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Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats.

透闪石诱导的大鼠恶性间皮瘤中Cdkn2a/2b的频繁纯合缺失。

  • 影响因子:4.60
  • DOI:10.1111/cas.14358
  • 作者列表:"Okazaki Y","Misawa N","Akatsuka S","Kohyama N","Sekido Y","Takahashi T","Toyokuni S
  • 发表时间:2020-04-01
Abstract

:The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

摘要

: 恶性间皮瘤 (MM) 的发病与接触石棉纤维有关。石棉纤维被分类为蛇纹石 (温石棉) 或角闪石,其包括青石棉、amosite、花石石、透闪石和阳起石类型。虽然很少进行研究,但已证明花石与间皮瘤有关,而滑石和温石棉中的污染物透闪石是致癌的危险因素。在这里,通过扫描电子显微镜表征这些纤维的长度和宽度后,我们在永生化的人间皮细胞系 (MeT5A) 的细胞中探索了透闪石和花枝石诱导的细胞毒性,鼠巨噬细胞 (RAW264.7),并在大鼠模型中。透射电子显微镜显示,透闪石和短花石纤维被吞噬并定位于液泡,而长花石纤维被捕获在MeT5A和Raw 264.7 细胞的假足上。2 天延时研究的结果显示,透闪石被吞噬并破坏了MeT5A和RAW264.7 细胞,但花枝石对这些细胞没有细胞毒性。大鼠腹腔注射透闪石诱导弥漫性浆膜增厚,而花毛石在腹膜浆膜表面形成局灶性纤维化和肉芽肿。此外,Cdkn2a/2b是人类MM中最常丢失的病灶,通过基于阵列的比较基因组杂交技术在 8 例大鼠MM (纯合缺失 [5/8] 和杂合性缺失 [3/8]) 中观察到。这些结果表明,透闪石引发间皮损伤并持续阻碍吞噬细胞,引起随后的腹膜纤维化和MM。讨论了基于纤维直径/长度的致癌性的可能机制。

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影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

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翻译标题与摘要 下载文献
影响因子:6.93
发表时间:2020-01-01
DOI:10.1002/ijc.32530
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肺肿瘤方向

肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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