Loss of Fragile Histidine Triad Gene Expression in Advanced Lung Cancer Is Consequent to Allelic Loss at 3p14 Locus and Promoter Methylation
Loss of Fragile Histidine Triad Gene Expression in Advanced Lung Cancer Is Consequent to Allelic Loss at 3p14 Locus and Promoter Methylation
复制标题
晚期肺癌中脆性组氨酸三联体基因表达的丧失是 3p14 位点和启动子甲基化等位基因丢失的结果
作者：
Anjilna Wali;R. Srinivasan;Mir Snober Shabnam;S. Majumdar;K. Joshi;D. Behera
位于3p14.2位点的脆性组氨酸三联体(FHIT)基因在肺癌的发病机制中起重要作用。本研究的目的是分析杂合性缺失和FHIT基因甲基化状态，并分析它们与FHIT表达的相关性。对30例组织学证实为III期肺癌患者的支气管镜下肺活检标本进行了FHIT基因改变的评估。免疫组织化学方法检测FHIT蛋白表达，逆转录-聚合酶链式反应(RT-PCR)检测FHIT蛋白转录水平。用聚合酶链式反应检测FHIT基因启动子的微卫星改变和甲基化状态。至少通过3个微卫星多态标记中的一个，所有30例患者均观察到3p14位点杂合性缺失。FHIT基因启动子完全甲基化占37%，部分甲基化占47%，无启动子甲基化的占16%。FHIT全长编码区(外显子5~9)转录本8例(26.6%)，异常转录本4例。FHIT基因表达缺失与FHIT启动子甲基化有关，但与3p14位点杂合性缺失无关。FHIT在转录本和蛋白水平的表达具有很强的相关性。末端脱氧核苷酸转移酶介导的缺口末端标记法测定的细胞凋亡指数与FHIT蛋白的表达显著相关。本研究结果表明，在局部晚期肺癌中，FHIT表达经常缺失，而FHIT基因启动子甲基化是其失活的重要机制。(摩尔癌症研究2006；4(2)：93-9)
The fragile histidine triad (FHIT) gene located at the 3p14.2 locus plays an important role in the pathogenesis of lung cancer. The objective of this study was to analyze loss of heterozygosity and FHIT gene methylation status and correlate them to fhit expression. Bronchoscopically obtained lung biopsies from 30 cases of histologically proven carcinoma of the lung in stage III were assessed for the alterations in the FHIT gene. Fhit protein expression was determined by immunohistochemistry, and transcript levels were determined by reverse transcription-PCR. Microsattelite alterations and methylation status of the Fhit gene promoter was determined by PCR. Loss of heterozygosity at the 3p14 locus was observed in all the 30 cases at least by one of the three microsatellite polymorphic markers. The FHIT gene promoter showed complete methylation in 37% cases and partial methylation in 47% cases, and 16% cases showed no promoter methylation. FHIT full-length coding region (exons 5-9) transcripts were present in eight cases (26.6%), and aberrant transcripts were additionally seen in four cases. Loss of FHIT mRNA expression correlated to FHIT promoter methylation but not to loss of heterozygosity at the 3p14 locus. There was a strong correlation between the expression of FHIT at the transcript and protein level. The apoptotic index estimated by the terminal deoxynucleotidyl transferase–mediated nick end labeling assay was significantly correlated to the fhit protein expression. The results of this study indicate that in locally advanced carcinoma of the lung, there is frequent loss of FHIT expression, and methylation of the FHIT gene promoter is an important mechanism of its inactivation. (Mol Cancer Res 2006;4(2):93–9)
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
许多非小细胞肺癌中微卫星序列的遗传不稳定性。
影响因子：
11.2
作者：
Shridhar,V;Siegfried,J;Hunt,J;delMarAlonso,M;Smith,DI
通讯作者：
Smith,DI
DOI：
10.1016/s0169-5002(97)80271-1
发表时间：
1997-08
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
I. Wistuba;S. Lam;C. Behrens;A. Virmani;K. Fong;J. Leriche;J. Samet;S. Srivastava;J. Minna;A. Gazdar
通讯作者：
I. Wistuba;S. Lam;C. Behrens;A. Virmani;K. Fong;J. Leriche;J. Samet;S. Srivastava;J. Minna;A. Gazdar
通过肿瘤细胞系中的纯合缺失鉴定出 3p14.2 FRA3B 位点的潜在胃肠道肿瘤抑制基因座。
影响因子：
11.2
作者：
Kastury,K;Baffa,R;Druck,T;Ohta,M;Cotticelli,MG;Inoue,H;Negrini,M;Rugge,M;Huang,D;Croce,CM;Palazzo,J;Huebner,K
通讯作者：
Huebner,K
影响因子：
2.9
作者：
Barnes, LD;Garrison, PN;Huebner, F
通讯作者：
Huebner, F