Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.
Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.
Cancer Sci. 2019 Mar;110(3):1054-1063. doi: 10.1111/cas.13945. Epub 2019 Feb 16.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The expression of nitric oxide synthase (NOS) and the inhibition of autophagy have been linked to cancer cell death. However, the involvement of serum nitric oxide (NO), the expression of NOS and autophagy have not been investigated in HCC. In the present study, we first established that the NO level was significantly higher in hepatitis B virus-related HCC than in the liver cirrhosis control (53.60 ± 19.74 vs 8.09 ± 4.17 μmol/L, t = 15.13, P < 0.0001). Using immunohistochemistry, we found that the source of NO was at least partially attributed to the expression of inducible NOS and endothelial NOS but not neuronal NOS in the liver tissue. Furthermore, in human liver cancer cells, NO-induced apoptosis and inhibited autophagy. Pharmacological inhibition of autophagy also induced apoptosis, whereas the induction of autophagy could ameliorate NO-induced apoptosis. We also found that NO regulates the switch between apoptosis and autophagy by disrupting the Beclin 1/Vps34 association and by increasing the Bcl-2/Beclin 1 interaction. Overall, the present findings suggest that increased NOS/NO promotes apoptosis through the inhibition of autophagy in liver cancer cells, which may provide a novel strategy for the treatment of HCC.
肝细胞癌 (HCC) 是全球癌症相关死亡的第二大主要原因。一氧化氮合酶 (NOS) 的表达和自噬的抑制与癌细胞死亡有关。然而，在 HCC 中尚未研究血清一氧化氮 (NO)、NOS 的表达和自噬的参与。在本研究中，我们首先确定乙型肝炎病毒相关 HCC 中的 NO 水平明显高于肝硬化对照组 (53.60±19.74 与 8.09±4.17 μmol/L，t=15.13，P<0.0001)。通过免疫组织化学，我们发现 NO 的来源至少部分归因于肝组织中诱导型 NOS 和内皮型 NOS 的表达，但不是神经元型 NOS。此外，在人肝癌细胞中，NO 诱导细胞凋亡并抑制自噬。自噬的药理学抑制也诱导细胞凋亡，而自噬的诱导可以减轻 NO 诱导的细胞凋亡。我们还发现，NO 通过破坏 Beclin 1/Vps34 相互作用和增加 Bcl-2/Beclin 1 相互作用来调节细胞凋亡和自噬之间的转换。总体而言，这些发现表明，NOS/NO 的增加通过抑制肝癌细胞中的自噬来促进细胞凋亡，这可能为 HCC 的治疗提供新的策略。
