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NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma.

ABSTRACT: Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease-free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial-mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia-inducible factor-1α (HIF-1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor-promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N-acetyl-l-cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor-promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.

SUBMITTER: Sun B

PROVIDER: S-EPMC8253267 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hypoxia, a condition characterized by low oxygen levels, serves an important role in the progression of hepatocellular carcinoma (HCC). However, the precise molecular mechanisms underlying hypoxia‑induced HCC progression are yet to be fully elucidated. The present study assessed the involvement of two key factors, hypoxia‑inducible factor‑1α (HIF‑1α) and Rac GTPase activating protein 1 (RACGAP1), in HCC development under hypoxic conditions. HIF‑1α and RACGAP1 genes were overexpressed and knocked down in Hep3B and Huh7 cells using lentiviral transduction and the levels of HIF‑1α and RACGAP1 in the cells were assessed using quantitative PCR, western blotting and immunofluorescence. Co‑immunoprecipitation experiments were performed to evaluate the interaction between HIF‑1α and RACGAP1. Subsequently, the proliferation, apoptosis, migration and invasion of Hep3B and Huh7 cells were assessed using the Cell Counting Kit‑8 assay, flow cytometry, Transwell assay and migration experiments. The expression levels of HIF‑1α and RACGAP1 in normal and HCC tumor samples were analyzed utilizing the Gene Expression Profiling Interactive Analysis database. Furthermore, correlations between HIF‑1α/RACGAP1 gene expression levels and patient survival outcomes were evaluated using the Kaplan‑Meier plotter. Knockdown of HIF‑1α resulted in a significant decrease in RACGAP1 expression, whilst overexpression of HIF‑1α resulted in a significant increase in RACGAP1 expression. Moreover, overexpression and knockdown of RACGAP1 had the same effect on HIF‑1α expression. Additionally, it was demonstrated that HIF‑1α and RACGAP1 interacted directly within a complex. Overexpression of HIF‑1α or RACGAP1 significantly increased proliferation, invasion and migration, and significantly decreased the proportion of apoptotic Hep3B and Huh7 cells. Conversely, knockdown of HIF‑1α or RACGAP1 significantly decreased proliferation, invasion and migration, and significantly increased the proportion of apoptotic Hep3B and Huh7 cells. In addition, the combined knockdown or overexpression of HIF‑1α and RACGAP1 had a more pronounced effect on HCC cell migration compared with knockdown of HIF‑1α alone. Furthermore, there was a significant positive correlation between the expression levels of HIF‑1α and RACGAP1 in HCC tissues and patients with HCC and upregulation of both HIF‑1α and RACGAP1 demonstrated a lower overall survival probability. In conclusion, HIF‑1α and RACGAP1 may synergistically contribute to the development of HCC, highlighting their potential as valuable targets for HCC therapy.

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NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma.

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