研究者詳細 - 豊國　伸哉

BRCA1のハプロ不全は発がん過程において、フェロトーシス抵抗性を獲得することにより染色体増幅を促進する(BRCA1 haploinsufficiency promotes carcinogenic chromosomal amplification by ferroptosis-resistance) 査読有り国際誌

プラズマ活性化された乳酸リンゲルに誘導されたフェロトーシスにおけるpcbp1/2とグルタチオンとの協同作用(Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasma-activated Ringer's Lactate)

鄭好, 蒋麗, 呂沁穎, 赤塚慎也, 本岡大社, 関戸好孝, 中村香江, 田中宏昌, 石川健治, 梶山広明, 水野正明, 堀勝, 豊國伸哉

日本癌学会総会記事 81回巻頁： E - 2004 2022年9月

個別化予防医療・先制医療 BRCA1のハプロ不全は、腎臓発がん過程において、フェロトーシス抵抗性を獲得することにより染色体増幅を促進する(BRCA1 haploinsufficiency promotes chromosomal amplification under renal carcinogenesis through ferroptosis-resistance)

孔穎怡, 赤塚慎也, 本岡大社, 鄭好, 白木之浩, 真下知士, 今岡達彦, 豊國伸哉

日本癌学会総会記事 81回巻頁： S20 - 7 2022年9月

環境因子であるタルクおよびアスベストの卵巣発がん性とゲノム毒性の検討(Carcinogenic genome toxicity of environmental factors, asbestos and talc in ovary)

本岡大社, 鬼丸洸, 鈴木洋, 片渕充沙子, 近藤英治, 田代浩徳, 片渕秀隆, 豊國伸哉

日本癌学会総会記事 81回巻頁： P - 2007 2022年9月

孔穎怡, 赤塚慎也, 本岡大社, 鄭好, 白木之浩, 真下知士, 今岡達彦, 豊國伸哉

Biomedical Research on Trace Elements 33 巻 ( 1 ) 頁： 130 - 130 2022年9月

孔穎怡, 赤塚慎也, 本岡大社, 鄭好, 白木之浩, 真下知士, 今岡達彦, 豊國伸哉

日本癌学会総会記事 81回巻頁： S20 - 7 2022年9月

Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers. 査読有り国際誌 Open Access

Soyama H, Nishio M, Otani J, Sakuma T, Takao S, Hara S, Masuda T, Mimori K, Toyokuni S, Lydon JP, Nakao K, Nishina H, Fukumoto T, Maehama T, Suzuki A

Proceedings of the National Academy of Sciences of the United States of America 119 巻 ( 29 ) 頁： e2123134119 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America

Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yes-associated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor+ luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents.

DOI： 10.1073/pnas.2123134119

Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells. 査読有り国際誌 Open Access

Igarashi N, Miyata K, Loo TM, Chiba M, Hanyu A, Nishio M, Kawasaki H, Zheng H, Toyokuni S, Kon S, Moriyama K, Fujita Y, Takahashi A

Nature communications 13 巻 ( 1 ) 頁： 4157 - 4157 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

Cellular senescence and cell competition are important tumor suppression mechanisms that restrain cells with oncogenic mutations at the initial stage of cancer development. However, the link between cellular senescence and cell competition remains unclear. Senescent cells accumulated during the in vivo aging process contribute toward age-related cancers via the development of senescence-associated secretory phenotype (SASP). Here, we report that hepatocyte growth factor (HGF), a SASP factor, inhibits apical extrusion and promotes basal protrusion of Ras-mutated cells in the cell competition assay. Additionally, cellular senescence induced by a high-fat diet promotes the survival of cells with oncogenic mutations, whereas crizotinib, an inhibitor of HGF signaling, provokes the removal of mutated cells from mouse livers and intestines. Our study provides evidence that cellular senescence inhibits cell competition-mediated elimination of oncogenic cells through HGF signaling, suggesting that it may lead to cancer incidence during aging.

DOI： 10.1038/s41467-022-31642-4

Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. 国際誌 Open Access

Murphy MP, Bayir H, Belousov V, Chang CJ, Davies KJA, Davies MJ, Dick TP, Finkel T, Forman HJ, Janssen-Heininger Y, Gems D, Kagan VE, Kalyanaraman B, Larsson NG, Milne GL, Nyström T, Poulsen HE, Radi R, Van Remmen H, Schumacker PT, Thornalley PJ, Toyokuni S, Winterbourn CC, Yin H, Halliwell B

Nature metabolism 4 巻 ( 6 ) 頁： 651 - 662 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Metabolism

Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo.

DOI： 10.1038/s42255-022-00591-z

Cytotoxicity of plasma-irradiated lactate solution produced under atmospheric airtight conditions and generation of the methyl amino group 査読有り国際誌

Ito D., Iwata N., Ishikawa K., Nakamura K., Hashizume H., Miron C., Tanaka H., Kajiyama H., Toyokuni S., Mizuno M., Hori M.

Applied Physics Express 15 巻 ( 5 ) 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Applied Physics Express

Ringer's lactate solution was irradiated with non-equilibrium plasma under airtight conditions. The plasma-activated lactate (PAL) was produced with argon, oxygen, and nitrogen gases following purging of Ar. Cytotoxicity could be controlled by diluting PAL, and a killing effect was selectively obtained on cancer cells compared to normal cells for Ar+O2+N2 PALs. Nonetheless, cytotoxicity was partly reproduced by similar concentrations of H2O2 and NO2- in the PALs. The organics produced by plasma irradiation to lactate were investigated using nuclear magnetic resonance, and the generation of methyl amino species was confirmed.

DOI： 10.35848/1882-0786/ac6360

Web of Science

PCBP2 knockdown promotes ferroptosis in malignant mesothelioma. 査読有り国際誌 Open Access

Yue L, Luo Y, Jiang L, Sekido Y, Toyokuni S

Pathology international 72 巻 ( 4 ) 頁： 242 - 251 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pathology International

Malignant mesothelioma (MM) is still increasing worldwide. The pathogenesis depends on asbestos-induced iron accumulation, which eventually leads to ferroptosis-resistance of mesothelial cells via somatic mutations. Poly (rC)-binding proteins 1 and 2 (PCBP1/2) are recently recognized cytosolic Fe(II) chaperones. Here we studied the role of PCBP1/2 in rat/human mesothelial and MM cells as well as rat/human MM specimens. Normal peritoneal mesothelial cells in rats exhibited PCBP1 but not PCBP2 immunopositivity whereas primary/immortalized mesothelial cells showed PCBP1/2 immunopositivity. Rat MM specimens induced by intraperitoneal injection of chrysotile, including in situ lesion, revealed PCBP1/2 immunopositivity (90% for both) in the nucleus and cytoplasm with a tendency of higher expression in epithelioid subtype. Knockdown of PCBP2 but not PCBP1 significantly decreased both TfR1 and FTH expression in MM cells with inhibition of proliferation, indicating stagnation of intracellular iron transport. Erastin, a cysteine-deprivation type ferroptosis inducer, decreased the expression of both PCBP1/2 in MM cells. Furthermore, PCBP2 knockdown significantly increased the sensitivity of MM cells to erastin-induced ferroptosis with increased catalytic Fe(II). In conclusion, PCBP2 works for ferroptosis-resistance not only during mesothelial carcinogenesis but also in MM, which warrants further investigation as a novel therapeutic target.

DOI： 10.1111/pin.13209

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

Editorial: Centennial anniversary of vitamin E discovery. 査読有り国際誌 Open Access

Toyokuni S, Noguchi N, Niki E

Free radical biology & medicine 183 巻頁： 125 - 126 2022年4月

タルクは曝露卵巣に鉄過剰状態とフェロトーシス抵抗性を誘導し発がんに関わる

井上陽太, 本岡大社, 豊國伸哉

日本病理学会会誌 111 巻 ( 1 ) 頁： 353 - 353 2022年3月

アスベストはヘモグロビンを吸着し卵巣表層上皮に鉄過剰状態を形成することで卵巣がん形成に関わる

本岡大社, 豊國伸哉

日本病理学会会誌 111 巻 ( 1 ) 頁： 249 - 249 2022年3月

Sato Yuki, Oguchi Akiko, Fukushima Yuji, Masuda Kyoko, Toriu Naoya, Taniguchi Keisuke, Yoshikawa Takahisa, Cui Xiaotong, Kondo Makiko, Hosoi Takeshi, Komidori Shota, Shimizu Yoko, Fujita Harumi, Jiang Li, Kong Yingyi, Yamanashi Takashi, Seita Jun, Yamamoto Takuya, Toyokuni Shinya, Hamazaki Yoko, Hattori Masakazu, Yoshikai Yasunobu, Boor Peter, Floege Jürgen, Kawamoto Hiroshi, Murakawa Yasuhiro, Minato Nagahiro, Yanagita Motoko

Journal of Clinical Investigation 132 巻 ( 2 ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153⁺PD-1⁺CD4⁺ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL21 and IFNγ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153-CD30 signaling in TLT formation and propose targeting CD153-CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. 国際誌

Sato Y, Oguchi A, Fukushima Y, Masuda K, Toriu N, Taniguchi K, Yoshikawa T, Cui X, Kondo M, Hosoi T, Komidori S, Shimizu Y, Fujita H, Jiang L, Kong Y, Yamanashi T, Seita J, Yamamoto T, Toyokuni S, Hamazaki Y, Hattori M, Yoshikai Y, Boor P, Floege J, Kawamoto H, Murakawa Y, Minato N, Yanagita M

The Journal of clinical investigation 132 巻 ( 2 ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Investigation

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

DOI： 10.1172/JCI146071

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

Journal of Clinical Investigation 132 巻 ( 2 ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis. 査読有り国際誌 Open Access

Cheng Z, Akatsuka S, Li GH, Mori K, Takahashi T, Toyokuni S

Cancer science 113 巻 ( 1 ) 頁： 65 - 78 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe-NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe-NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter-strain difference in the susceptibility to Fe-NTA-induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe-NTA-induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe-NTA treatment. After 3-week Fe-NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe-NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin-2. Lipocalin-2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe-NTA-induced RCC in A/J strain.

DOI： 10.1111/cas.15175

Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma 査読有り国際誌 Open Access

Tanaka H., Matsumura S., Ishikawa K., Hashizume H., Ito M., Nakamura K., Kajiyama H., Kikkawa F., Ito M., Ohno K., Okazaki Y., Toyokuni S., Mizuno M., Hori M.

Japanese Journal of Applied Physics 61 巻 ( SA ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Applied Physics

Ethanol production by budding yeast was compared between direct and indirect plasma irradiation. We observed enhancement of ethanol production and cell growth not by indirect plasma irradiation but by direct plasma irradiation. Glucose consumption was increased in budding yeast by direct plasma irradiation. Extracellular flux analysis revealed that glycolytic activity in the budding yeast was elevated by direct plasma irradiation. These results suggest that direct plasma irradiation enhances ethanol production in budding yeast by elevating the glycolytic activity.

DOI： 10.35848/1347-4065/ac2037