Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Divison of Hematology, Department of Laboratory Sciences, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan.
Cancer Sci. 2021 Jun;112(6):2542-2555. doi: 10.1111/cas.14890. Epub 2021 Apr 7.
We previously indicated that Hodgkin lymphoma (HL) cells contain a small side population (SP) that differentiate into a large major population (MP) with giant Hodgkin and Reed-Sternberg (H and RS)-like cells. However, its molecular mechanisms are not fully understood. In this study, we found that intracellular reactive oxygen species (ROS) are low in the SP compared to the MP. Hydrogen peroxide induces large H- and RS-like cells in HL cell lines, but induces cell death in unrelated lymphoid cell lines. Microarray analyses revealed the enrichment of upregulated genes under hypoxic conditions in the SP compared to the MP, and we verified that the SP cells are hypoxic. Hypoxia inducible factor (HIF)-1α was preferentially expressed in the SP. CoCl , a HIF-1α stabilizer, blunted the effect of hydrogen peroxide. Heme oxygenase-1 (HO-1), a scavenger of ROS, was triggered by HIF-1α. The effect of hydrogen peroxide was inhibited by HO-1 induction, whereas it was promoted by HO-1 knockdown. HO-1 inhibition by zinc protoporphyrin promoted the differentiation and increased ROS. These results stress the unique roles of ROS in the differentiation of HL cells. Immature HL cells are inhibited from differentiation by a reduction of ROS through the induction of HO-1 via HIF-1α. The breakdown of this might cause the accumulation of intracellular ROS, resulting in the promotion of HL cell differentiation.
我们之前曾表明霍奇金淋巴瘤（HL）细胞含有一个小的侧群（SP），该侧群分化为具有巨大霍奇金和里德-斯特恩伯格（H 和 RS）样细胞的大主要群体（MP）。然而，其分子机制尚未完全阐明。在这项研究中，我们发现与 MP 相比，SP 中的细胞内活性氧（ROS）水平较低。过氧化氢可诱导 HL 细胞系中出现大的 H 和 RS 样细胞，但诱导无关淋巴样细胞系死亡。微阵列分析显示，与 MP 相比，SP 中缺氧条件下上调基因的富集，我们验证了 SP 细胞处于缺氧状态。SP 中优先表达缺氧诱导因子（HIF）-1α。CoCl，一种 HIF-1α稳定剂，削弱了过氧化氢的作用。血红素加氧酶-1（HO-1）是 ROS 的清除剂，受 HIF-1α触发。HO-1 诱导可抑制过氧化氢的作用，而 HO-1 敲低则促进其作用。HO-1 抑制剂锌原卟啉 IX 促进分化并增加 ROS。这些结果强调了 ROS 在 HL 细胞分化中的独特作用。ROS 通过诱导 HIF-1α诱导 HO-1 减少，从而抑制不成熟 HL 细胞的分化。这种破坏可能导致细胞内 ROS 的积累，从而促进 HL 细胞的分化。
