Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis.
Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis.
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DOI：
10.1111/cas.15175
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发表时间：
2022-01
期刊：
影响因子：
5.7
通讯作者：
Toyokuni S
中科院分区：
文献类型：
--
作者：
Cheng Z;Akatsuka S;Li GH;Mori K;Takahashi T;Toyokuni S
癌症易感性是理解癌症发生的关键因素。腹膜内（i. p.）注射铁螯合物，次氮基三乙酸铁（Fe-NTA），通过芬顿反应产生羟基自由基，以诱导肾近端小管中的铁凋亡。重复腹膜内注射Fe-NTA的大鼠或小鼠发生肾细胞癌（RCC）。为了阐明导致对肾癌发生易感性的分子机制，我们首先在小鼠中建立了对Fe-NTA诱导的肾癌发生易感性的品系间差异。基于先前在C57 BL/6 J品系小鼠中观察到该模型的RCC发生率较低，我们在此研究了A/J品系小鼠，其表现出对Fe-NTA诱导的肾癌发生的显著更高的易感性。首次在A/J系小鼠中检测到Cdkn 2a/2b肿瘤抑制基因位点的纯合性缺失。我们以铁凋亡和铁代谢为重点，探讨了导致肾细胞癌发生差异的机制。我们比较了Fe-NTA处理后A/J和C57 BL/6 J菌株的肾脏中的保护性应答。在3周的Fe-NTA治疗后，A/J小鼠保持了较高水平的谷胱甘肽过氧化物酶4和xCT（SLC 7A 11）表达，导致脂质过氧化水平较低。同时，A/J小鼠的转铁蛋白受体的表达降低，铁蛋白的表达增加到更大的程度比C57 BL/6小鼠。在单次Fe-NTA注射后，在C57 BL/6 J小鼠中观察到更高水平的氧化性细胞损伤和细胞溶质催化Fe（II），伴随着脂质运载蛋白-2的更大增加。脂质运载蛋白-2缺乏显著降低氧化性肾损伤。我们的研究结果表明，有利于铁凋亡抗性的遗传性状有助于A/J菌株对Fe-NTA-诱导的RCC的高易感性。在考虑癌症预防时，癌症易感性是一个重要问题。在本文中，我们使用了铁介导的氧化应激诱导的小鼠肾癌发生模型，发现铁凋亡抵抗是决定癌症易感性的重要因素。
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. Cancer susceptibility is an important issue when considering cancer prevention. In this paper, we used an iron‐mediated oxidative stress‐induced renal carcinogenesis model in mice and found that ferroptosis resistance is an important factor determining cancer susceptibility.
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