Evolving roles of lysyl oxidase family in tumorigenesis and cancer therapy

Ye, Miaomiao; Song, Yizuo; Pan, Shuya; Chu, Maoping; Wang, Zhi-wei; Zhu, Xueqiong

doi:10.1016/j.pharmthera.2020.107633

Cited by 66 publications

(48 citation statements)

References 148 publications

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“…In fact, our in silico analyses of the TCGA transcriptome database confirmed the previously reported high expression of LOXL3 in such tumors. These findings were also supported by a recently reported similar analysis [ 28 ]. Interestingly, GBM, the most frequent and malignant type of brain tumor in adults, was among the top 10 tumors presenting LOXL3 overexpression.…”

Section: Discussionsupporting

confidence: 91%

LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells

Laurentino

Soares

Lerário

et al. 2021

IJMS

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Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family, is responsible for the crosslinking in collagen or elastin. The cellular localization of LOXL3 is in the extracellular space by reason of its canonical function. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among tumors with the highest LOXL3 expression levels. LOXL3 silencing of U87MG cells by siRNA led to the spreading of the tumor cell surface, and the transcriptome analysis of these cells revealed an upregulation of genes coding for extracellular matrix, cell adhesion, and cytoskeleton components, convergent to an increase in cell adhesion and a decrease in cell invasion observed in functional assays. Significant correlations of LOXL3 expression with genes coding for tubulins were observed in the mesenchymal subtype in the TCGA RNA-seq dataset of glioblastoma (GBM). Conversely, genes involved in endocytosis and lysosome formation, along with MAPK-binding proteins related to focal adhesion turnover, were downregulated, which may corroborate the observed decrease in cell viability and increase in the rate of cell death. Invasiveness is a major determinant of the recurrence and poor outcome of GBM patients, and downregulation of LOXL3 may contribute to halting the tumor cell invasion.

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Section: Discussionsupporting

confidence: 91%

LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells

Laurentino

Soares

Lerário

et al. 2021

IJMS

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“…Furthermore, LOX overexpression is an indicator of poor patient prognosis, as seen in several tumors 33 , 35 – 38 . Thus, there is potential application of LOX inhibitors in clinical trials to facilitate permeability of drugs and infiltration by tumor-killing immune cells 39 , taking into consideration that LOX inhibitors can only reduce the further crosslinking of collagen fibers, but not restore the already cross-linked ECM.…”

Section: Key Contributors To a Stiffer Matrixmentioning

confidence: 99%

Causal contributors to tissue stiffness and clinical relevance in urology

et al. 2021

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Mechanomedicine is an emerging field focused on characterizing mechanical changes in cells and tissues coupled with a specific disease. Understanding the mechanical cues that drive disease progression, and whether tissue stiffening can precede disease development, is crucial in order to define new mechanical biomarkers to improve and develop diagnostic and prognostic tools. Classically known stromal regulators, such as fibroblasts, and more recently acknowledged factors such as the microbiome and extracellular vesicles, play a crucial role in modifications to the stroma and extracellular matrix (ECM). These modifications ultimately lead to an alteration of the mechanical properties (stiffness) of the tissue, contributing to disease onset and progression. We describe here classic and emerging mediators of ECM remodeling, and discuss state-of-the-art studies characterizing mechanical fingerprints of urological diseases, showing a general trend between increased tissue stiffness and severity of disease. Finally, we point to the clinical potential of tissue stiffness as a diagnostic and prognostic factor in the urological field, as well as a possible target for new innovative drugs.

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“…The lysyl oxidase family members are secreted copper-dependent oxidases, including five paralogues: LOX , LOX -like 1–4 ( LOXL 1–4), which act to exert catalytic activity to remodel the cross-linking of the extracellular matrix (ECM) of fibrotic liver and that of a corrupted tumor microenvironment (TME) [ 4 ]. To date, the roles of LOX and LOXL 2 in the clinical significance and therapeutic implication of HCC are mostly studied as compared to the other family members [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA

Yang

Tsai

Chang

et al. 2021

IJMS

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Primary liver cancer accounts for the third most deadly type of malignant tumor globally, and approximately 80% of the cases are hepatocellular carcinoma (HCC), which highly relies on the activity of hypoxia responsive pathways to bolster its metastatic behaviors. MicroRNA-29a (MIR29A) has been shown to exert a hepatoprotective effect on hepatocellular damage and liver fibrosis induced by cholestasis and diet stress, while its clinical and biological role on the activity hypoxia responsive genes including LOX, LOXL2, and VEGFA remains unclear. TCGA datasets were retrieved to confirm the differential expression and prognostic significance of all genes in the HCC and normal tissue. The Gene Expression Omnibus (GEO) dataset was used to corroborate the differential expression and diagnostic value of MIR29A. The bioinformatic identification were conducted to examine the interaction of MIR29A with LOX, LOXL2, and VEGFA. The suppressive activity of MIR29A on LOX, LOXL2, and VEGF was verified by qPCR, immunoblotting, and luciferase. The effect of overexpression of MIR29A-3p mimics in vitro on apoptosis markers (caspase-9, -3, and poly (ADP-ribose) polymerase (PARP)); cell viability and wound healing performance were examined using immunoblot and a WST-1 assay and a wound healing assay, respectively. The HCC tissue presented low expression of MIR29A, yet high expression of LOX, LOXL2, and VEGFA as compared to normal control. Serum MIR29A of HCC patients showed decreased levels as compared to that of normal control, with an area under curve (AUC) of 0.751 of a receiver operating characteristic (ROC) curve. Low expression of MIR29A and high expression of LOX, LOXL2, and VEGFA indicated poor overall survival (OS). MIR29A-3p was shown to target the 3′UTR of LOX, LOXL2, and VEGFA. Overexpression of MIR29A-3p mimic in HepG2 cells led to downregulated gene and protein expression levels of LOX, LOXL2, and VEGFA, wherein luciferase reporter assay confirmed that MIR29A-3p exerts the inhibitory activity via directly binding to the 3′UTR of LOX and VEGFA. Furthermore, overexpression of MIR29A-3p mimic induced the activity of caspase-9 and -3 and PARP, while it inhibited the cell viability and wound healing performance. Collectively, this study provides novel insight into a clinical-applicable panel consisting of MIR29, LOX, LOXL2, and VEGFA and demonstrates an anti-HCC effect of MIR29A via comprehensively suppressing the expression of LOX, LOXL2, and VEGFA, paving the way to a prospective theragnostic approach for HCC.

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Evolving roles of lysyl oxidase family in tumorigenesis and cancer therapy

Cited by 66 publications

References 148 publications

LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells

LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells

Causal contributors to tissue stiffness and clinical relevance in urology

MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA

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