Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis.
Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis.
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DOI：
10.1111/cas.12865
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发表时间：
2016-03
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：
Wang Y;Okazaki Y;Shi L;Kohda H;Tanaka M;Taki K;Nishioka T;Hirayama T;Nagasawa H;Yamashita Y;Toyokuni S
多壁碳纳米管(MWCNT)是一种具有高导电性和导热性的柔性纤维纳米材料。然而，直径50纳米的MWCNT会导致啮齿动物的恶性间皮瘤(MM)，因此，国际癌症研究机构已将其指定为可能的人类致癌物。为了阐明MWCNT在间皮细胞中的致癌机制，我们使用了多种裂解产物来综合鉴定不同直径的原始MWCNT(50 nm，NT50；100 nm，NT100；150 nm，NT150；和15 nm/Tangular，NTtngl)上特异性吸附的蛋白质。我们鉴定了>；400蛋白质，包括血红蛋白、组蛋白、转铁蛋白和各种与氧化应激相关的蛋白质，其中我们选择了血红蛋白和转铁蛋白包被多壁碳纳米管，以进一步评估细胞毒性、伤口愈合、细胞内催化亚铁和大鼠腹膜间皮细胞(RPMC)的氧化应激。NT50对RPMC有明显的细胞毒作用，而NTNTngl对RPMC无细胞毒作用。NT50包被血红蛋白或转铁蛋白后，对RPMC的细胞毒作用明显加重，细胞催化亚铁和DNA损伤也明显增加。用铁蛋白II敲除转铁蛋白受体不仅可以减少NT50的摄取，还可以减少细胞催化亚铁的摄取。我们的结果表明，血红蛋白和转铁蛋白在NT50表面的吸附在导致间皮铁超载，促进氧化损伤和可能随后的间皮细胞癌变中起作用。NT50的摄取至少部分依赖于转铁蛋白受体1。NT50表面的修饰可能会降低这种人类风险。
Multi‐wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50‐nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified >400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.