Deletion of mouse lysyl oxidase in megakaryocytes affects bone properties in a sex-dependent manner.

ABSTRACT: Lysyl oxidase (LOX) is a facilitator of extracellular matrix cross-linking. Using newly developed megakaryocyte-specific LOX knockout mice, we show that LOX expressed in these scarce bone marrow cells affects bone volume and collagen architecture in a sex-dependent manner.

Lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) lncRNA differentially regulates gene and protein expression, signaling and morphology of human ocular cells.

Pseudoexfoliation glaucoma (PEXG) is characterized by dysregulated extracellular matrix (ECM) homeostasis that disrupts conventional outflow function and increases intraocular pressure (IOP). Prolonged IOP elevation results in optic nerve head damage and vision loss. Uniquely, PEXG is a form of open angle glaucoma that has variable penetrance, is difficult to treat and does not respond well to common IOP-lowering pharmaceuticals. Therefore, understanding modulators of disease severity will aid in targeted therapies for PEXG. Genome-wide association studies have identified polymorphisms in the long non-coding RNA lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) as a risk factor for PEXG. Risk alleles, oxidative stress and mechanical stretch all alter LOXL1-AS1 expression. As a long non-coding RNA, LOXL1-AS1 binds hnRNPL and regulates global gene expression. In this study, we focus on the role of LOXL1-AS1 in the ocular cells (trabecular meshwork and Schlemm's canal) that regulate IOP. We show that selective knockdown of LOXL1-AS1 leads to cell-type-specific changes in gene expression, ECM homeostasis, signaling and morphology. These results implicate LOXL1-AS1 as a modulator of cellular homeostasis, altering cell contractility and ECM turnover, both of which are well-known contributors to PEXG. These findings support LOXL1-AS1 as a key target for modifying the disease.

Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma.

BACKGROUND & AIMS: Metabolic and transcriptional programs respond to extracellular matrix-derived cues in complex environments, such as the tumor microenvironment. Here, we demonstrate how lysyl oxidase (LOX), a known factor in collagen crosslinking, contributes to the development and progression of cholangiocarcinoma (CCA). METHODS: Transcriptomes of 209 human CCA tumors, 143 surrounding tissues, and single-cell data from 30 patients were analyzed. The recombinant protein and a small molecule inhibitor of the LOX activity were used on primary patient-derived CCA cultures to establish the role of LOX in migration, proliferation, colony formation, metabolic fitness, and the LOX interactome. The oncogenic role of LOX was further investigated by RNAscope and in vivo using the AKT/NICD genetically engineered murine CCA model. RESULTS: We traced LOX expression to hepatic stellate cells and specifically hepatic stellate cell-derived inflammatory cancer-associated fibroblasts and found that cancer-associated fibroblast-driven LOX increases oxidative phosphorylation and metabolic fitness of CCA, and regulates mitochondrial function through transcription factor A, mitochondrial. Inhibiting LOX activity in vivo impedes CCA development and progression. Our work highlights that LOX alters tumor microenvironment-directed transcriptional reprogramming of CCA cells by facilitating the expression of the oxidative phosphorylation pathway and by increasing stemness and mobility. CONCLUSIONS: Increased LOX is driven by stromal inflammatory cancer-associated fibroblasts and correlates with diminished survival of patients with CCA. Modulating the LOX activity can serve as a novel tumor microenvironment-directed therapeutic strategy in bile duct pathologies.

Pan-Cancer Analysis of the LOX Family Reveals that LOX Affects Tumor Prognosis by Affecting Immune Infiltration.

The lysyl oxidase (LOX) gene family encodes for a group of copper-dependent enzymes that play a crucial role in the cross-linking of collagen and elastin fibers in the extracellular matrix (ECM). Dysregulation of LOX gene expression has been implicated in various pathological conditions, including cancer. Several studies have shown that the LOX gene family is involved in cancer progression and metastasis. The goal of this article is to conduct a comprehensive analysis of the LOX family's role in pan-cancer multiplexes. We utilized pan-cancer multi-omics sequencing data from TCGA to investigate the relationship between LOX family genes and tumors at four different levels: mutation, copy number variation, methylation, and gene expression. In addition, we also examined the relationship between LOX family genes and tumors at the cell line level using tumor cell line sequencing data from CCLE. Taking into account the impact of LOX family genes on lung cancer, we developed a LOX family lung cancer prognostic model to forecast the disease's prognosis. Our findings revealed that LOXL2 had the highest mutation frequency in tumors, while all four LOX family genes experienced some degree of copy number variation in diverse tumors. We observed that LOX, LOXL1 to LOXL3 were predominantly highly expressed in tumors including LUAD. The expression trends of LOX and LOXL1 to LOXL3 were consistent across tumor cell lines, but differed somewhat from LOXL4. Utilizing 25 LOX family-related genes, we constructed a LOX family prognostic model that performed well in predicting the prognosis of lung cancer. Through pan-cancer analysis, we gain further knowledge of the role of LOX family genes in different tumors, offering a novel pathway for future research into the relationship between LOX family genes and tumors.

Lysyl oxidase like-1 deficiency in optic nerve head astrocytes elicits reactive astrocytosis and alters functional effects of astrocyte derived exosomes.

Glaucoma is a multifactorial progressive ocular pathology that manifests clinically with damage to the optic nerve (ON) and the retina, ultimately leading to blindness. The optic nerve head (ONH) shows the earliest signs of glaucoma pathology, and therefore, is an attractive target for drug discovery. The goal of this study was to elucidate the effects of reactive astrocytosis on the elastin metabolism pathway in primary rat optic nerve head astrocytes (ONHA), the primary glial cell type in the unmyelinated ONH. Following exposure to static equibiaxial mechanical strain, we observed prototypic molecular and biochemical signatures of reactive astrocytosis that were associated with a decrease in lysyl oxidase like 1 (Loxl1) expression and a concomitant decrease in elastin (Eln) gene expression. We subsequently investigated the role of Loxl1 in reactive astrocytosis by generating primary rat ONHA cultures with ∼50% decreased Loxl1 expression. Our results suggest that reduced Loxl1 expression is sufficient to elicit molecular signatures of elastinopathy in ONHA. Astrocyte derived exosomes (ADE) significantly increased the length of primary neurites of primary neurons in vitro. In contrast, ADE from Loxl1-deficient ONHA were deficient of trophic effects on neurite outgrowth in vitro, positing that Loxl1 dysfunction and the ensuing impaired elastin synthesis during reactive astrocytosis in the ONH may contribute to impaired neuron-glia signaling in glaucoma. Our data support a role of dysregulated Loxl1 function in eliciting reactive astrocytosis in glaucoma subtypes associated with increased IOP, even in the absence of genetic polymorphisms in LOXL1 typically associated with exfoliation glaucoma. This suggests the need for a paradigm shift toward considering lysyl oxidase activity and elastin metabolism and signaling as contributors to an altered secretome of the ONH that may lead to the progression of glaucomatous changes. Future research is needed to investigate cargo of exosomes in the context of reactive astrocytosis and identify the pathways leading to the observed transcriptome changes during reactive astrocytosis.

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome.

BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to ß-aminopropionitrile, an inhibitor of lysyl oxidase-mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong ß-aminopropionitrile-associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of ß-aminopropionitrile-exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.

Lysyl oxidase like-2 in fibrosis and cardiovascular disease.

Fibrosis is an important and essential reparative response to injury that, if left uncontrolled, results in the excessive synthesis, deposition, remodeling, and stiffening of the extracellular matrix, which is deleterious to organ function. Thus, the sustained activation of enzymes that catalyze matrix remodeling and cross linking is a fundamental step in the pathology of fibrotic diseases. Recent studies have implicated the amine oxidase lysyl oxidase like-2 (LOXL2) in this process and established significantly elevated expression of LOXL2 as a key component of profibrotic conditions in several organ systems. Understanding the relationship between LOXL2 and fibrosis as well as the mechanisms behind these relationships can offer significant insights for developing novel therapies. Here, we summarize the key findings that demonstrate the link between LOXL2 and fibrosis and inflammation, examine current therapeutics targeting LOXL2 for the treatment of fibrosis, and discuss future directions for experiments and biomedical engineering.

Sox6 impairs the adipogenic commitment of mesenchymal stem cells by targeting lysyl oxidase and preadipocyte factor 1.

The commitment of mesenchymal stem cells (MSCs) to preadipocytes and the termination of differentiation to adipocytes are critical for maintaining systemic energy homeostasis. However, our knowledge of the molecular mechanisms governing the commitment of MSCs to preadipocytes and the subsequent termination of their differentiation into adipocytes remain limited. Additionally, the role of Sox6 sex-determining region Y (SRY)-box6 (Sox6), a transcription factor that regulates gene transcription, is reportedly involved in various cellular processes, including adipogenesis; however, its function in regulating preadipocyte development and the factors involved in the termination of adipogenic differentiation remain unexplored. Therefore, we investigated the role of Sox6 in regulating the differentiation of adipocytes by monitoring the effects of its overexpression in C3H10T1/2 cells (in vitro) and C57BL/6J mouse (in vivo) models of adipogenesis. We observed lower Sox6 expression in the adipose tissue of obese mice than that in control mice. Sox6 overexpression inhibited the differentiation of MSC by directly binding to the lysyl oxidase (Lox) and preadipocyte factor 1 (Pref1) promoters, which was potentiated by histone deacetylase-1(HDAC1). Our findings suggest that Sox6 is a key regulator of MSC commitment to adipocytes; therefore, targeting the Sox6-mediated regulation of this process could offer potential therapeutic avenues for addressing obesity and related metabolic disorders.

The apoptotic and anti-proliferative effect of Lysyl oxidase propeptide in Y79 human retinoblastoma cells.

Purpose: Retinoblastoma (RB) caused by the mutation of the RB1 gene is one of the most common ocular malignancies in children The propeptide region of lysyl oxidase (LOX), the enzyme involved in the cross-linking of collagen and elastin, has been identified to be anti-tumorigenic in various cancers. However, this role of lysyl oxidase propeptide (LOX-PP) in RB is still elusive. This study aims to identify the anti-tumorigenic effect of LOX-PP in human Y79 RB cells. Methods: LOX-PP was overexpressed in Y79 RB cells, and differential gene expression was assessed by microarray followed by pathway analysis using transcriptome analysis console (TAC) software. Additionally, cell proliferation was studied by PrestoBlue assay, and DNA content was evaluated by cell cycle and apoptosis assays. The pro-apoptotic and anti-proliferative mechanisms induced by the overexpression of/exogenously added LOX-PP was evaluated by western blotting and real-time PCR. Results: The expression of the LOX-PP transcript was significantly decreased in Y79 RB cells compared to human retinal endothelial cells. Gene expression analysis in LOX-PP overexpressed Y79 RB cells showed deregulation of pathways involved in apoptosis, cell cycle, focal adhesion-PI3K-AKT signaling, and DNA repair mechanisms. Interestingly, LOX-PP overexpressed Y79 RB cells showed significantly increased apoptosis, decreased proliferation, and cell cycle arrest at S-phase with a concordant reduction of proliferative cell nuclear antigen and Cyclin D1 protein expressions. Moreover, pAKT (S473) was significantly downregulated in Y79 RB cells, which decreased NFκB leading to significantly reduced BCL2 expression. Conclusions: Our results demonstrate the anti-tumorigenic effect of LOX-PP in Y79 RB cells by inducing apoptosis and decreasing proliferation. This effect was mediated by the downregulation of AKT signaling. These results suggest that LOX-PP can be explored as a therapeutic molecule in RB.

Differential roles for lysyl oxidase (like), family members in chronic obstructive pulmonary disease; from gene and protein expression to function.

Chronic obstructive pulmonary disease (COPD) is characterized by long-term airflow obstruction with cigarette smoke as a key risk factor. Extracellular matrix (ECM) alterations in COPD may lead to small airway wall fibrosis. Altered collagen cross-linking, potentially mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4), orchestrates disturbed ECM homeostasis. In this study, we investigated the effects of smoking status and presence and severity of COPD on LOs gene and protein expression in the airways and the impact of LOs inhibition on airway contraction in an ex vivo mouse model. We used gene expression data from bronchial brushings, airway smooth muscle (ASM) cells in vitro and immunohistochemistry in lung tissue to assess smoke- and COPD-associated differences in LOs gene and protein expression in the small airways. We found higher LOX expression in current- compared to ex-smokers and higher LOXL1 expression in COPD compared to non-COPD patients. LOX and LOXL2 expression were upregulated in COPD ASM cells treated with cigarette smoke extract. LOXL1 and LOXL2 protein levels were higher in small airways from current- compared to non-smokers. In COPD patients, higher LOXL1 and lower LOX protein levels were observed, but no differences for LOXL2, LOXL3, and LOXL4 protein were detected in small airways. Inhibiting LOs activity increased airway contraction in murine lung slices. COPD-associated changes in LOs, in particular LOX and LOXL1, may be related to smoking and contribute to impaired airway function, providing potential novel targets for preventing or treating small airways changes in COPD.

The possibilities of LOXL4 as a prognostic marker for carcinomas.

Lysyl oxidase-like 4 (LOXL4), a member of lysyl oxidase family, is a copper and lysine tyrosylquinone-dependent amine oxidase that serves the role of catalyzing the cross-linking of elastin and collagen in the extracellular matrix. Numerous studies have shown a significant association between LOXL4 expression levels and tumor proliferation, migration, invasion and patients' prognosis and overall survival in different types of tumors. Here we review their relationship and the molecular pathogenesis behind them, aiming to explore the possibilities of LOXL4 as a prognostic marker for diverse carcinomas and provide some indications for further research in this field.

Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals.

OBJECTIVE: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. APPROACH AND RESULTS: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P<5×10-8. Seven novel loci (ZNF385D, ADAMTS9, EDNRA, HAND2, MYOCD, ITCH/EDEM2/MMP24, and MRTFA) were identified in all 3 phenotypes. An additional new locus (LOXL1) was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus (SYNE3) in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci (APOB, FIP1L1, and LOXL4). Transcriptome-wide association analyses implicated additional genes ARHGAP42, NDRG4, and KANK2. Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease rg=0.21 (P=1.4×10-7), peripheral artery disease rg=0.45 (P=5.3×10-5), and systolic blood pressure rg=0.30 (P=4.0×10-18). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found rg=-0.12 (P=7.0×10-4). CONCLUSIONS: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.

Inhibition of the Renin-Angiotensin System Fails to Suppress ß-Aminopropionitrile-Induced Thoracic Aortopathy in Mice-Brief Report.

BACKGROUND: Cross-linking of lysine residues in elastic and collagen fibers is a vital process in aortic development. Inhibition of lysyl oxidase by BAPN (ß-aminopropionitrile) leads to thoracic aortopathies in mice. Although the renin-angiotensin system contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the renin-angiotensin system protects against aortopathy caused by the impairment of elastic fiber/collagen crosslinking. METHODS: BAPN (0.5% wt/vol) was started in drinking water to induce aortopathies in male C57BL/6J mice at 4 weeks of age for 4 weeks. Five approaches were used to investigate the impact of the renin-angiotensin system. Bulk RNA sequencing was performed to explore potential molecular mechanisms of BAPN-induced thoracic aortopathies. RESULTS: Losartan increased plasma renin concentrations significantly, compared with vehicle-infused mice, indicating effective angiotensin II type 1 receptor inhibition. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor of the renin-angiotensin system, irbesartan, an insurmountable inhibitor, was also tested. Although increased plasma renin concentrations indicated effective inhibition, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin II type 1 receptor blockade. Next, we inhibited angiotensin II production by pharmacological or genetic depletion of AGT (angiotensinogen), the unique precursor of angiotensin II. However, neither suppressed BAPN-induced thoracic aortic rupture and dilatation. Aortic RNA sequencing revealed molecular changes during BAPN administration that were distinct from other types of aortopathies in which angiotensin II type 1 receptor inhibition protects against aneurysm formation. CONCLUSIONS: Inhibition of either angiotensin II action or production of the renin-angiotensin system does not attenuate BAPN-induced thoracic aortopathies in mice.

MiR-590-3p Promotes the Phenotypic Switching of Vascular Smooth Muscle Cells by Targeting Lysyl Oxidase.

ABSTRACT: We investigated the clinical characteristics of patients with acute aortic dissection (AAD) and miR-590-3p levels in serum, tissue, and vascular smooth muscle cells. The effect of miR-590-3p on the vascular smooth muscle cell phenotype was assessed, and the regulation of lysyl oxidase by miR-5903p was determined. C57BL/6 mice were used to investigate the incidence of AAD and effects of miR-5903p on AAD. The miR-590-3p levels were measured in the aortae of mice, and hematoxylin and eosin staining and Masson staining were performed to identify the morphological features of the aorta. Comparative analysis revealed significant differences in clinical characteristics between patients with AAD and healthy control subjects, with most patients with AAD exhibiting concomitant hypertension and nearly 50% having atherosclerosis. Lysyl oxidase was a direct target of miR-590-3p. Lysyl oxidase overexpression inhibited switching of the vascular smooth muscle cell phenotype from contractile to synthetic, but miR-590-3p overexpression significantly reversed this change. In the mouse model, miR-590-3p upregulation increased the incidence of AAD to 93.3%, and its incidence decreased to 13.3% after miR-590-3p inhibition. Hematoxylin and eosin and Masson staining revealed that the miR-590-3p agomiR group had a greater loss of the contractile phenotype in the dissected aortic wall and an increased number of muscle fibers in the aortic wall, which contributed to thickening of the aortic wall and the formation of a false lumen in aortic dissection. miR-590-3p might be pivotal in the pathogenesis of AAD. Thus, targeting miR-590-3p or its downstream pathways could represent a therapeutic approach for AAD.

Nucleus pulposus cell senescence is regulated by substrate stiffness and is alleviated by LOX possibly through the integrin ß1-p38 MAPK signaling pathway.

Intervertebral disc degeneration (IVDD) is a main contributor to induce low back pain, and the pathogenic mechanism of IVDD remains unclear. The nucleus pulposus (NP) is a component of the intervertebral disc (IVD) that provides protection from mechanical stimuli. The matrix stiffness of NP tissue increases during the process of disc degeneration. Although several studies have found that pathological mechanical stimuli induce NP cell senescence, which is relevant for NP degeneration, however, the effect of matrix stiffness on NP cell senescence is not clear. Therefore, in the present study, we used polyvinyl alcohol (PVA) hydrogel with controllable stiffness to mimic the matrix stiffness of normal (4 kPa) and severely degenerated (20 kPa) NP tissue. Rat NP cells were isolated and cultured on substrates with different stiffness, and the cell proliferation, SA-ß-gal activity, cell cycle, telomerase activity and the phenotype markers of NP cells were analyzed. Moreover, cytoskeleton staining and NP cellular Young's modulus on different substrates were also measured. To further investigate how substrate stiffness affects NP cell senescence, lysyl oxidase (LOX) was used to restore the extracellular matrix (ECM) synthesis of NP cells. The expression levels of integrin ß1 and p38 MAPK were then measured. Our results showed that the 20 kPa substrate significantly induced NP cell senescence compared to the 4 kPa substrate. NP cells cultured on the 20 kPa substrate failed to maintain the expression of their phenotype markers. Furthermore, the 20 kPa substrate induced an increase of Young's modulus of NP cells, which possibly through up regulating the expressions of integrin ß1 and p38 MAPK. These results indicated that the integrin ß1-p38 MAPK signaling pathway may participated in substrate stiffness induced senescence of NP cells. LOX significantly increased ECM synthesis and inhibited substrate stiffness induced NP cell senescence, which indicated that matrix mechanics may be essential for maintaining the function of NP cell. Our results may provide a new perspective on the mechanism of IVDD by pathological matrix mechanics.

Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration.

Copper ions are needed for several hallmarks of cancer. However, the involved pathways, mechanisms, and copper-binding proteins are mostly unknown. We recently found that cytoplasmic Antioxidant 1 copper chaperone (Atox1), which is up-regulated in breast cancer, is localized at the lamellipodia edges of aggressive breast cancer cells. To reveal molecular insights into a putative role in cell migration, we here investigated breast cancer cell (MDA-MB-231) migration by video microscopy as a function of Atox1. Tracking of hundreds of individual cells (per condition) over a 9-h time series revealed that cell migration velocity and directionality are significantly reduced upon Atox1 silencing in the cells. Because silencing of the copper transporter ATP7A also reduced cell migration, these proteins appear to be on the same pathway, suggesting that their well-known copper transport activity is involved. In-cell proximity ligation assays demonstrated that Atox1, ATP7A, and the proenzyme of lysyl oxidase (LOX; copper-loaded via ATP7A) are all in close proximity and that LOX activity is reduced upon Atox1 silencing in the cells. Since LOX is an established player in cancer cell migration, our results imply that Atox1 mediates breast cancer cell migration via coordinated copper transport in the ATP7A-LOX axis. Because individual cell migration is an early step in breast cancer metastasis, Atox1 levels in tumor cells may be a predictive measure of metastasis potential and serve as a biomarker for copper depletion therapy.

Multifunctional Lysyl Oxidases.

This Special Issue on lysyl oxidases, which are proteins derived from five related genes known as Lox, and Loxl1-Loxl4, brings together articles that reflect some of the diverse approaches and perspectives needed to better understand the biology of these multifunctional proteins [...].

The Expression Pattern and Clinical Significance of Lysyl Oxidase Family in Gliomas.

LOX (Lysyl oxidase) family participates in the catalysis of collagen and elastin to maintain ECM homeostasis. Glioma is the most common primary brain tumor and LOX family has not been systemic studied in glioma. In this study, we found LOX family members are upregulated expressed in gliomas samples. A protein-protein interaction network (PPIN) was construct to visualize and understand the differential expression pattern, as well as functional annotation, for LOX family and their interacting proteins, which involved in collagen fibril organization and MAPK signaling pathway. Through subcellular localization distribution, the LOX family members distribute both intracellular and extracellular. All five LOX members are consistently significantly correlate with dendritic cell both in immune infiltrate of GBM and LGG. Survival analysis showed that high expression of LOX family is associated with a poor prognosis of gliomas patients. These analyses provide important clues to identify the potential biological roles for LOX family in gliomas, which might serve as diagnosis markers.

Liver tumor-initiating cells initiate the formation of a stiff cancer stem cell microenvironment niche by secreting LOX.

Accumulating evidence has shown that the traits of tumor-initiating cells (TICs) are controlled by the microenvironment niches (MENs), but the composition and remodeling mechanisms of the MENs of TICs are poorly defined. Here, we report that the voltage-gated calcium channel α2δ1 subunit-positive TICs of hepatocellular carcinoma (HCC) specifically secret lysyl oxidase (LOX), which leads to the cross-linking of collagen, forming a stiff extracellular matrix (ECM) that is sufficient to drive the formation of TICs with a stiff mechanical trait and is subsequently required for the maintenance the properties of HCC TICs. Furthermore, the cross-linked collagen results in the upregulation of integrin α7 (ITGA7), increased phosphorylation of FAK and extracellular signal-regulated kinase 1/2 (ERK1/2). Inhibition of ITGA7 abolishes all the effects of cross-linked collagen mediated by LOX. Hence, the α2δ1+ HCC TICs initiate ECM remodeling by secreting LOX to create a stiff MEN of TIC with cross-linked collagen, which drives the acquisition and subsequent maintenance of the properties of HCC TICs through ITGA7-FAK-ERK1/2 signaling pathway.