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

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Abstract

Background

Lysyl oxidase (LOX) is frequently overexpressed in a variety of malignancies and involved in tumor invasion and metastasis. Furthermore, it has been shown that LOX is closely related to vascular endothelial growth factor (VEGF).

Aims

In this study, we aimed to investigate the exact role of LOX and the correlation between LOX and VEGF in hepatocellular carcinoma (HCC).

Methods

The expression levels of LOX in HCC tissue and adjacent noncancerous tissue were evaluated by quantitative reverse transcription polymerase chain reaction and immunohistochemical analysis. The effect of LOX knockdown on cell proliferation, migration, and invasion was investigated in vitro. The role of LOX in the regulation of VEGF was further characterized in HCC cells that had been treated with transforming growth factor beta (TGF-β).

Results

Our study showed that LOX was up-regulated in HCC cell lines and tissue. HCC patients with elevated expression of LOX had relatively shorter disease-free survival and overall survival. Knockdown of LOX reduced the proliferation, migration, and invasion of HCC cells. Additionally, the expression level of LOX positively correlated with that of VEGF. After treatment with TGF-β, the levels of LOX and VEGF were both up-regulated in a dose-dependent manner. In the cells treated with siRNA of LOX, levels of VEGF and phosphorylated p38 were significantly decreased and could not be up-regulated by TGF-β. Inhibition of p38 MAPK signaling abrogated TGF-β-mediated up-regulation of VGEF but did not affect LOX expression.

Conclusions

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

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Acknowledgments

The authors wish to thank the assistance of all the staff, especially Junqi Huang, at the Department of Pathology, Guangxi Tumor Hospital. This work was supported by National Natural Science Foundation of China (No. 81360315).

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None.

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    Authors and Affiliations

    1. Department of Hepatobiliary Surgery, Guangxi Tumor Hospital, Nanning, 530000, People’s Republic of China

      Jiye Zhu, Shan Huang, Guobin Wu, Chaoyuan Huang, Xianjian Li, Zhigang Chen, Lei Zhao & Yinnong Zhao

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    1. Jiye Zhu
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    2. Shan Huang
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    3. Guobin Wu
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    4. Chaoyuan Huang
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    7. Lei Zhao
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    8. Yinnong Zhao
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    Correspondence to Yinnong Zhao.

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    Jiye Zhu and Shan Huang contributed equally to this work.

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    Fig. S1

    (a) Efficiency of transfection in Hep-SK-1 cells; (b) LOX mRNA expression in MHCC-97-H cells was inhibited by siRNA of LOX; (c) The density of bars were measured in comparison with corresponding controls; (d) Protein level of LOX in MHCC-97-H cells was inhibited by siRNA of LOX; Experimental schematic for combination of siRNA and proliferation assay (e), or migration and invasion assay (f). (TIFF 1259 kb)

    Fig. S2

    (a) Representative images from migration and invasion assay of MHCC-97-H cells; Magnification, ×100 for all the pictures. (b) Representative pictures of IHC staining of LOX and VEGF from same tumor areas; Magnification, ×100 for all the pictures. (c) Correlation between total IHC scores of LOX and VEGF. (TIFF 7604 kb)

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    Zhu, J., Huang, S., Wu, G. et al. Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma. Dig Dis Sci 60, 3019–3031 (2015). https://doi.org/10.1007/s10620-015-3734-5

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    • DOI: https://doi.org/10.1007/s10620-015-3734-5

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