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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Chromosome 14 transfer and functional studies identify a candidate tumor suppressor gene, Mirror image polydactyly 1, in nasopharyngeal carcinoma
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Chromosome 14 transfer and functional studies identify a candidate tumor suppressor gene, Mirror image polydactyly 1, in nasopharyngeal carcinoma

机译：染色体14的转移和功能研究确定了鼻咽癌的候选抑癌基因多镜像1

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摘要

Chromosome 14 allelic loss is common in nasopharyngeal carcinoma (NPC) and may reflect essential tumor suppressor gene loss in tumor-igenesis. An intact chromosome 14 was transferred to an NPC cell line using a microcell-mediated chromosome transfer approach. Microcell hybrids (MCHs) containing intact exogenously transferred chromosome 14 were tumor suppressive in athymic mice, demonstrating that intact chromosome 14 NPC MCHs are able to suppress tumor growth in mice. Comparative analysis of these MCHs and their derived tumor segregants identified 4 commonly eliminated tumor-suppressive CRs. Here we provide functional evidence that a gene, Mirror-Image POLydactyly 1 (MIPOL1), which maps within a single 14q13.1-13.3 CR and that hitherto has been reported to be associated only with a developmental disorder, specifically suppresses in vivo tumor formation. MIPOL1 gene expression is down-regulated in all NPC cell lines and in ≈63% of NPC tumors via promoter hypermethylation and allelic loss. SLC2SA21 and FOXA1, 2 neighboring genes mapping to this region, did not show this frequent down-regulated gene expression or promoter hypermethylation, precluding possible global meth-ylation effects and providing further evidence that MIPOL1 plays a unique role in NPC. The protein localizes mainly to the nucleus. Re-expression of MIPOL1 in the stable transfectants induces cell cycle arrest. MIPOL1 tumor suppression is related to up-regulation of the p21(WAF1/CIP1) and p27(KIP1) protein pathways. This study provides compelling evidence that chromosome 14 harbors tumor suppressor genes associated with NPC and that a candidate gene, MIPOL1, is associated with tumor development.
机译：染色体14等位基因缺失在鼻咽癌（NPC）中很常见，并且可能反映了肿瘤发生过程中必需的抑癌基因缺失。使用微细胞介导的染色体转移方法将完整的染色体14转移到NPC细胞系。含有完整的外源转移的14号染色体的微细胞杂种（MCH）在无胸腺小鼠中具有抑癌作用，表明完整的14号染色体NPC MCH能够抑制小鼠中的肿瘤生长。这些MCHs及其衍生的肿瘤分离子的比较分析确定了4个通常消除的肿瘤抑制CR。在这里，我们提供功能性证据，即在单个14q13.1-13.3 CR中作图的Mirror-Image POLydactyly 1基因（MIPOL1），迄今已报道仅与发育障碍有关，特别抑制了体内肿瘤的形成。通过启动子高度甲基化和等位基因缺失，所有NPC细胞系和≈63％的NPC肿瘤中的MIPOL1基因表达均下调。 SLC2SA21和FOXA1是2个映射到该区域的邻近基因，未显示出这种频繁下调的基因表达或启动子过度甲基化，从而排除了可能的整体甲基化作用，并进一步提供了MIPOL1在NPC中发挥独特作用的证据。该蛋白质主要定位于细胞核。 MIPOL1在稳定转染子中的重新表达诱导细胞周期停滞。 MIPOL1肿瘤抑制与p21（WAF1 / CIP1）和p27（KIP1）蛋白途径的上调有关。这项研究提供了令人信服的证据，即第14号染色体带有与NPC相关的抑癌基因，而候选基因MIPOL1与肿瘤的发展有关。

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    Arthur Kwok Leung Cheung; Hong Lok Lung; Josephine Mun Yee Ko; Yue Cheng; Eric J. Stanbridge; Eugene R. Zabarovsky; John M. Nicholls; Daniel Chua; Sai Wah Tsao; Xin-Yuan Guan; Maria Li Lung;

  • 作者单位

    Department of Biology and Center for Cancer Research, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (SAR), People's Republic of China;

    Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

    Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

    Department of Biology and Center for Cancer Research, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (SAR), People's Republic of China Department of Biology, City of Hope, Beckman Research Institute, Duarte, CA 91010;

    Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697;

    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden;

    Departments of Pathology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

    Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

    Departments of Anatomy, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

    Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

    Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    microcell-mediated chromosome transfer; MIPOL1; cell cycle arrest; promoter hypermethylation;

    机译：微细胞介导的染色体转移;MIPOL1;细胞周期停滞;启动子高甲基化;

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