The aim of this study was to locate the candidate tumor suppressor genes (TSGs) loci in the chromosomal 4p15-16, 4q22-23 and 4q34-35 regions associated with the development of uterine cervical carcinoma (CA-CX). Deletion mapping of the regions by microsatellite markers identified six discrete areas with high frequency of deletions, viz. 4p16.2 (D1: 40%), 4p15.31 (D2: 35-38%), 4p15.2 (D3: 37-40%), 4q22.2 (D4: 34%), 4q34.2-34.3 (D5: 37-59%) and 4q35.1 (D6: 40-50%). Significant correlation was noted among the deleted regions D1, D2 and D3. The deletions in D1, D2, D5 and D6 regions are suggested to be associated with the cervical intraepithelial neoplasia (CIN), and deletions in the D2, D3, D5 and D6 regions seems to be associated with progression of CA-CX. The deletions in the D2 and D6 regions showed significant prognostic implications (P = 0.001; 0.02). The expression of the candidate TSG SLIT2 mapped to D2 region gradually reduced from normal cervix uteri -->CIN --> CA-CX. SLIT2 promoter hypermethylation was seen in 28% CIN samples and significantly increased with tumor progression (P = 0.04). Significant correlation was seen between SLIT2 deletion and its promoter methylation (P = 0.001), indicating that both these phenomena could occur simultaneously to inactivate this gene. Immunohistochemical analysis showed reduced expression of SLIT2 in cervical lesions and CA-CX cell lines. Although no mutation was detected in the SLIT2 promoter region (-432 to + 55 bp), CC and AA haplotypes were seen in -227 and -195 positions, respectively. Thus, it indicates that inactivation of SLIT2-ROBO1 signaling pathway may have an important role in CA-CX development.

译文

这项研究的目的是在与子宫颈癌 (ca-cx) 发展相关的4p15-16、4q22-23和4q34-35染色体区域中定位候选肿瘤抑制基因 (tsg) 位点。通过微卫星标记对区域进行的缺失映射确定了六个具有高缺失频率的离散区域,即。4p16.2 (D1: 40%),4p15.31 (D2: 35-38%),4p15.2 (D3: 37-40%),4q22.2 (D4: 34%),4q34.2-34.3 (D5: 37-59%) 和4q35.1 (D6: 40-50%)。在删除的区域D1,D2和d3之间注意到显着的相关性。建议D1,D2,D5和D6区域的缺失与宫颈上皮内瘤变 (CIN) 有关,而D2,D3,D5和D6区域的缺失似乎与ca-cx的进展有关。D2和D6区的缺失显示出显著的预后意义 (P = 0.001; 0.02)。定位于D2区域的候选TSG SLIT2的表达从正常宫颈->CIN-> CA-CX逐渐减少。在28% CIN样品中观察到SLIT2启动子高甲基化,并且随着肿瘤进展而显着增加 (P = 0.04)。SLIT2缺失与其启动子甲基化之间存在显著相关性 (P = 0.001),表明这两种现象可以同时发生以使该基因失活。免疫组织化学分析显示,宫颈病变和ca-cx细胞系中SLIT2的表达降低。尽管在SLIT2启动子区域 (-432至 + 55 bp) 中未检测到突变,但在-227和-195位置分别观察到CC和AA单倍型。因此,这表明SLIT2-ROBO1信号通路的失活可能在ca-cx的发育中起重要作用。

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