Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma

Zhu, Jinmin; Huang, Shan; Wu, Guobin; Huang, Chung-Chi; Li, Xian-Jian; Chen, Zhigang; Zhao, Lei; Zhao, Yi‐Fang

doi:10.1007/s10620-015-3734-5

Cited by 20 publications

(24 citation statements)

References 33 publications

(49 reference statements)

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“…In this study, using esophageal cancer specimens and cell lines we revealed that LOX was highly expressed in esophageal cancer, suggesting that LOX is involved in ESCC pathogenesis. Overexpression of LOX has been reported in various cancers including nasopharyngeal carcinoma, head and neck tumors, breast cancer, hepatocellular carcinoma, and colorectal cancer and has been associated with poor clinical outcome . Similarly, we found that esophageal cancer patients highly expressing LOX had a poorer prognosis in terms of shorter OS and cancer‐specific survival.…”

Section: Discussionsupporting

confidence: 72%

Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer

et al. 2019

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Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE‐1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer‐specific survival (log‐rank, P < .001). The prognostic effect of LOX expression was not significantly modified by other clinical variables. Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2. An integrated gene analysis in tissues and cell lines revealed that LOX was the most highly upregulated gene in LINE‐1 hypomethylated tumors. In vitro, LOX expression was upregulated following DNA demethylation. LOX promoter methylation was not associated with LOX expression. Conclusively LOX expression was associated with poor prognosis in ESCC and was regulated epigenetically by genome‐wide hypomethylation. It could serve as a prognostic biomarker in ESCC patients, and therapeutically targeting LOX could reverse the progression of esophageal cancer.

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Section: Discussionsupporting

confidence: 72%

Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer

et al. 2019

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“…High LOX expression is reportedly associated with cancer malignancy and cancer metastasis, and reflects patient prognosis in several types of cancer . In the context of HCC, it has been reported that high LOX expression is associated with a marker of tumor angiogenesis, but the association between LOX expression and patient outcome, especially HCC metastasis of IM, is still unclear . We aimed to comprehensively analyze the role of LOX in HCC by interrogating a large transcriptome database and to validate the impact of LOX expression in the recurrence of HCC from IM.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12][13][14][25][26][27][28] In the context of HCC, it has been reported that high LOX expression is associated with a marker of tumor angiogenesis, but the association between LOX expression and patient outcome, especially HCC metastasis of IM, is still unclear. 28,29 We aimed to comprehensively analyze the role of LOX in HCC by interrogating a large transcriptome database and to validate the impact of LOX expression in the recurrence of HCC from IM. CT angiography, for diagnosis and staging of HCC before surgery.…”

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confidence: 99%

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

et al. 2019

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Hepatocellular carcinoma ( HCC ) has high recurrence rates even after curative hepatectomy. Drug therapy for recurrence of HCC is still limited; therefore, identifying new therapeutic targets is urgently needed. We searched for genes that would predict HCC recurrence from intrahepatic metastasis in an exhaustive DNA microarray database by searching genes associated with high early recurrence rate and having higher expression in the tumor area compared to background liver. We detected lysyl oxidase ( LOX ) and validated the clinical significance of LOX in 358 patients who underwent hepatectomy. Expression of LOX was evaluated by qRT ‐ PCR , and immunohistochemical ( IHC ) staining. High LOX expression group had a significantly higher recurrence rate than the low LOX expression group (2‐year recurrence rate was 64.0% vs 24.2%, P < .0001 for IHC ) and poorer survival rate (5‐year rate was 60.1% vs 86.2%, P < .0001 for IHC ). Multivariate analysis showed that high LOX expression was an independent risk factor for early recurrence ( IHC : HR , 2.52; P < .0001). Bioinformatic analysis showed that LOX expression was associated with hypoxia‐inducible factor‐1α ( HIF ‐1α) and the hypoxia cascade, suggesting that HIF ‐1α or hypoxia regulates LOX expression and induces epithelial‐mesenchymal transition ( EMT ). In vitro, LOX and HIF ‐1α were involved in migration and invasion capability. High LOX expression is associated with EMT markers and predicts early recurrence and poor survival in patients with HCC . These findings indicate that lysyl oxidase could be a potential therapeutic target for early recurrence of HCC .

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“…Accordingly, LOX expression is upregulated in various cancers including HCC and is associated with poor prognosis. [128][129][130][131][132] In HCC, LOX-like 2 (LOXL2) can be upregulated by TGFβ, 128 hypoxia-inducible factor 1-α (HIF-1α), 129,133 and stiffness, 134 and has been suggested to be involved in HCC development and metastasis. 129,130,133 Indeed, LOX overexpression increases ECM stiffness and promotes tumor cell invasion and progression.…”

Section: Stiffness and Hepatocarcinogenesismentioning

confidence: 99%

Contributions of Fibroblasts, Extracellular Matrix, Stiffness, and Mechanosensing to Hepatocarcinogenesis

Filliol

Schwabe

2019

Semin Liver Dis

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. A unique feature of liver cancer is its close association with liver fibrosis. About 90% of HCCs develop in advanced liver fibrosis or cirrhosis, suggesting an important role for the fibrotic microenvironment in driving HCC development. Here, the authors will discuss functional contributions of liver fibrosis to the development of HCC, focusing on mechanisms through which fibrosis may promote HCC development such as hepatic stellate cell-derived extracellular matrix, growth factors, and cytokines, stiffness-induced signaling pathways, and immunosuppression. Better understanding of these factors in HCC development and progression may provide the basis for novel stromal-based therapies for tumor prevention or therapy.

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Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma

Abstract: LOX appears to be a predictor of less favorable outcomes and may regulate the expression of VEGF via p38 MAPK signaling.

Cited by 20 publications

References 33 publications

Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer

Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

Contributions of Fibroblasts, Extracellular Matrix, Stiffness, and Mechanosensing to Hepatocarcinogenesis

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