Loss of Lysyl Oxidase-like 3 Attenuates Embryonic Lung Development in Mice

Zhang, Jian; Liu, Ziyi; Zhang, Tingting; Lin, Zhuchun; Li, Zhenzu; Zhang, Aizhen; Sun, Xiaoyang; Gao, Jiangang

doi:10.1038/srep33856

Cited by 21 publications

(21 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LOX proteins have a well-established role as secreted enzymes contributing to tissue homeostasis by cross-linking ECM substrates [ 2 , 3 ]. Nonetheless, the generation of independent loss-of-function mouse models of Lox , Loxl1 , Loxl2 , and Loxl3 genes has revealed non-redundant roles and distinct contribution to tissue fitness and proper embryonic development [ 19 – 21 , 44 – 46 ]. In addition to their extracellular roles, recent data support equally important intracellular functions for some LOX family members [ 6 – 9 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Extensive work by our lab and others has established the deregulation of lysyl oxidases in cancer and their status has been associated with patient outcome in specific neoplasias [ 5 , 6 ]. Regarding LOXL3, substantial information reinforces its role in ECM remodeling linking deregulated LOXL3 to different connective tissue disorders [ 16 , 18 – 21 ]; however, LOXL3 involvement in cancer has not been systematically investigated. Our current in silico analyses in different tumor samples uncovered a clear association of LOXL3 expression to melanoma with LOXL3 mRNA being particularly higher among melanomas carrying well-known oncogenic mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Human LOXL3 presents differential tissue expression regarding other LOX proteins [ 12 – 15 ] and has been recently proposed as a candidate gene responsible for recessive autosomal Stickler syndrome [ 16 ], a collagenopathy [ 17 ], whereas null mutations in LOXL3 have been associated with early-onset high myopia [ 18 ]. Genetic inactivation in mice has revealed Loxl3 involvement in skeletal, muscular, and lung development [ 19 – 21 ]. Thus far the reported roles for LOXL3 were essentially associated with LOXL3 extracellular activity regarding ECM maturation, whereas LOXL3 involvement in cancer remains limited.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability

et al. 2017

View full text Add to dashboard Cite

Lysyl oxidase-like 3 (LOXL3) is a member of the lysyl oxidase family comprising multifunctional enzymes with depicted roles in extracellular matrix maturation, tumorigenesis, and metastasis. In silico expression analyses followed by experimental validation in a comprehensive cohort of human cell lines revealed a significant upregulation of LOXL3 in human melanoma. We show that LOXL3 silencing impairs cell proliferation and triggers apoptosis in various melanoma cell lines. Further supporting a pro-oncogenic role in melanoma, LOXL3 favors tumor growth in vivo and cooperates with oncogenic BRAF in melanocyte transformation. Upon LOXL3 depletion, melanoma cells display a faulty DNA damage response (DDR), characterized by ATM checkpoint activation and inefficient ATR activation leading to the accumulation of double-strand breaks (DSBs) and aberrant mitosis. Consistent with these findings, LOXL3 binds to proteins involved in the maintenance of genome integrity, in particular BRCA2 and MSH2, whose levels dramatically decrease upon LOXL3 depletion. Moreover, LOXL3 is required for efficient DSB repair in melanoma cells. Our results reveal an unexpected role for LOXL3 in the control of genome stability and melanoma progression, exposing its potential as a novel therapeutic target in malignant melanoma, a very aggressive condition yet in need for more effective treatment options.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability

et al. 2017

View full text Add to dashboard Cite

show abstract

“…(35) In embryonic lungs of LOXL3 -/mice, expression of pulmonary LOX and LOXL1 remained unchanged, that of LOXL2 was down-regulated, and that of LOXL4 was upregulated. (36) However, in an in vivo study of bleomycin (BLM)-induced pulmonary fibrosis, no interdependence of LOX family enzymes could be shown, given that knockdown of individual members by specific siRNAs did not significantly affect the expression of other members. (17) The mutual regulation among the LOX family members in the liver is even less clear, which may limit the utility of targeting a single LOX member to treat LF.…”

Section: Interplay Among Lox Family Membersmentioning

confidence: 99%

Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

et al. 2020

View full text Add to dashboard Cite

The cross‐linking of structural extracellular matrix (ECM) components, especially fibrillar collagens and elastin, is strongly implicated in fibrosis progression and resistance to fibrosis reversal. Lysyl oxidase family members (LOX and LOXL1 [lysyl oxidase‐like 1], LOXL2 [lysyl oxidase‐like 2], LOXL3 [lysyl oxidase‐like 3], and LOXL4 [lysyl oxidase like 4]) are extracellular copper‐dependent enzymes that play a key role in ECM cross‐linking, but have also other intracellular functions relevant to fibrosis and carcinogenesis. Although the expression of most LOX family members is elevated in experimental liver fibrosis of diverse etiologies, their individual contribution to fibrosis is incompletely understood. Inhibition of the LOX family as a whole and of LOX, LOXL1, and LOXL2 specifically has been shown to suppress fibrosis progression and accelerate its reversal in rodent models of cardiac, renal, pulmonary, and liver fibrosis. Recent disappointing clinical trials with a monoclonal antibody against LOXL2 (simtuzumab) in patients with pulmonary and liver fibrosis dampened enthusiasm for LOX family member inhibition. However, this unexpected negative outcome may be related to the inefficient antibody, rather than to LOXL2, not qualifying as a relevant antifibrotic target. Moreover, LOX family members other than LOXL2 may prove to be attractive therapeutic targets. In this review, we summarize the structural hallmarks, expression patterns, covalent cross‐linking activities, and modes of regulation of LOX family members and discuss the clinical potential of their inhibition to treat fibrosis in general and liver fibrosis in particular.

show abstract

“…LOXL3 has a role in palatal, vertebral and lung development in mice. Accordingly, Loxl3- deficient mice show perinatal lethality with severe craniofacial defects, spinal deformity [55] and impaired lung development [56].…”

Section: Lox Family Members and Their Role In Developmentmentioning

confidence: 99%

Interplay Between LOX Enzymes and Integrins in the Tumor Microenvironment

Amendola

Reuten

Erler

2019

Cancers

View full text Add to dashboard Cite

Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues. LOX enzymes can also remodel the tumor microenvironment and have been implicated in all stages of tumor initiation and progression of many cancer types. Changes in the ECM can influence several cancer cell phenotypes. Integrin adhesion complexes (IACs) physically connect cells with their microenvironment. This review article summarizes the main findings on the role of LOX proteins in modulating the tumor microenvironment, with a particular focus on how ECM changes are integrated by IACs to modulate cells behavior. Finally, we discuss how the development of selective LOX inhibitors may lead to novel and effective therapies in cancer treatment.

show abstract

Loss of Lysyl Oxidase-like 3 Attenuates Embryonic Lung Development in Mice

Cited by 21 publications

References 46 publications

Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability

Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability

Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

Interplay Between LOX Enzymes and Integrins in the Tumor Microenvironment

Contact Info

Product

Resources

About