αⅡbβ3 cells, the 293T-αⅡbβ3ΔNITY cells showed a partial impairment of adhesion and spreadability on immobilized fibrinogen. while the 293T-αⅡbβ3Δ754 cells and 293T-αⅡbβ3Δ759 cells failed to adhere or spread on immobilized fibrinogen. CONCLUSION To the cell spreading function mediated by integrin β3, RGT motif is vital, while NITY can be dispensable. These established 293T cell lines stably expressing different β3 mutants provide a solid basis for a further analysis of mass spectrometry.
Amino Acid Motifs ; Animals ; CHO Cells ; Cell Adhesion ; Cricetinae ; Cricetulus ; HEK293 Cells ; Humans ; Integrin beta3 ; genetics ; metabolism ; Platelet Glycoprotein GPIIb-IIIa Complex ; genetics ; metabolism ; Signal Transduction