Laminin subunit alpha 4 (LAMA4),a member of the laminin family,is present in the intercellular matrix of adult tissues as a major component of basement membrane.LAMA4 is involved in the adhesion of cells and can bind to corresponding integrins to activate relevant signaling pathways,playing an essential role in the growth,proliferation,and migration of cells.It has been demonstrated that LAMA4 is associated with the occurrence and development of a variety of diseases including tumors,and the expression of LAMA4 can be used as a biomarker of tumor diagnosis and prognosis.This paper summarizes the current research progress in LAMA4 with the focus on the relationship between LAMA4 and diseases,especially tumor,with a view to provide new directions for the future research.
Adult ; Humans ; Laminin ; Extracellular Matrix

Microenvironmental biophysical factors play a fundamental role in controlling cell behaviors including cell morphology, proliferation, adhesion and differentiation, and even determining the cell fate. Cells are able to actively sense the surrounding mechanical microenvironment and change their cellular morphology to adapt to it. Although cell morphological changes have been considered to be the first and most important step in the interaction between cells and their mechanical microenvironment, their regulatory network is not completely clear. In the current study, we generated silicon-based elastomer polydimethylsiloxane (PDMS) substrates with stiff (15:1, PDMS elastomer vs. curing agent) and soft (45:1) stiffnesses, which showed the Young's moduli of ~450 kPa and 46 kPa, respectively, and elucidated a new path in cytoskeleton re-organization in chondrocytes in response to changed substrate stiffnesses by characterizing the axis shift from the secreted extracellular protein laminin β1, focal adhesion complex protein FAK to microfilament bundling. We first showed the cellular cytoskeleton changes in chondrocytes by characterizing the cell spreading area and cellular synapses. We then found the changes of secreted extracellular linkage protein, laminin β1, and focal adhesion complex protein, FAK, in chondrocytes in response to different substrate stiffnesses. These two proteins were shown to be directly interacted by Co-IP and colocalization. We next showed that impact of FAK on the cytoskeleton organization by showing the changes of microfilament bundles and found the potential intermediate regulators. Taking together, this modulation axis of laminin β1-FAK-microfilament could enlarge our understanding about the interdependence among mechanosensing, mechanotransduction, and cytoskeleton re-organization.
Cell Adhesion ; Chondrocytes ; Cytoskeleton/metabolism* ; Elastomers/metabolism* ; Laminin/metabolism* ; Mechanotransduction, Cellular

Epidermolysis bullosa (EB) is a group of clinically and genetically heterogeneous diseases characterized by trauma-induced mucocutaneous fragility and blister formation. Here, we investigated five Chinese families with EB, and eight variants including a novel nonsense variant (c.47G>A, p.W16*) in LAMA3, a known recurrent variant (c.74C>T, p.P25L) in KRT5, 2 novel (c.2531T>A, p.V844E; c.6811_6814del, p.R2271fs) and 4 known (c.6187C>T, p.R2063W; c.7097G>A, p.G2366D; c.8569G>T, p.E2857*; c.3625_3635del, p.S1209fs) variants in COL7A1 were detected. Notably, this study identified a nonsense variant in LAMA3 that causes EB within the Chinese population and revealed that this variant resulted in a reduction in LAMA3 mRNA and protein expression levels by nonsense-mediated mRNA decay. Our study expands the mutation spectra of Chinese patients with EB.
Humans ; Asian People/genetics* ; China ; Collagen Type VII/genetics* ; Epidermolysis Bullosa/genetics* ; Epidermolysis Bullosa Dystrophica/genetics* ; Keratin-5/genetics* ; Mutation ; Pedigree ; Laminin/genetics*

Biallelic pathogenic mutations of the LAMA2 gene result in congenital muscular dystrophy type 1A (CMD1A). The patient in this study was a boy aged 19 months, with the clinical manifestations of motor development delay and increases in the serum levels of creatine kinase, aminotransferases, and lactate dehydrogenase. Genetic analysis showed that the patient had compound heterozygous mutations in the LAMA2 gene, among which c.7147C>T (p.Ala2383Ter) from his mother was a known nonsense mutation, and c.8551_8552insAA (p.Ile2852ArgfsTer2) from his father was a frameshift mutation which had never been reported before and was identified as a pathogenic mutation based on the ACMG guideline. The boy was confirmed with CMD1A. A literature review of related articles in China and overseas revealed that most children with CMD1A have disease onset within 6 months after birth, with the features of motor developmental delay, elevated serum creatine kinase, and white matter impairment on imaging examination. The mutations of the LAMA2 gene have remarkable heterogeneity, the majority of which are null mutations. There are no specific treatment methods for CMD1A currently, and children with CMD1A usually have a poor long-term prognosis.
China ; Genetic Testing ; Humans ; Infant ; Laminin ; genetics ; Male ; Muscular Dystrophies ; genetics ; Mutation

OBJECTIVE: With the emerging significance of genetic profiles in the management of endometrial cancer, the identification of tumor-driving genes with prognostic value is a pressing need. The LAMC1 gene, encoding the laminin subunit gamma 1 (LAMC1) protein, has been reported to be involved in the progression of various malignant tumors. In this study, we aimed to investigate the role of LAMC1 in endometrial cancer and elucidate the underlying mechanism.METHODS: We evaluated the immunohistochemical expression of LAMC1 in atypical endometrial hyperplasia and endometrial cancer. Within the endometrial cancer cases, we analyzed the association of LAMC1 overexpression with clinicopathological factors and prognosis. Furthermore, to indentify genes influenced by LAMC1 overexpression, we transfected HEC50B and SPAC-S cells with siRNA targeting LAMC1 and conducted microarray gene expression assays.RESULTS: While none of the atypical endometrial hyperplasia specimens exhibited LAMC1 overexpression, endometrial cancer possessed a significantly higher LAMC1 overexpression rate. LAMC1 overexpression was strongly associated with histological type, lymphovascular space invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics stage, and poor overall survival in endometrial cancer. Gene expression microarray analysis identified 8 genes correlated with tumor progression (LZTFL1, TAPT1, SEL1L, PAQR6, NME7, TMEM109, CCDC58, and ANKRD40) that were commonly influenced in HEC50B and SPAC-S by LAMC1 silencing.CONCLUSION: LAMC1 overexpression is a potent biomarker for identifying endometrial cancer patients needing aggressive adjuvant therapy. We elucidated 8 candidate genes that may mediate progression of LAMC1 overexpressing cancer. Further investigation of the underlying mechanism should lead to the discovery of new therapeutic targets.
Endometrial Hyperplasia ; Endometrial Neoplasms ; Female ; Gene Expression ; Gene Expression Profiling ; Gynecology ; Humans ; Laminin ; Lymph Nodes ; Microarray Analysis ; Neoplasm Metastasis ; Obstetrics ; Prognosis ; RNA, Small Interfering

Coculture with adipose-derived stem cells (ADSCs) can stimulate proliferation and migration of melanocytes. To enhance outcomes of skin disorders caused by melanocyte loss or death, mixed transplantation with ADSCs has been suggested. However, role of cocultured ADSCs in proliferation and migration of melanocytes remains unclear. This study determined the effect of ADSCs on production of growth factors and expression levels of intergrins in primary culture of adult human melanocytes with or without ADSCs and in nude mice grafted with such melanocytes. Higher amounts of growth factors for melanocytes, such as bFGF and SCF were produced and released from ADSCs by coculturing with melanocytes. Relative levels of integrins β1, α5, and α6 as well as adhesion to fibronectin and laminin were increased in melanocytes cocultured with ADSCs. Such increases were inhibited by neutralization of bFGF or SCF. Relative levels of bFGF, SCF and integrins were increased in nude mice skin after grafting with melanocyte+ADSC cocultures. Collectively, these results indicate that ADSCs can stimulate proliferation and migration of melanocytes by increasing expression of integrins in melanocytes through upregulation of production/release of melanocyte growth factors such as bFGF and SCF.
Adult ; Animals ; Coculture Techniques ; Extracellular Matrix ; Fibronectins ; Humans ; Integrins ; Intercellular Signaling Peptides and Proteins ; Laminin ; Melanocytes ; Mice ; Mice, Nude ; Skin ; Stem Cells ; Transplants ; Up-Regulation

BACKGROUND: Human adipose tissue is routinely discarded as medical waste. However, this tissue may have valuable clinical applications since methods have been devised to effectively isolate adipose-derived extracellular matrix (ECM), growth factors (GFs), and stem cells. In this review, we analyze the literature that devised these methods and then suggest an optimal method based on their characterization results. METHODS: Methods that we analyze in this article include: extraction of adipose tissue, decellularization, confirmation of decellularization, identification of residual active ingredients (ECM, GFs, and cells), removal of immunogens, and comparing structural/physiological/biochemical characteristics of active ingredients. RESULTS: Human adipose ECMs are composed of collagen type I–VII, laminin, fibronectin, elastin, and glycosaminoglycan (GAG). GFs immobilized in GAG include basic fibroblast growth factor (bFGF), transforming growth factor beta 1(TGF-b1), insulin like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), BMP4 (bone morphogenetic protein 4), nerve growth factor (NGF), hepatocyte growth factor (HGF), and epithermal growth factor (EGF). Stem cells in the stromal-vascular fraction display mesenchymal markers, self-renewal gene expression, and multi-differentiation potential. CONCLUSION: Depending on the preparation method, the volume, biological activity, and physical properties of ECM, GFs, and adipose tissue-derived cells can vary. Thus, the optimal preparation method is dependent on the intended application of the adipose tissue-derived products.
Adipose Tissue ; Collagen ; Elastin ; Extracellular Matrix ; Fibroblast Growth Factor 2 ; Fibronectins ; Gene Expression ; Hepatocyte Growth Factor ; Humans ; Insulin ; Intercellular Signaling Peptides and Proteins ; Laminin ; Medical Waste ; Methods ; Nerve Growth Factor ; Platelet-Derived Growth Factor ; Stem Cells ; Transforming Growth Factor beta ; Vascular Endothelial Growth Factor A

PURPOSEMicrogravity is known to cause endothelium dysfunction in astronauts returning from spaceflight. We aimed to reveal the regulatory mechanism in alterations of human endothelial cells after simulated microgravity (SMG).

METHODSWe utilized the rotary cell culture system (RCCS-1) to explore the subsequent effects of SMG on human umbilical vein endothelial cells (HUVECs).

RESULTSSMG-treated HUVECs appeared obvious growth inhibition after return to normal gravity, which might be attributed to a set of responses including alteration of cytoskeleton, decreased cell adhesion capacity and increased apoptosis. Expression levels of mTOR and its downstream Apaf-1 were increased during subsequent culturing after SMG. miR-22 was up-regulated and its target genes SRF and LAMC1 were down-regulated at mRNA levels. LAMC1 siRNAs reduced cell adhesion rate and inhibited stress fiber formation while SRF siRNAs caused apoptosis.

CONCLUSIONSMG has the subsequent biological effects on HUVECs, resulting in growth inhibition through mTOR signaling and miR-22-mediated mechanism.

Apoptosis ; Cell Proliferation ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells ; physiology ; Humans ; Laminin ; genetics ; MicroRNAs ; physiology ; Weightlessness Simulation

To determine the effect of andrographolide (Andro) on angiogenesis of human umbilical vein endothelial cells (HUVECs).
 Methods: HUVECs were treated with different concentrations of Andro and the cell viability was detected with Cell Counting Kit-8 (CCK-8). HUVECs were treated with half lethal dose (IC50) of Andro. Matrigel was used to make capillary formation of HUVECs and the effect of Andro on capillary formation was evaluated by calculating the percentage of capillary formation. Moreover, the effects of Andro and the supernatant from cultured A549 tumor cells on capillary formation were evaluated by calculating the percentage of capillary formation. The effect of Andro on the expression of matrix metalloproteinase-9 (MMP-9) was determined with Western blot.
 Results: The cell viability of HUVECs decreased with the increase of Andro concentrations. IC50 was 20 μmol/L. The capillary formation of HUVECs was inhibited when treated with 20 μmol/L Andro for 24 hours. Moreover, Andro was able to antagonize the promotion of the capillary formation induced by the supernatant from cultured tumor cells. Andro could suppress the expression of MMP-9 and antagonize the capillary formation.
 Conclusion: Andro inhibits the capillary formation of HUVECs and can antagonize the promotion of angiogenesis induced by the supernatant from cultured tumor cells.
Capillaries ; drug effects ; Cell Survival ; Collagen ; Culture Media ; Diterpenes ; pharmacology ; Drug Combinations ; Human Umbilical Vein Endothelial Cells ; drug effects ; Humans ; Laminin ; Matrix Metalloproteinase 9 ; metabolism ; Neovascularization, Pathologic ; enzymology ; etiology ; prevention & control ; Proteoglycans ; Tumor Cells, Cultured

Urine-derived stem cells (USCs) are considered as a promising cell source capable of neuronal differentiation. In addition, specific growth factors and extracellular matrix are essential for enhancing their neuronal differentiation efficiency. In this study, we investigated the possibility of neuronal differentiation of USCs and the role of laminin and platelet-derived growth factor BB (PDGF-BB) as promoting factors. USCs were isolated from fresh urine of healthy donors. Cultured USCs were adherent to the plate and their morphology was similar to the cobblestone. In addition, they showed chromosome stability, rapid proliferation rate, colony forming capacity, and mesenchymal stem cell characteristics. For inducing the neuronal differentiation, USCs were cultured for 14 days in neuronal differentiation media supplemented with/without laminin and/or PDGF-BB. To identify the expression of neuronal markers, RT-PCR, flow cytometry analysis and immunocytochemistry were used. After neuronal induction, the cells showed neuron-like morphological change and high expression level of neuronal markers. In addition, laminin and PDGF-BB respectively promoted the neuronal differentiation of USCs and the combination of laminin and PDGF-BB showed a synergistic effect for the neuronal differentiation of USCs. In conclusion, USCs are noteworthy cell source in the field of neuronal regeneration and laminin and PDGF-BB promote their neuronal differentiation efficiency.
Chromosomal Instability ; Extracellular Matrix ; Flow Cytometry ; Humans* ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins ; Laminin* ; Mesenchymal Stromal Cells ; Neurons* ; Platelet-Derived Growth Factor ; Regeneration ; Stem Cells* ; Tissue Donors