Open Access

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

  • Authors:
    • Zhiyong Fan
    • Wei Zheng
    • Hui Li
    • Wujun Wu
    • Xiaogang Liu
    • Zhongjie Sun
    • Haitian Hu
    • Lixue Du
    • Qingan Jia
    • Qingguang Liu
  • View Affiliations

  • Published online on: March 10, 2020     https://doi.org/10.3892/or.2020.7541
  • Pages: 1641-1649
  • Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lysyl oxidase‑like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial‑mesenchymal transition by reducing E‑cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose‑1, 6‑biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail‑dependent manner. Overexpression of the point‑mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia‑inducible factor 1α (HIF‑1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild‑type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2‑IN‑1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF‑1α and VEGF in HCC cells, but not in FBP1‑knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF‑1α/VEGF signaling pathways via the Snail‑FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

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May 2020
Volume 43 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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APA
Fan, Z., Zheng, W., Li, H., Wu, W., Liu, X., Sun, Z. ... Liu, Q. (2020). LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells. Oncology Reports, 43, 1641-1649. https://doi.org/10.3892/or.2020.7541
MLA
Fan, Z., Zheng, W., Li, H., Wu, W., Liu, X., Sun, Z., Hu, H., Du, L., Jia, Q., Liu, Q."LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells". Oncology Reports 43.5 (2020): 1641-1649.
Chicago
Fan, Z., Zheng, W., Li, H., Wu, W., Liu, X., Sun, Z., Hu, H., Du, L., Jia, Q., Liu, Q."LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells". Oncology Reports 43, no. 5 (2020): 1641-1649. https://doi.org/10.3892/or.2020.7541