Somatic mutations of the lysyl oxidase gene on chromosome 5q23.1 in colorectal tumors

Csiszár, Katalin; Fong, Sheri F. T.; Újfalusi, Anikó; Krawetz, Stephen A.; Salvati, Eugene P.; Mackenzie, James W.; Boyd, Charles D.

doi:10.1002/ijc.10035

Cited by 64 publications

(61 citation statements)

References 33 publications

(34 reference statements)

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“…LOX expression was down-regulated in immortalized rat fibroblasts after transformation by activated H-ras (38,39). Other investigations reported a decrease of lysyl oxidase activity due to a decrease of LOX synthesis in malignantly transformed human cell lines (40), or LOX somatic mutations in colon cancer (41), or reduction of LOX mRNA expression in head and neck squamous cell carcinomas (19) and gastric cancer (16,17). In addition, we confirm here the absence of LOX in both BCC and SCC, expanding the role of LOX absence in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

The Lysyl Oxidase LOX Is Absent in Basal and Squamous Cell Carcinomas and Its Knockdown Induces an Invading Phenotype in a Skin Equivalent Model

Bouez

Reynaud

Noblesse³

et al. 2006

Clinical Cancer Research

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Lysyl oxidase initiates the enzymatic stage of collagen and elastin cross-linking. Among five isoforms comprising the lysyl oxidase family, LOX is the better studied. LOX is associated to an antitumor activity in ras-transformed fibroblasts, and its expression is down-regulated in many carcinomas. The aim of this work was to shed light on LOX functions within the epidermis by studying its expression in human basal and squamous cell carcinomas and analyzing the effect of its enzymatic activity inhibition and protein absence on human keratinocytes behavior in a skin equivalent. In both carcinomas, LOX expression by epidermal tumor cells was lacking, while it was up-regulated around invading tumor cells in association with the stromal reaction. Lysyl oxidase activity inhibition using h-aminoproprionitrile in a skin equivalent model prepared with both primary human keratinocytes and HaCaT cell line affected keratin 10 and filaggrin expression and disorganized the collagen network and the basement membrane. In spite of all these changes, no invasion phenotype was observed. Modelization of the invasive phenotype was only noticed in the skin equivalent developed with LOX antisense HaCaT cell line, where the protein LOX is specifically absent. Our results clearly indicate that lysyl oxidase enzymatic activity is essential not only for the integrity maintenance of the dermis but also for the homeostasis of the epidermis. Moreover, LOX protein plays a role in the skin carcinomas and invasion but not through its enzymatic activity.Lysyl oxidase gene family comprises five members acting as extracellular modulating enzymes: LOX, LOXL, LOXL2, LOXL3, and LOXL4 (1). The first identified and the better-studied isoform of this family is LOX. It is a copper-dependent amine oxidase that initiates the covalent cross-linking of collagens and elastin in extracellular matrices (ECM; refs. 2,3). LOX is secreted as a glycosylated proenzyme, processed by procollagen C-proteinase into a mature active form. LOX activity modulation, due to either an increase or a decrease in its expression, induces multiple effects on the structure and major characteristics of the ECM. LOX is essential in maintaining the characteristics of blood vessels and arteries, where its activity modulation is correlated to atherosclerosis (4), aneurism (5), and human arterial dissection (6) as well as to Alzheimer disease (7). LOX down-regulation is correlated to many connective tissue disorders seen in Ehler-Danlos syndrome, cutis laxa, and Menke's syndrome (8 -10). In tumors, LOX upregulation is found in the stromal reaction observed around tumor foci in ductal breast carcinomas (11) and in bronchopulmonary carcinomas (12).LOX might also have a role on nonmesenchymal cells. Indeed, LOX expression has been recently associated to differentiated keratinocytes in a skin equivalent model (13). Besides, LOX, which is expressed in healthy skin (13, 14), has not been detected in tumor cells from invading ductal breast carcinomas (11) in primary and metastatic prost...

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Section: Discussionmentioning

confidence: 99%

The Lysyl Oxidase LOX Is Absent in Basal and Squamous Cell Carcinomas and Its Knockdown Induces an Invading Phenotype in a Skin Equivalent Model

Bouez

Reynaud

Noblesse³

et al. 2006

Clinical Cancer Research

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“…Both LOX down-and up-regulation has been described in CRC as well as other cancers, initially, decreased LOX mRNA expression levels were reported in CRC patients with non-metastatic disease [26]. However, work from both us and other groups observed an association of LOX overexpression and CRC progression [15,20,27,28].…”

Section: Discussionmentioning

confidence: 83%

Untitled

2017

Oncotarget

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Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.

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“…LOXL-1, similarly to LOX, plays a critical role in the formation and repair of the ECM by oxidizing lysine residues in elastin and collagen, thereby stabilizing the fibrous proteins (18,27). In addition to its fibrogenic function, LOX expression is associated with tumor suppression and tumor progression, and its role in tumorigenesis appears to be dependent on cellular location, cell type and transformation status (27)(28)(29)(30)(31)(32). Microarray studies have shown that the expression of LOX is elevated in hypoxic human tumor cells (33), suggesting that the LOX expression is regulated by hypoxiainducible factor (HIF) and is associated with hypoxia in human breast, head and neck tumors (28).…”

Section: Discussionmentioning

confidence: 99%

Lysyl oxidase-like-1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved

et al. 2011

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Abstract. The role that lysyl oxidase-like-1 (LOXL-1) may play in cancer metastasis due to its specific collagen accumulation characteristics has not been investigated extensively. This study was performed to examine the role of LOXL-1 in cancer metastasis. In vitro and in vivo cancer metastasis experiments were performed with B16F10 cells. Using the immunoblotting technique, the expression of LOXL-1, monocarboxylate transporter (MCT)1/2 and matrix metalloproteinase (MMP)2/9 was examined in a cell culture model and in primary and metastatic site samples from non-small cell lung carcinoma patients. Immunohistochemistry was also performed. According to immunohistochemical analysis of the non-small cell lung carcinoma patient samples, LOXL-1, MCT1/2 and MMP2/9 were expressed more highly in metastatic sites compared to primary sites. In in vivo studies, LOXL-1-overexpressing B16F10 cells yielded higher numbers of cancer nodules following their injection into mouse tail veins. Transfection of LOXL-1 siRNA into the cells prior to injection blocked lung metastasis. In vitro, the overexpression of LOXL-1 increased cell mobility and invasiveness, with increased extracellular accumulation of lactate at a low pH. The lactate transporter, MCT1/2, was highly expressed in LOXL-1-overexpressing cells. LOXL-1 knockdown through siRNA inhibited cell motility and invasiveness, showing relatively lower lactate accumulation and expression of MCT1/2 than under control conditions. This study elucidates extracellular pH-associated matrix degradation as a potential mechanism for LOXL-1-induced cancer metastasis.

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Somatic mutations of the lysyl oxidase gene on chromosome 5q23.1 in colorectal tumors

Cited by 64 publications

References 33 publications

The Lysyl Oxidase LOX Is Absent in Basal and Squamous Cell Carcinomas and Its Knockdown Induces an Invading Phenotype in a Skin Equivalent Model

The Lysyl Oxidase LOX Is Absent in Basal and Squamous Cell Carcinomas and Its Knockdown Induces an Invading Phenotype in a Skin Equivalent Model

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Lysyl oxidase-like-1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved

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