Lysyl oxidase expression and inhibition in uveal melanoma

Abstract

Lysyl oxidase is a marker of poor prognosis in several malignancies and is hypothesized to promote a migratory phenotype in hypoxic breast carcinomas. This study aims to characterize the expression of the lysyl oxidase and lysyl oxidase-like proteins in human uveal melanoma cell lines and archival choroidal melanomas using immunohistochemistry. The transcriptional control of lysyl oxidase will also be investigated under simulated hypoxic conditions using cobalt chloride. Lastly, changes in cellular proliferation and invasion will be assessed after the treatment of cell lines with beta-aminopropionitrile, a lysyl oxidase catalytic inhibitor. Retrospective analysis of lysyl oxidase expression in primary human uveal melanoma showed 82% (27 of 33) of tumors being stained positive. High lysyl oxidase expression correlated with the aggressive epithelioid cell type and was associated with shorter metastasis-free survival. Simulated hypoxia resulted in a significant increase in lysyl oxidase mRNA expression. Inhibiting lysyl oxidase's catalytic activity significantly reduced cellular invasion but had no effect on cell proliferation. Our study is the first to show lysyl oxidase expression in primary choroidal melanomas. This protein may represent a potential therapeutic target that warrants further study in this malignancy.

The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth

“…However, the role of LOX in primary tumor formation remains little explored. Interestingly, the upregulation of LOX expression has recently been described in precancerous lesions of oral squamous cell carcinoma and primary choroidal melanoma (40,41). These reports support our observation of a role of LOX in early cancer progression.…”

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

“…It promotes cell growth and metastasis of a variety of cancer cells in vitro and in vivo [10,11,28,31,32], whereas other researchers found that LOX is a suppressor of proliferation and migration in human osteosarcoma cells [6]. In our study, the data from MTT assay demonstrated that siLOX intensively inhibited proliferative activity of MHCC-97-H and HepG2 cells.…”

LOXL2 in epithelial cell plasticity and tumor progression

“…Breast ns IHQ Expression related to malignancy [32] 286 RNA expression (m) Overexpression related to overall survival in N0 tumors [41] ns IF Intracellular localization in epithelial cells of mammary, prostate and gastric glands, and in kidney tubules [37] ns RNA expression Associated with ER -breast tumor progression [34] 202 IHQ/RNA expression Overexpression and perinuclear pattern in metastatic basal breast carcinomas [40] Colon 58 IHQ Overexpression related to tumor progression [76] 104 RNA expression Overexpression associated with absence of lymphovascular invasion (also LOX and LOXL4) [75] Gastric 514 † IHQ Overexpression correlated with depth of tumor invasion, lymph node metastasis and shorter overall survival [62] Head and neck 66 RNA expression No changes in tumor samples in relation to normal mucosa of the upper aerodigestive tract [77] 50 IF Overexpression related to tumor progression in esophageal lesion [76] 256 IHQ/RNA expression Overexpression and perinuclear pattern associated with poor prognosis and overall survival in larynx SCC [41] Lung 137 IHQ/RNA expression Downregulation correlated with poor differentiation and advanced disease [79] 51 RNA expression (m) Overexpression related to overall survival in squamous carcinomas [41] Melanoma 33 IHQ Overexpression associated with poor prognosis and metastasis-free survival [78] Several histologies ‡ 137/78 § RNA expression Overexpression frequently detected in breast carcinoma specimens (primary site and effusions) [74] Several histologies ¶~1 future science group a specific perinuclear/cytoplasmic localization was observed in larynx SCC [41]. Significantly, perinuclear LOXL2 localization was associated with local recurrence and also with poor prognosis or metastasis of SCC (Table 1) [41].…”

“…Both upregulation and overexpression of LOXL2 were observed depending on the analyzed tumor type. Thus, LOXL2 upregulation at the mRNA and/ or protein level has been detected in undifferentiated breast [34,40,61,74], colon [75], esophagus [76,77] and larynx [41] carcinomas, and in primary choroidal melanomas [78]. In several instances, the upregulation of LOXL2 was associated with tumor progression and/or prognosis (Table 1).…”