| Written | 2009-02 | Sheri FT Fong, Keith SK Fong, Katalin Csiszar |
| John A. Burns School of Medicine, University of Hawaii, 1960 East West Road, Biomed T415, Honolulu, HI 96822, USA |
| Identity |
| Other alias | |
| HGNC (Hugo) | LOX |
| LocusID (NCBI) | 4015 |
| Atlas_Id | 41191 |
| Location | 5q23.1 [Link to chromosome band 5q23] |
| Location_base_pair | Starts at 122063195 and ends at 122077223 bp from pter ( according to hg19-Feb_2009) [Mapping LOX.png] |
| Local_order | FTMT - SRFBP1 - LOX - ZNF474 - SNCAIP |
| Fusion genes (updated 2016) | CORO7-PAM16 (16p13.3) / LOX (5q23.1) | LOX (5q23.1) / LOC642852 (21q22.3) |
| DNA/RNA |
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| Figure 1. Lysyl oxidase gene structure. Exons are depicted as boxes separated by intron sequences (solid lines). The size of each exon and intron is shown in base pairs, above (exons) and below (introns) of the gene, respectively. The exons shaded in red encode amino acids sequences that are conserved in all lysyl oxidase family members. The exon shaded in blue contains the 3' UTR sequence. | |
| Description | The LOX gene is composed of seven exons and six introns, distributed through approximately 14.5 kb of genomic DNA (Hamalainen et al., 1993; Boyd et al., 1995). Three transcripts of sizes 2.0 kb, 3.8 kb and 4.8 kb are produced (Mariani et al., 1992), as a consequence of differential use of several polyadenylation signals within the 3' UTR (Boyd et al., 1995). There is a heritable restriction fragment length polymorphism within a PstI restriction site in the first exon (Csiszar et al., 1993). Three additional polymorphisms were also identified: Ala75Ala, Arg103Pro, Arg158Gln (Kaneda et al., 2004). There are no microsatellites within the LOX gene, but three have been described in the LOX gene locus within 20 kb and 5 kb centromeric, and 7 kb telomeric to the LOX gene (Csiszar et al., 2002). The 5' region of LOX also contains a CpG island which extends into exon 1 (Kaneda et al., 2002; Kaneda et al., 2004). |
| Transcription | The rat LOX promoter contains a metal-response element, a hypoxia-response element, an antioxidant-response element, at least four positive regulatory segments and 2 negative regulatory segments. Multiple transcriptional start sites have been described (Gao et al., 2007). The regulation of LOX gene expression has been described in different tissues and cells from several species, and has revealed multiple complex mechanisms that regulate the expression and activity of LOX. Many of these effectors are reviewed in Csiszar, 2001, and encompass cytokines and growth factors, such as fibroblast growth factor, basic fibroblast growth factor, insulin-like growth factor-1, interferon-gamma and transforming growth factor-beta; hormones and mediators, such as testosterone, progestin and prostaglandin E2; signaling molecules, such as cAMP, interferon regulatory factor-1 and ras; and drugs, such as adriamycin, bleomycin and hydralazine. Additional effectors have since been described, including follicle stimulating hormone (Slee et al., 2001; Harlow et al., 2003), hyperosmotic solution (Omori et al., 2002), secretory leukocyte protease inhibitor (Zhang et al., 2002), interleukin-1alpha (Rae et al., 2004), cigarette smoke condensate (Chen et al., 2005; Gao et al., 2005), tumor necrosis factor-alpha (Rodriguez et al., 2008), granulocyte macrophage colony-stimulating factor (Weissen-Plenz et al., 2008), hyaluronan with insulin-like growth factor-1 (Kothapalli and Ramamurthi, 2008) and parathyroid hormone (Lowry et al., 2008). LOX expression is promoted in MCF-7 breast cancer cells by contact with fibroblast-conditioned media, collagen I matrix conditioned by fibroblasts (Kirschmann et al., 2002), and in HK-2 renal proximal tubule cells co-cultured with HMEC-1 microvascular endothelial cells (Aydin et al., 2008). LOX expression is also induced by hypoxia. Hypoxia-inducible factor-1alpha (HIF-1alpha) stimulates LOX mRNA transcription (Erler et al., 2006; Higgins et al., 2007). LOX expression in hypoxia can be modulated by pH (Sorensen et al., 2007). The recruitment of HIF-1alpha to the LOX promoter is potentiated by Notch, which also increases Snail-1 expression (Sahlgren et al., 2008). Transcription of the LOX gene is also affected by the methylation status of its CpG island (Kaneda et al., 2002; Kaneda et al., 2004). |
| Pseudogene | No known pseudogene. |
| Protein |
 | |
| Figure 2. Lysyl oxidase protein structure. All members of the lysyl oxidase family of proteins share two highly conserved domains: a unique copper-binding (Cu) domain containing four histidines, shaded in red; and a cytokine-receptor like (CRL) domain similar to type I cytokine receptors, shaded in green. The predicted signal sequence is shaded in purple. The BMP-1 cleavage site, shaded in yellow, is noted by the arrow. | |
| Description | The lysyl oxidase transcript encodes for a 417-amino acid protein, including a signal peptide of 21 amino acids (Hamalainen et al., 1991; Mariani et al., 1992). Removal of the signal sequence and N-glycosylation within the propeptide region produces a 50 kDa proenzyme (Trackman et al., 1992). Incorporation of copper is thought to occur either in the endoplasmic reticulum or in the Golgi in prior to and independently of glycosylation (Kosonen et al., 1997). After secretion into the extracellular space, the mature, non-glycosylated 32 kDa protein (Trackman et al., 1992) is generated by proteolytic cleavage of the propeptide region between Gly-168 and Asp-169 by C-proteinase (Cronshaw et al., 1995), encoded by the bone morphogenic protein-1 (BMP-1), and the related tolloid-like-1 and -2 (Kessler et al., 1996; Uzel et al., 2001). LOX may also be a substrate of human meprin, an astacin-like metallopeptidase belonging to the same subfamily as BMP-1 and mammalian tolloid (Ambort et al., 2008). |
| Expression | As LOX is necessary for the assembly and tensile strength and mechanical stability of collagen fibrils, and for the assembly and repetitive and reversible deformation of elastin, it is highly expressed in tissues containing fibrillar collagen and/or elastic fibers. These include skin, lung, cartilage, the cardiovascular system and the fibrous laminia propria in the small intestine. LOX was also detected in the liver, kidney, stomach, retina, and brain (Hayashi et al., 2004). In the eye, LOX has been identified in the vitreous, iris/ciliary body, lens, choroid/retinal pigment epithelium and retina (Coral et al., 2008). LOX has also been described in the mesencephalon, corpus callosum, cerebral cortex and cerebellum of the brain (Laczko et al., 2007). Protein expression of LOX may be influenced by microRNAs. The 3' UTR of LOX mRNA contains a binding site for mir-145, which is down-regulated in many cancers (Dalmay and Edwards, 2006). |
| Localisation | LOX has been classically characterized as an extracellular matrix enzyme (Kagan and Trackman, 1991). However, less is known about intracellular LOX. The LOX protein has been localized within the nuclei of various cells and tissues (Li et al., 1997; Hayashi et al., 2004; Li et al., 2004), and retains its catalytic activity inhibited by beta-aminopropionitrile (bAPN) (Li et al., 1997). Nuclear LOX has been shown to originate from extracellular LOX that enters the cytosol and concentrates within the nucleus (Nellaiappan et al., 2000). Histones have been reported as substrates for lysyl oxidase (Kagan et al, 1983; Giampuzzi et al, 2003), and transfection of LOX yielded less tightly packed chromatin (Mello et al., 1995). Electron microscopy confirmed association of LOX with condensed chromatin in the nucleus (Kagan and Li, 2003). In addition to its nuclear localization, LOX has also been identified in the cytoplasm of numerous cells and tissues (Wakasaki and Ooshima, 1990; Kobayashi et al., 1994; Hayashi et al., 2004; Jansen and Csiszar, 2007). This cytoplasmic LOX was localized to cytoskeletal filaments and microtubule networks (Wakasaki and Ooshima, 1990; Guo et al., 2007). The propeptide of LOX (LOX-PP), which has been described to have a different function than the LOX enzyme, differs in its localization compared to the active LOX enzyme, and is dependent on cell stage. LOX-PP, which is generated extracellularly, is able to reenter the cells. In differentiating osteoblasts, both LOX-PP and LOX enzyme localized to the cytoplasm associated with tubulin and the microtubule network, while in proliferating osteoblasts, LOX-PP localized perinuclearly in the Golgi complex and endoplasmic reticulum while LOX enzyme was mainly in the nucleus (Guo et al., 2007). |
| Function | Lysyl oxidase oxidizes peptidyl lysine and hydroxylysine residues in collagen and lysine residues in elastin to produce peptidyl alpha-aminoadipic-delta-semialdehydes. These aldehyde residues can spontaneously condense with vicinal peptidyl aldehydes or with epsilon-amino groups of peptidyl lysine to form the covalent cross-links that stabilize and insolubilize several fibrillar collagen types and elastin fibers (reviewed in Lucero and Kagan, 2006). This catalytic reaction can be irreversibly inhibited by bAPN, a specific inhibitor that binds to the active site of LOX (Tang et al., 1983). Semicarbazide is a partial inhibitor of LOX (Mercier et al., 2007), as is 2-mercaptopyridine-N-oxide, although it acts through a different mechanism than bAPN (Anderson et al., 2007). Pathological concentrations of homocysteine also inhibit LOX activity (Raposa et al., 2004). The activity of LOX in the extracellular matrix may be coordinated by its interaction with fibronectin (Fogelgren et al, 2005). The critical nature of LOX enzyme activity was demonstrated in the LOX "knockout" mouse, which expires immediately after birth due to rupture of the aorta and diaphragm from incomplete cross-linking of elastin (Maki et al., 2002; Hornstra et al., 2003). Local administration of LOX resulted in inhibition of abdominal aortic aneurysm development in a mouse model (Yoshimura et al., 2006). LOX is also essential for development of the distal and proximal airways, and alveolarization in the lungs (Maki et al., 2005), and is increased in preterm lamb lungs compared to full-term (Bland et al., 2007). In zebrafish, LOX is critical for notochord formation and muscle development (Anderson et al., 2007; Gansner et al., 2007; Reynaud et al., 2008), a process that may involve the fibrillin-2 gene or alpha1 chain of type VIII collagen (Gansner et al., 2008; Gansner and Gitlin, 2008). In sea urchins, inhibition of LOX caused developmental arrest at the mesenchymal blastula state (Butler et al., 1987), and in Xenopus laevis, LOX was shown to antagonize p21-Ha-Ras-induced and progesterone-dependent oocyte maturation (Di Donato et al., 1997). LOX also has a role in cell differentiation. LOX was identified as an early marker in adipocyte differentiation responsive to retinoic acid (Dimaculangan et al., 1994). Increased LOX may affect osteoblastic differentiation through cross-link formation in the surrounding collagen matrix (Kaku et al., 2007; Turecek et al., 2008). LOX may also modulate cartilage growth (Asanbaeva et al., 2008). Alterations in LOX expression were observed in development and aging of the skin, as well as physiological and pathological processes of the skin, including wound healing, fibrosis, hypertrophic scarring, keloids, and scleroderma (reviewed in Szauter et al., 2005). Inhibition of LOX activity resulted in inhibition of skin graft contraction in a human skin model (Harrison et al., 2006) Decreased LOX expression was noted in pelvic organ prolapse (Klutke et al., 2008), in pregnant mouse vagina and cervix compared to non-pregnant and post-partum tissues (Drewes et al., 2007), in proliferative diabetic retinopathy and rhegmatogenous retinal detachment (Coral et al., 2008), and early atherosclerosis (reviewed in Rodriguez et al., 2008). Induction of LOX was reported in inflamed oral tissue (Trackman et al., 1998) and gingival atrophy from experimental occlusal hypofunction (Ishida et al., 2008); rheumatoid arthritis (Kaufmann et al., 2003); inflammatory bowel disease (Rivera et al., 2006); liver stiffness preceding liver fibrosis (Georges et al., 2007); fibrosis of the liver (reviewed in Kagan, 1994), lung (Counts et al., 1981; Almassian et al., 1991; Peyrol et al., 1997), kidney (Di Donato et al., 1997; Goto et al., 2005; Higgins et al., 2007), oral submucosa (reviewed in Tilakaratne et al., 2006) and heart (Lopez et al., 2008; Sivakumar et al., 2008; Spurney et al., 2008; Urashima et al., 2008); systemic sclerosis (Meyringer et al., 2007); amyotrophic lateral sclerosis (Malaspina et al., 2001; Li et al., 2004); senile plaque development in Alzheimer's and non-Alzheimer's dementia (Gilad et al., 2005) and stromal reactions in cancer, which are described in more detail below. Besides collagen and elastin, other substrates have been identified for LOX. The oxidation of lysine residues in basic fibroblast growth factor (bFGF) caused covalent crosslinking of bFGF monomers to form dimers and higher order oligomers, leading to reduced mouse fibroblast proliferation (Li et al., 2003). LOX also oxidizes the platelet-derived growth factor (PDGF) receptor beta, which increases its binding affinity for PDGF-BB and decreases the turnover of PDGF receptor beta signal transduction pathway (Lucero et al., 2008). LOX also interacts with mature transforming growth factor-beta (TGF-b). LOX and TGF-b colocalize to mineral associated bone matrix, and LOX was able to suppress TGF-b1-induced Smad3 phosphorylation (Atsawasuwan et al., 2008). LOX has been shown to regulate the promoters of collagen III (COL3A1) and elastin (Giampuzzi et al., 2000; Oleggini et al., 2007; Lelievre et al., 2008). LOX also interacts with histones H1 and H2, and may be able to modulate the condensation status of chromatin to affect transcription of other genes as well (Giampuzzi et al., 2003). LOX has chemokinetic and chemotactic effects on human blood monocytes (Lazarus et al., 1995), a predominantly chemotactic effect on rat vascular smooth muscle cells and mouse embryonic fibroblasts (Li et al., 2000; Lucero et al., 2008), and has been demonstrated to regulate breast cancer cell migration and adhesion and astrocytoma migration through a hydrogen-peroxide mediated mechanism (Payne et al., 2005; Laczko et al., 2007). The same mechanism may also play a role in the promotion of normal breast epithelial cell proliferation and migration by the interaction of LOX and hormone placental lactogen (PL), although PL is not a substrate for LOX (Polgar et al., 2007). The catalytic domain of LOX is able to interact with Snail-1 in vitro, a transcription factor crucial to EMT (Peinado et al., 2005). LOX is responsible for increased migratory ability of renal tubular epithelial cells induced by hypoxia (Higgins et al., 2007). Smooth muscle migration may be modulated through the interaction with VE-statin/egfl7 to inhibit LOX enzyme activity (Lelievre et al., 2008). LOX also interacts and oxidizes PDGF receptor beta to modulate chemokine activity (Lucero et al., 2008). LOX also has multiple roles in cancer, including its opposing effect on ras-transformation, tumor suppression, stromal reaction in cancer, and the promotion of cancer cell adhesion, migration, invasion and metastases, and these are described in more detail in the following sections. |
| Homology | In the human lysyl oxidase protein family, there are five members, named LOX, LOXL1, LOXL2, LOXL3 and LOXL4. They all contain a lysine tyrosylquinone (LTQ), the only mammalian cofactor derived from the cross-linking of two amino acid side chains (reviewed in Anthony, 1996), and which is unique to the LOX family. The other highly conserved motif that is unique to the LOX family is the copper-binding domain, which contains four histidines (Krebs and Krawetz, 1993). All LOX family members also contain a cytokine receptor-like (CRL) domain, which has part of the consensus sequence of Class 1 cytokine receptors (Bazan, 1990). LOX has closest homology to LOXL1, and both seem to be found exclusively in vertebrates. |
| Mutations |
| Note | Despite the implication of LOX in many diseases and disorders, including inflammation and inflammatory diseases, fibrosis of distinct organs and fibrotic disorders, and cancer promotion and progression, there are only sparse reports of any mutations or epigenetic alterations in the LOX gene. |
| Epigenetics | The CpG island of LOX was described to be methylated in 27% of a primary gastric cancer panel. Silencing of LOX expression by methylation was also observed in gastric, colon, lung and ovarian cancer cell lines (Kaneda et al., 2002, Kaneda et al., 2004). Our group has also noted increase in LOX expression following treatment with the demethylating agent, 5-aza-2'-deoxycytidine, in breast cancer cell lines (unpublished data). Methylation is thought to be the mechanism of LOX suppression after ras-transformation (Contente et al., 1999). |
| Somatic | Loss of heterozygosity has been documented in colon and gastric cancers. In 42 colon tumors informative for the microsatellites flanking the LOX gene, 38% demonstrated loss of heterozygosity (Csiszar et al., 2002). In gastric cancer, 33% of 27 informative tumors demonstrated loss of heterozygosity (Kaneda et al., 2004). Somatic mutations of the LOX gene have been documented in colon cancer and possibly, an ovarian cancer cell line. One nonsense mutation that affected codon 332, a 3' rearrangement affecting exons 5-7, and six 5' intragenic alterations or deletions, were detected out of the 8 colon tumors that demonstrated both loss of heterozygosity and reduced LOX expression (Csiszar et al., 2002). Of 96 gastric cancer samples and 58 gastric, lung, colon, ovarian and pancreatic cancer cell lines, only one somatic mutation or rare polymorphism was found in an ovarian cancer cell line: Ala147Gly (Kaneda et al., 2004). The polymorphism Arg158Glu is associated with earlier clinical stage, lower tumor grade and decreased lymph node metastases in oral squamous cell carcinomas. The polymorphism also did not induce anchorage independent growth as did the wild type LOX (Shieh et al., 2007). As point mutations and deletions appear to be infrequent, the loss of LOX expression may be due to a combination of the more frequent loss of heterozygosity and epigenetic regulation. Indeed, some gastric cancers demonstrated biallelic methylation or loss of heterozygosity of one allele with methylation of the other allele (Kaneda et al., 2004). |
| Implicated in |
| Note | |
| Entity | Tumor suppression, stromal reactions and cancer progression |
| Note | Due to its multiple functions both extracellularly and intracellularly, lysyl oxidase has been implicated in several processes in the tumorigenic pathway, in many different cancer types and stages. These are addressed separately below. |
| Entity | Inhibition of ras transformation |
| Note | A putative tumor suppressor gene named the ras recision gene (rrg) was discovered to be greatly reduced in NIH 3T3 cells transformed by LTR-c-H-ras, and re-expressed in revertant cells, despite retaining high levels of ras expression (Contente et al., 1990). Analysis of rrg cDNA revealed that it was lysyl oxidase (Kenyon et al., 1991; Mariani et al., 1992), and the expression of LOX in revertant ras-transformed cells was confirmed by other investigators (Krzyzosiak et al., 1992; Hajnal et al., 1993; Friedman et al., 1997), and in other cell lines such as v-Ki-ras-transformed mouse osteoblastic cells (Shibanuma et al., 1993), EJ-ras-transformed rat fibroblasts (Oberhuber et al., 1995) and c-Ha-ras-transformed human osteosarcoma cell line (Csiszar et al., 1996), and transformed enterocytes (Sagiv et al., 2007). Ras-transformed NIH 3T3 cells transfected with rrg were non-tumorigenic in athymic mice (Contente et al., 1990), and anchorage independence of transformed cells was dependent on down-regulation of rrg (Hajnal et al., 1993). Even in a non-transformed normal rat kidney fibroblast cell line (NRK-49F), down-regulation of LOX was able to induce a oncogenic phenotype accompanied by p21ras activation, phosphorylation of c-jun and up-regulation of beta-catenin and cyclin D1 (Giampuzzi et al., 2001; Giampuzzi et al., 2003; Giampuzzi et al., 2005). The initial loss of LOX expression with ras transformation is thought to be due to methylation (Contente et al., 1999). This counter-effect of ras by LOX was confirmed by the ability of LOX to inhibit ras-induced meiotic maturation downstream of the ras-MEK1-Erk2 pathway in normal Xenopus laevis oocytes, an action that was blocked by bAPN, a selective inhibitor of LOX enzyme activity (DiDonato et al., 1997). In ras-transformed NIH 3T3 cells, LOX was able to partially inhibit MEK kinase activity, but was more potent against PI3K and Akt kinases and blocked membrane localization of Akt and PDK1, preventing activation of NF-kB (Jeay et al., 2003). It was determined that the 18 kD propeptide domain of LOX (LOX-PP), released during proteolytic cleavage to mature LOX, not LOX enzyme activity, was responsible for inducing phenotypic reversion. LOX-PP inhibited ras-transformation, anchorage independent growth and migration of fibroblasts, lung and pancreatic cancer cells (Palakumbura et al., 2004; Wu et al., 2007), and invasive phenotype of Her-2/neu breast cancer (Min et al., 2007). LOX-PP is thought to inhibit ras signaling via Akt and ERK pathways, the expression and activity of downstream effectors NF-kB, Bcl-2 and cyclin D1, and EMT (Min et al., 2007; Wu et al., 2007). LOX-PP inhibits primary rat aorta smooth muscle cell proliferation, DNA synthesis, MMP-9 mRNA expression and TNF-a stimulated Erk 1 / Erk 2 activation (Hurtado et al., 2008). LOX-PP has also been described to attenuate fibronectin-stimulated activation of FAK and its downstream activation of p130Cas, leading to inhibition of fibronectin-stimulated cell migration (Zhao et al., 2009). |
| Entity | Basal and squamous cell carcinoma |
| Note | Lysyl oxidase expression was present in the basal and spinous layers of the epidermis, but absent in basal and squamous cell carcinomas. Silencing of LOX expression in the human keratinocyte cell line, HaCaT, by transfection with anti-sense LOX, induced invasive ability as demonstrated by invasion of the dermis in a skin equivalent model (Bouez et al., 2006). In the stromal reactions around basal and squamous cell carcinoma foci, LOX protein expression indicated the fibrillar reaction and discriminated the tumor-stroma interface of late densely organized desmoplasia (Bouez et al., 2006). |
| Entity | Bone cancer |
| Note | Treatment of human osteosarcoma cells with suramin, an anti-cancer agent, caused decreased proliferation and upregulation of LOX and genes involved in osteoblast differentiation (Buchinger et al., 2008). Mututally subtractive RNA fingerprinted demonstrated up-regulation of LOX in the osteosarcoma cell line, MG63, compared to absent expression in normal osteoblasts (Fuchs et al., 2000). In five closely related murine osteosarcoma cell lines derived from the same tumor, LOX mRNA expression was elevated, but varied, and did not strictly correspond with collagen mRNA levels, insoluble collagen accumulation or LOX enzyme activity (Uzel et al., 2000). |
| Entity | Brain cancer |
| Note | LOX was found to be highly expressed in a panel of glioblastoma cell lines (Ross et al., 2000). Gene expression profiling of gliomas identified over-expressed lysyl oxidase as part of a molecular signature indicative of invasion, and associated with higher-grade tumors that are strongly correlated with poor patient survival (Freije et al., 2004). LOX protein expression was increased in glioblastoma and astrocytoma tissues, and in invasive U343 and U251 cultured astrocytoma cells. LOX was shown to be responsible for astrocytoma cell migration and FAK and paxillin phosphorylation (Laczko et al., 2007). |
| Entity | Breast cancer |
| Note | LOX-PP is able to attenuate fibronectin-stimulated activation of FAK and its downstream activation of p130Cas, leading to inhibition of fibronectin-stimulated breast cancer cell migration (Zhao et al., 2008). LOX mRNA expression was down-regulated in invasive breast cancer tumor vasculature compared to normal vasculature, indicating that LOX may be involved in regulating tumor vasculature plasticity (Parker et al., 2004). LOX could be detected at the invasion front of infiltrating breast tumors, but decreased in late stromal reactions and disappeared from the stroma of invading ductal carcinomas (Peyrol et al., 1997). LOX mRNA was demonstrated to be up-regulated in the invasive and metastatic cell lines, MDA-MB-231 and Hs578T, compared to the poorly-invasive and non-metastatic cell lines, MCF-7 and T47D, as well as in more aggressive breast cancer cell lines and distant metastatic tissues compared with primary cancer tissues (reviewed in Payne et al., 2007; Nagaraja et al., 2006; Mbeunkui et al., 2007). Transfection of MDA-MB-231 and Hs578T with antisense LOX, resulted in repression of invasive ability. Treatment of MDA-MB-231 and Hs578T with bAPN also inhibited invasive ability as well as cell migration and adhesion. Conversely, transfection of MCF-7 with LOX increased cell invasiveness, migration and adhesion (reviewed in Payne et al., 2007). Focal adhesion kinase (FAK) and src kinase were decreased with bAPN treatment and increased with LOX transfection. Hydrogen peroxide, a by-product of LOX activity, was necessary for FAK activity in hypoxic cells and src activation. In addition, inhibition of LOX was associated with increased Rho activity, and decreased Rac and Cdc42 activity. LOX was determined to promote p130Cas phosphorylation and formation of the p130Cas/Crk/DOCK180 signaling complex that would increase Rac-GTP, decrease actin stress fiber formation and increase formation of lamellipodium (reviewed in Payne et al., 2007). Intense staining of extracellular LOX was observed at the leading edge of MDA-MB-231 cells grown on collagen, localizing along the hairlike fibers protruding from the cell surface, accompanied by remodeling of the actin cytoskeleton, and increased formation of stress fibers and focal adhesion (Erler et al., 2006). Cell migration may also be influenced by the interaction of LOX with placental lactogen (Polgar et al., 2007), a protein implicated in breast cancer and associated with increased incidence of lymph node metastases (Latham et al., 2001). Cell invasion, migration and adhesion may also involve interaction between LOX and fibronectin (Fogelgren et al., 2005). LOX mRNA expression was determined to be regulated by HIF-1 through a hypoxia-responsive element in the LOX promoter. Increased LOX expression was found in hypoxic patients, and was associated with negative estrogen receptor status (ER-), decreased overall survival in ER- patients and node-negative patients who did not receive adjuvant systemic treatment, and shorter metastasis-free survival in ER- patients and node negative patients (Erler et al., 2006; Helleman et al., 2008). Another study found LOX expression to only correlate with tumor hypoxia in primary breast cancers, thus LOX expression may not be stimulated by hypoxia in later stages of tumor progression (Postovit et al., 2008). Intratumoral administration of bAPN resulted in growth inhibition of tumors formed by orthotopic injection of the 13 762NF cell line into rats (reviewed in Chvapil, 2005). Orthotopic injection of either MDA-MB-231 cells transfected with LOX shRNA, or MDA-MB-231 cells followed by treatment with bAPN or LOX antibody (which also inhibited LOX activity), demonstrated fewer or no lung metastasis, respectively, and no liver metastasis. Increased in vitro invasive ability of MDA-MB-231 under hypoxic/anoxic conditions, was repressed by inhibition of extracellular catalytically active LOX by treatment with LOX antisense oligos, bAPN, LOX antibody, LOX shRNA or an extracellular copper chelator (Erler et al., 2006). In an computational model of oxidative stress in vascular smooth muscle cells, lysyl hydroxylase, syk tyrosine kinase and osteopontin, markers of breast cancer cell growth, migration, invasion and metastases, were identified as behavioral predictors of lysyl oxidase (Johnson et al., 2007). |
| Entity | Cervical cancer |
| Note | SiHa cervical cancer cells demonstrated increased invasion in vitro under hypoxic/anoxic conditions, that was repressed by inhibition of extracellular catalytically active LOX by treatment with LOX antisense oligos, bAPN, LOX antibody, LOX shRNA or an extracellular copper chelator (Erler et al., 2006). |
| Entity | Choriocarcinoma |
| Note | Choriocarcinoma cell lines BeWo and JEG-3 had decreased levels of lysyl oxidase activity (Kuivaniemi et al., 1986). JEG-3 was also shown to have decreased LOX mRNA expression (Hamalainen et al., 1995). |
| Entity | Colon cancer |
| Note | Reduced LOX mRNA levels were described in a colon cancer cell line panel, two of which (HCT-116, Colo205) demonstrated complete methylation of the LOX promoter and loss of LOX expression. Treatment of HCT-116 cells with 5-aza-dC induced gain of LOX expression (Kaneda et al., 2004). Significant loss of heterozygosity or allelic imbalance was reported in colon cancer, and a panel of colon cancer samples was noted to have reduced LOX mRNA levels. Somatic mutations emcompassing one nonsense mutation that affected codon 332, a 3' rearrangement affecting exons 5-7, and six 5' intragenic alterations or deletions, were detected out of the 8 colon tumors that demonstrated both loss of heterozygosity and reduced LOX expression (Csiszar et al., 2002). |
| Entity | Esophageal cancer |
| Note | Reduced lysyl oxidase mRNA expression was observed in esophageal cancers, and was further reduced in tumors with lymph node metastasis (He et al., 2002). |
| Entity | Fibrosarcoma |
| Note | Fibrosarcoma cell lines 8387 and HT-1080 had decreased levels of lysyl oxidase activity (Kuivaniemi et al., 1986). HT-1080 was also shown to have decreased LOX mRNA expression (Hamalainen et al., 1995). |
| Entity | Gastric cancer |
| Note | Reduced expression rate of lysyl oxidase mRNA was observed in gastric cardiac and gastric cancers, and was further reduced in tumors with lymph node metastasis (He et al., 2002). Reduced LOX mRNA expression was described in a gastric cancer cell line panel, four of which (KATOIII, MKN28, MKN74, AGS) demonstrated complete methylation of the LOX promoter and loss of LOX expression which was reversed upon treatment with 5-aza-dC. Transfection of LOX into the gastric cancer cell lines, MKN28 and KATOIII, resulted in decreased numbers of colonies in soft agar, reduced number of anchorage-dependent colonies, and smaller tumors after injection into nude mice (Kaneda et al., 2004). |
| Entity | Head and neck squamous cell carcinoma (HNSCC) |
| Note | Reduced LOX mRNA levels were noted in HNSCC cell lines and tissues. In the tissues, there was also a negative correlation between LOX levels and UICC- or T-stage of the tumor (Rost et al., 2003). In oral squamous cell carcinoma cultured cells, LOX expression was highest in precancerous lesions. LOX overexpression induced reduced migration and invasion, with lower LOX expression associated with increased neck lymph node metastasis (Shieh et al., 2007). Increased levels of LOX protein were distributed in the stromal reactions of squamous cell carcinomas, directly adjacent to invading epithelial cells. The increased expression was less than the up-regulation seen in oral submucous fibrosis (Trivedy et al., 1999). In oral squamous cell carcinoma, LOX mRNA expression was upregulated compared to normal mucosa (Ziober et al., 2006). In head and neck squamous cell carcinomas, increased LOX expression was found in association with CA-IX, a marker of hypoxia, and was associated with decreased cancer specific survival, decreased overall survival and lower metastasis-free survival (Erler et al., 2006; Le et al., 2007). |
| Entity | Lung cancer |
| Note | Reduced LOX mRNA expression was described in a lung cancer cell line panel, one of which (VRMC-LCD) demonstrated complete methylation of the LOX promoter and loss of LOX expression which was reversed upon treatment with 5-aza-dC (Kaneda et al., 2004). The epigenetic modulation of LOX was supported by the induction of LOX expression by 5-aza-dC in non-small cell lung cancer cell lines (Shames et al., 2006). In bronchogenic carcinoma tissues, LOX mRNA expression levels in Stage I, II and IV were 161%, 83% and 47% of normal adjacent lung tissue, respectively, with a similar pattern of reduction in LOX protein expression (Woznick et al., 2005). Microarray analysis demonstrated decreased LOX mRNA expression in primary lung adenocarcinoma tissues and lung cancer cell lines compared to normal lung tissues and lung cells (Wu et al., 2007). In the fibrous stromal reaction typically seen in non-small cell adenocarcinoma, strong LOX expression was observed with the fibrillar reaction (mainly collagens type I and III, fibronectin and elastic fibers), and discriminated the tumor-stroma interface of late densely organized desmoplasia. In the microfibrillar angiogenic stromal reaction seen with small cell carcinoma and neuroendocrine carcinoma, there was slight LOX expression, co-localized with type I collagen that was a minor component of the stroma (mainly laminin and fibrillin), and increased LOX expression in the thickened alveolar septa adjacent to the progression front. In the pseudostromal reaction seen with non-sclerosing broncho-alveolar carcinoma, LOX stained the thickened septa (fibronectin and numerous elastic fibers) edged by tumor cells (Peyrol et al., 2000). Repression of TGFbRII by siRNA in the lung carcinoma cell line H23, was associated with increased number of invasive cells and increased levels of LOX mRNA (Borczuk et al., 2005). |
| Entity | Melanoma |
| Note | The melanoma cell line G-361 had decreased levels of lysyl oxidase activity (Kuivaniemi et al., 1986). LOX mRNA expression was demonstrated to be absent in poorly invasive cutaneous and uveal melanoma cell lines (A375P and OCM-1A), and highly expressed in highly invasive cutaneous and uveal melanoma cell lines (C8161, M619, C918) (Kirschmann et al., 2002). B16F-10 melanoma cells treated with beta-carotene had decreased LOX mRNA expression, and with Biophytum sensitivum or amentoflavone had decreased motility, invasion, in vivo metastasis and decreased LOX mRNA expression in lung metastases (Guruvayoorappan and Kuttan, 2007; Guruvayoorappan and Kuttan, 2008; Guruvayoorappan and Kuttan, 2008). |
| Entity | Multiple endocrine neoplasia (MEN) |
| Note | Lysyl oxidase mRNA expression was repressed in NIH 3T3 cells expressing either RET-MEN2A or RET-MEN2B mutant proteins (Watanabe et al., 2002). |
| Entity | Ovarian cancer |
| Note | Evaluation of an ovarian cancer cell line panel revealed reduced LOX mRNA levels, three of which (RMUG-L, RTSG, TYK-nu) demonstrated complete methylation of the LOX promoter and loss of LOX expression (Kaneda et al., 2004). |
| Entity | Pancreatic cancer |
| Note | Reduced levels of LOX mRNA was noted in a pancreatic cancer cell line panel (Kaneda et al., 2004). Microarray analysis demonstrated decreased LOX mRNA expression in primary pancreatic tumor tissues and cell lines compared to normal pancreatic tissues and cultured cells (Wu et al., 2007). |
| Entity | Prostate cancer |
| Note | LOX was detected by differential display PCR in primary vs. metastatic prostate cancer cells following TGF-b1 stimulation. LOX was detectable in more primary prostate tumor-derived cell lines than metastasis-derived cell lines, indicating that reduced LOX mRNA levels may be an acquired feature of the metastatic phenotype in cultured cells. Immunohistochemistry showed progressive reduction of lysyl oxidase expression with the transition from normal prostate epithelium to malignant prostate epithelium to metastatic tumors in both human and mouse tissues (Ren et al., 1998). LOX mRNA expression was demonstrated to be absent in a poorly invasive rat prostate cancer cell line, compared to highly invasive rat prostate cancer cell lines (Kirschmann et al., 2002). In tissues, LOX mRNA was upregulated in prostate cancer compared to benign prostatic hypertrophy, correlated with Gleason score, and associated with both high grade and short time to recurrence (Lapointe et al., 2004; Stewart et al., 2008). LOX mRNA is upregulated in the PC-3 prostate cancer cell line cultured under hypoxic conditions (Stewart et al., 2009). |
| Entity | Renal cell carcinoma (RCC) |
| Note | Up-regulation of LOX mRNA expression was detected in RCC cell lines and tissues (Ross et al., 2000; Stassar et al., 2001). Clear cell RCC also demonstrated LOX up-regulation (Takahashi et al., 2001). Indeed, LOX overexpression appeared preferentially in clear cell RCC compared to mixed clear and granular, granular, oxyphil, tubulopapillary, and chromophobe RCC/ontocytomas (Stassar et al., 2001; Young et al., 2001). In clear cell RCC, smoking was associated with allelic imbalances at chromosome 5q23.1, where the LOX gene is localized, and may involve duplication of the gene (Korenaga et al., 2005). |
| Entity | Rhabdomyosarcoma |
| Note | Rhabdomyosarcoma cell lines RD and A-204 had decreased levels of lysyl oxidase activity (Kuivaniemi et al., 1986). RD was also shown to have decreased LOX mRNA expression (Hamalainen et al., 1995). |
| Breakpoints |
| Note | None involving the LOX gene. |
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| Citation |
| This paper should be referenced as such : |
| Fong, SFT ; Fong, KSK ; Csiszar, K |
| LOX (lysyl oxidase) |
| Atlas Genet Cytogenet Oncol Haematol. 2010;14(1):15-28. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/LOXID41191ch5q23.html |
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