Increased Tissue Factor Expression Is Associated with Reduced Survival in Non-Small Cell Lung Cancer and with Mutations of TP53 and PTEN
Increased Tissue Factor Expression Is Associated with Reduced Survival in Non-Small Cell Lung Cancer and with Mutations of TP53 and PTEN
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DOI：
10.1373/clinchem.2009.123695
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发表时间：
2009-10-01
影响因子：
9.3
通讯作者：
Gruel, Yves
中科院分区：
文献类型：
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作者：
Regina, Sandra;Valentin, Jean-Baptiste;Gruel, Yves
背景：组织因子是凝血的主要起始物，也是调节肿瘤进展的信号蛋白。近来发现肿瘤细胞系中的肿瘤抑制基因(TSG)会影响TF的合成。因此，我们研究了Tf基因(F3)在非小细胞肺癌(NSCLC)中的表达及其编码肿瘤蛋白P53(TP53)、磷酸酶和紧张素同源物(PTEN)以及丝氨酸/苏氨酸激酶11(STK11)基因的状态。肝素酶(HPSE)的基因表达也被检测，因为这种内切的-β-D-葡萄糖醛酸苷酶最近被发现增强了TF基因的表达。方法：用实时定量聚合酶链式反应检测53例NSCLC肿瘤组织中TF和乙酰肝素酶基因的表达。从基因组DNA中测定了TP53基因的第5-8外显子。结果：PTEN和STK11基因在T-3~T-4肿瘤组织中的表达显著高于非小细胞肺癌组织(P=0.04)，在NSCLC的III~IV期(P=0.03)。TP53、STK11和PTEN基因突变分别在20例(37.7%)、21例(39%)和20例(37.7%)肿瘤中检出。突变的TP53(TP53(Mut))(P=0.02)和PTENMut(P=0.03)组织中Tf的表达较高。此外，当3个TSG突变时，TFm RNA从2700拷贝(未突变)增加到116415。肝素酶基因的表达与Tf基因(F3)表达或Tsg突变无明显差异。肿瘤组织转铁蛋白基因表达水平高于中位数(相对危险度2.2；P=0.03，多因素分析)和TP53基因突变患者的中位生存期较短(相对危险度1.8；P=0.02)。结论：这些结果提供了明确的证据，表明联合影响TSG的癌基因事件显著增加了肺癌组织中转铁蛋白基因的表达。此外，本研究提示，TF基因的表达可作为非小细胞肺癌的预后指标。(C)2009年美国临床化学协会
BACKGROUND: Tissue factor (TF), the main initiator of blood coagulation, is also a signaling protein that regulates cancer progression. TF synthesis was recently shown to be affected by tumor suppressor genes (TSGs) in tumor cell lines. We therefore studied TF gene (F3) expression and the status of genes coding for tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and serine/threonine kinase 11 (STK11) in non-small cell lung cancer (NSCLC). Heparanase (HPSE) gene expression was also measured because this endo-beta-D-glucuronidase was recently shown to enhance TF gene expression.METHODS: TF and heparanase mRNA expression was measured by real-time PCR in 53 NSCLC tumors. Exons 5-8 of TP53 were sequenced from genomic DNA. Mutations of PTEN and STK11 were screened by multiplex ligation-dependent probe amplification.RESULTS: TF mRNA levels were significantly higher in T-3-T-4 tumors (P = 0.04) and in stages III-IV of NSCLC (P = 0.03). Mutations of TP53, STK11, and PTEN were identified in 20 (37.7%), 21 (39%), and 20 (37.7%) of tumors, respectively. TF expression was higher in mutated TP53 (TP53(Mut)) (P = 0.02) and PTENMut (P = 0.03) samples. Moreover, TF mRNA increased from 2700 copies (no mutation) to 116415 when 3 TSG were mutated. Heparanase gene expression did not differ according to TF gene (F3) expression or TSG mutation. The median survival time was shorter in patients with tumor TF mRNA levels above median values (relative risk 2.2; P = 0.03, multivariate analysis) and when TP53 was mutated (relative risk 1.8; P = 0.02).CONCLUSIONS: These results provide clear evidence that combined oncogene events affecting TSG dramatically increase TF gene expression in lung tumors. Moreover, this study suggests that TF gene expression could be used as a prognostic marker in NSCLC. (C) 2009 American Association for Clinical Chemistry