Open AccessDifferentiation of Hodgkin lymphoma cells by reactive oxygen species and regulation by heme oxygenase‐1 through HIF‐1α
Author(s) -
Nakashima Makoto,
Watanabe Mariko,
Nakano Kazumi,
Uchimaru Kaoru,
Horie Ryouichi
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14890
Subject(s) - heme oxygenase , reactive oxygen species , chemistry , population , microbiology and biotechnology , cell culture , intracellular , cellular differentiation , nadph oxidase , biology , heme , biochemistry , gene , medicine , enzyme , genetics , environmental health
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 2 , 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.