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Molecular roles of Lysyl Oxidase-Like 3 (LOXL3) in melanoma proliferation and progression Zhang, Xue


Background: Melanoma is a devastating cancer with 17% 5-year survival rate when it is metastasized. Clinically, finding new biomarkers will provide more options in patient early diagnosis and treatments. Previously, Lysyl Oxidase-like 3 (LOXL3) was discovered as one of the most upregulated genes in metastatic melanoma compared to normal nevi and normal skin. LOXL3 is an extracellular protein that induces the cross-linkage formation in collagen and elastin. LOXL3 has never reported in melanoma and barely been studied in tumours. The previous knowledge about LOXL3 makes it an attractive gene to study in melanoma. Objective: The objectives of this study are to investigate LOXL3 expression profile, bio-functions, clinical significance, and potential downstream regulators in melanoma. Experimental Methods: A panel of cell lines and tissues was utilized to evaluate LOXL3 expression in mRNA and protein levels. Two melanoma cell lines, A375 and WM-115, were transfected with siRNAs to create transiently-decreased LOXL3 expression, to study the functional differences of LOXL3 in vitro. Further, immunohistochemical staining of tissue microarray with 373 biopsies was used to observe the correlation between LOXL3 expression levels and patient survival outcomes. Results: We detected a significantly higher expression of LOXL3 on mRNA and protein levels in melanoma compared to melanocytes and normal skins. LOXL3 deficiency could inhibit proliferation, migration and invasion in vitro. Tissue microarray revealed that higher LOXL3 cytoplasmic staining was associated with thicker tumour, the presence of mitosis, more advanced melanoma, and worse primary melanoma patient survival. LOXL3 knockdown did not induce any differences in FAK/Src phosphorylation levels or E-cadherin expression levels. Discussion: LOXL3 promotes cell proliferation, cell motility and cell invasion in vitro, and LOXL3 cytoplasmic overexpression is associated with enhanced tumour mitosis and thickness in melanoma in vivo. This suggests LOXL3 has an essential impact on melanoma growth and potentially metastasis due to the invasive potential. In addition, no correlations are found in FAK/Src activation and E-cadherin restoration by LOXL3, suggesting LOXL3 may use a different pathway beyond previous knowledge. Conclusion: LOXL3 positively regulates cellular growth and invasion in melanoma cells and tissues, making LOXL3 a promising prognostic marker and a therapeutic target.

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