Purpose

Peroxiredoxin 4 (PRDX4) has been reported to play a dual role in the progression of hepatocellular carcinoma (HCC). As yet, however, the underlying molecular mechanism has not been fully elucidated.

Methods

We examined the effects of PRDX4 on the growth and survival of HCC cells in an anchorage-independent microenvironment. The regulation of β-catenin stability and activity by PRDX4 was investigated.

Results

We found that PRDX4 depletion reduced, and PRDX4 overexpression increased, both anchorage-dependent and anchorage-independent growth of HCC cells. We also found that PRDX4 depletion caused an overproduction of reactive oxygen species (ROS) in HCC cells, especially under suspension conditions. PRDX4 knockdown predisposed HCC cells to anoikis, whereas PRDX4 overexpression induced resistance to anoikis. Subsequent in vivo studies confirmed that PRDX4 deficiency blocks HCC tumor growth and pulmonary metastasis. Mechanistically, we found that RDX4 reduced β-TrCP-mediated β-catenin ubiquitination and enhanced β-catenin protein stability, consequently leading to activation of β-catenin signaling. Silencing of β-catenin impaired PRDX4-mediated anchorage-independent growth and survival, whereas β-catenin overexpression increased the survival and growth of PRDX4-depleted cells under anchorage-independent conditions. Further investigation revealed that the β-catenin downstream gene ID2 is responsible for the oncogenic activity of PRDX4 in HCC cells, promoting anchorage-independent growth and anoikis resistance.

Conclusions

PRDX4 reduces anoikis and promotes tumorigenesis and metastasis of HCC cells through stabilization of the β-catenin protein and upregulation of ID2. Targeting of PRDX4 may represent a promising strategy to block HCC cell growth and metastasis.

中文翻译：

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Peroxiredoxin 4 通过 β-catenin/ID2 通路抑制失巢凋亡并促进肝细胞癌细胞的生长和转移。

目的

据报道，过氧还蛋白 4 (PRDX4) 在肝细胞癌 (HCC) 的进展中起双重作用。然而，迄今为止，潜在的分子机制尚未完全阐明。

方法

我们研究了 PRDX4 在不依赖锚定的微环境中对 HCC 细胞生长和存活的影响。研究了 PRDX4 对 β-连环蛋白稳定性和活性的调节。

结果

我们发现 PRDX4 耗竭减少，PRDX4 过表达增加，HCC 细胞的贴壁依赖性和非贴壁依赖性生长。我们还发现 PRDX4 耗竭导致 HCC 细胞中活性氧 (ROS) 的过度产生，尤其是在悬浮条件下。PRDX4 敲低使 HCC 细胞易发生失巢凋亡，而 PRDX4 过表达诱导对失巢凋亡的抗性。随后的体内研究证实，PRDX4 缺乏阻止 HCC 肿瘤生长和肺转移。从机制上讲，我们发现 RDX4 减少了 β-TrCP 介导的 β-catenin 泛素化并增强了 β-catenin 蛋白质的稳定性，从而导致 β-catenin 信号传导的激活。β-连环蛋白的沉默损害了 PRDX4 介导的不依赖锚定的生长和存活，而β-连环蛋白过表达增加了PRDX4耗尽细胞在非锚定条件下的存活和生长。进一步的研究表明，β-catenin 下游基因 ID2 负责 PRDX4 在 HCC 细胞中的致癌活性，促进不依赖锚定的生长和抗失巢凋亡。

结论

PRDX4 通过稳定 β-catenin 蛋白和上调 ID2 减少失巢凋亡并促进 HCC 细胞的肿瘤发生和转移。靶向 PRDX4 可能代表了阻止 HCC 细胞生长和转移的一种有前景的策略。