RBSP3 Is Frequently Altered in Premalignant Cervical Lesions: Clinical and Prognostic Significance
RBSP3 Is Frequently Altered in Premalignant Cervical Lesions: Clinical and Prognostic Significance
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DOI：
10.1002/gcc.20726
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发表时间：
2010-02-01
影响因子：
3.7
通讯作者：
Panda, Chinmay K.
中科院分区：
文献类型：
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作者：
Mitra, Sraboni;Indra, Dipanjana Mazumder;Panda, Chinmay K.
为了了解 3p22.3 频繁缺失在宫颈癌发生中的重要性，我们对 24 个宫颈上皮内瘤变 (CIN) 和 137 个宫颈癌 (CACX) 样本中位于该区域的候选基因 STAC、MLH1、ITGA9 和 RBSP3 的改变（缺失/甲基化/表达）进行了分析。在 CIN 中，与其他基因 (4-9%) 相比，RBSP3 缺失 (48%) 和甲基化 (26%) 较高。在CACX中，这些基因的改变如下：缺失：STAC（54％）> MLH1（46％）> RBSP3（45％）> ITGA9（41％），甲基化：RBSP3（25％）> ITGA9（24％）> STAC（19％）> MLH1（13％）。总体而言，RBSP3 的改变显示与 CIN 相关，而对于 STAC 和 MLH1，该频率从 CIN -> I/II 期显着增加，而 ITGA9 从 CIN -> I/II 期以及 I/II 期 -> III/IV 期显着增加。定量 mRNA 表达分析显示，CACX 中这些基因的表达差异降低，与其分子变化一致。更活跃的 RBSP3B 剪接变体在 CACX 中表达不足。 CACX 中 RBI 很少被删除 (i) RBSP3 失活和强烈的 p-RBI 核免疫染色和 (ii) CACX 中 MLH1 表达低/缺失及其分子改变之间存在一致性。 在正常宫颈上皮中，分化细胞中 p-RBI 免疫染色较低，而细胞核和细胞质中均可见 MLH1 染色 与分化阶段无关。基因的改变与不良预后显着相关。高胎次（>= 5）/早期性行为首次亮相（
To understand the importance of frequent deletion of 3p22.3 in cervical carcinogenesis, alterations (deletion/methylation/expression) of the candidate genes STAC, MLH1, ITGA9, and RBSP3, located in the region, were analyzed in 24 cervical intraepithelial neoplasia (CIN) and 137 uterine cervical carcinoma (CACX) samples. In CIN, RBSP3 deletion (48%) and methylation (26%) were high compared with the other genes (4-9%). In CACX, alterations of these genes were as follows: deletion: STAC (54%) > MLH1 (46%) > RBSP3 (45%) > ITGA9 (41%), methylation: RBSP3 (25%) > ITGA9 (24%) > STAC (19%) > MLH1 (13%). Overall, alterations of RBSP3 showed association with CIN, whereas for STAC and MLH1, this frequency increased significantly from CIN -> Stage I/II and for ITGA9 from CIN -> Stage I/II and also from Stage I/II -> Stage III/IV. Quantitative mRNA expression analysis showed differential reduced expression of these genes in CACX concordant to their molecular alterations. The more active RBSP3B splice variant was underexpressed in CACX. RBI was infrequently deleted in CACX Concordance was seen between (i) inactivation of RBSP3 and intense p-RBI nuclear immunostaining and (ii) low/absence of MLH1 expression and its molecular alterations in CACX In normal cervical epithelium, p-RBI immunostaining was low in differentiated cells, whereas MLH1 staining was seen in both nucleus and cytoplasm irrespective of differentiation stage. Alterations of the genes were significantly associated with poor prognosis. High parity (>= 5)/early sexual debut (