Nrf3 Functions Reversely as a Tumorigenic to an Antitumorigenic Transcription Factor in Obese Mice

Nrf3 Functions Reversely as a Tumorigenic to an Antitumorigenic Transcription Factor in Obese Mice

Tsuyoshi Waku,¹ Takuya Iwami,¹ Haruka Masuda,² Shuuhei Hirose,^2,3 Iori Aketa² and Akira Kobayashi^1,2

¹Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
²Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
³Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan

Tumor tissue includes cancer cells and their associated stromal cells, such as adipocytes, myocytes, and immune cells. Obesity modulates tumor microenvironment through the secretion of several inflammatory mediators by inducing adipogenesis and myogenesis. Previously, we indicated that tumor growth is promoted by a transcription factor nuclear factor erythroid 2-related factor 3 (NRF3) in human cancer cells. However, the impact of obesity on NRF3-mediated tumorigenesis remains unknown. Here we show that obesity reprograms the tumorigenic to the antitumorigenic function of Nrf3 using a diet-induced obese mouse model. Nrf3 knockdown decreased tumor growth in mice fed a normal diet (ND), whereas it reversely increased tumor growth in mice fed a high-fat diet (HFD). Then, the tumor tissues derived from Nrf3 knockdown or control cancer cells in ND- or HFD-fed mice were subjected to a DNA microarray-based analysis. Similar to the tumor formation results, the expressions of genes related to adipogenesis, myogenesis, and interferon-alpha response were reversed by obesity, implying an increase or recruitment (or both combined) of adipocytes, myocytes, and immune cells. Among these gene sets, we focused on adipocytes. We showed that Nrf3 knockdown reduced cancer cell growth in the preadipocyte culture medium, while the growth inhibitory effect of Nrf3 knockdown on cancer cells was abolished in the adipocyte culture medium. These results suggest the possibility that cancer-associated adipocytes secrete the potential reprogramming factor from the tumorigenic to the antitumorigenic function of Nrf3 in cancer cells.

Keywords —— adipogenesis; Nrf3; obesity; tumor growth; tumor microenvironment

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Tohoku J. Exp. Med 2023, 259, 1-8.

Correspondence: Akira Kobayashi, Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.

e-mail: akobayas@mail.doshisha.ac.jp