Alterations of the FHIT gene in human hepatocellular carcinoma.
Alterations of the FHIT gene in human hepatocellular carcinoma.
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DOI：
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发表时间：
2000-02
期刊：
影响因子：
11.2
通讯作者：
Bao-Zhu Yuan;C. Keck-Waggoner;D. Zimonjic;S. Thorgeirsson;N. Popescu
中科院分区：
文献类型：
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作者：
Bao-Zhu Yuan;C. Keck-Waggoner;D. Zimonjic;S. Thorgeirsson;N. Popescu
FHIT（脆弱组氨酸三联体）是一种候选肿瘤抑制基因，包含FRA3B，这是人类基因组中最脆弱的区域，在许多人类癌症中发生改变，特别是那些上皮细胞起源的癌症，并与已知的致癌物质相关。人类肝细胞癌（HCC）是世界范围内的一种主要癌症，它与乙型肝炎和丙型肝炎病毒感染、饮食黄曲霉毒素、饮酒和接触化学致癌物等致癌物密切相关。为了评估FHIT基因改变的程度和性质及其在HCC发展中的意义，我们对几种细胞系和原发肿瘤进行了细胞学和分子检查。FHIT基因在正常肝细胞中表达，在培养的肝癌肿瘤细胞中不表达或异常表达。在14株细胞系中，有9株检测到FHIT基因的下调，但在逆转录pcr产物（2-9外显子）的DNA序列中未发现异常FHIT转录本或点突变。10例原发肿瘤中有5例未检测到FHIT蛋白的表达。Western blot分析显示，4株mRNA下调的细胞株不表达FHIT蛋白。34例原发肿瘤样本中有10例检测到FHIT基因内含子5的等位基因缺失。13株HCC细胞系中有8株存在染色体3p结构改变。利用YAC850A6探针在FHIT基因表达异常细胞系的染色体上跨越FHIT位点，通过荧光原位杂交鉴定涉及3p14.2区域的缺失或易位。这些综合结果表明，FHIT基因是一个常见的靶标，可能与肝癌的一个亚群有关。
FHIT (fragile histidine triad), a candidate tumor suppressor gene, encompasses FRA3B, a region with the highest fragility in the human genome, and is altered in a large number of human cancers, particularly those of epithelial cell origin and associated with known carcinogenic agents. Human hepatocellular carcinoma (HCC), a major cancer worldwide, is closely related to carcinogenic agents such as hepatitis B and C virus infections, dietary aflatoxin, alcohol consumption, and exposure to chemical carcinogens. To assess the extent and the nature of the FHIT gene alterations and their implications in the development of HCC, several cell lines and primary tumors were cytologically and molecularly examined. The FHIT gene is expressed in normal hepatic cells and is not expressed or is abnormally expressed in cultured tumor cells derived from HCC. Down-regulation of the FHIT gene was detected by Northern blot analysis in 9 of 14 cell lines However, neither abnormal FHIT transcripts nor point mutations in DNA sequences of reverse transcription-PCR products (exons 2-9) were identified. Expression of FHIT protein was not detected by immunostaining in 5 of 10 primary tumors. Four cell lines showing mRNA down-regulation did not express FHIT protein as demonstrated by Western blot analysis. Allelic loss of intron 5 of the FHIT gene was detected in 10 of 34 informative samples from primary tumors. Structural alterations of chromosome 3p were identified in 8 of 13 HCC cell lines. Deletions or translocations involving region 3p14.2 were identified by fluorescence in situ hybridization with a YAC850A6 probe spanning the FHIT locus on chromosomes derived from cell lines with an abnormal FHIT gene expression. These combined results indicate that the FHIT gene is a frequent target and may be implicated in a subset of liver cancers.