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Cancer Sci. 2020 Jan 22;:
Authors: Shimokawa M, Yoshizumi T, Itoh S, Iseda N, Sakata K, Yugawa K, Toshima T, Harada N, Ikegami T, Mori M
Abstract
The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid-derived 2-like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage-independent culture, HCC cells showed increased ROS, leading to the up-regulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β-lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability; which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Nrf2/Nqo1 overexpression in primary HCC was associated with tumor size, high alpha-fetoprotein and des-gamma-carboxy-prothrombin levels. Nrf2/Nqo1 overexpression was associated with multiple intrahepatic recurrences (P = 0.0073) and was an independent risk factor for poor prognosis (P = 0.0031). Nqo1 plays an important role in anchorage-independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggesting that targeting Nqo1 activity may be a potential strategy for HCC adjuvant therapy.
PMID: 31968140 [PubMed - as supplied by publisher]
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