Amplification of CyclinL1 in Uterine Cervical Carcinoma Has Prognostic Implications
Amplification of CyclinL1 in Uterine Cervical Carcinoma Has Prognostic Implications
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DOI：
10.1002/mc.20671
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发表时间：
2010-11-01
影响因子：
4.6
通讯作者：
Panda, Chinmay K.
中科院分区：
文献类型：
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作者：
Mitra, Sraboni;Mazumder (Indra), Dipanjana;Panda, Chinmay K.
染色体3q25.31区域在原发性宫颈癌（CACX）中持续扩增。CyclinL1是该区域的候选基因，并且已经被认为是头颈癌中的癌基因。在这项研究中，我们的目的是探讨细胞周期蛋白L1在宫颈癌发生的参与，并为此目的，其拷贝数变异（CNV）在23宫颈上皮内瘤样病变（CIN）和110 CACX样本进行了研究。在CIN病变中，CyclinL1未扩增;然而，在I/II期肿瘤中扩增频率为16%（9/56），在肿瘤发生的后续阶段中保持可比性。这意味着CyclinL1扩增与早期侵袭性的发展有关。mRNA表达定量显示，该基因在原发性CACX中过表达2.6 +/-1.53倍。在肿瘤中，CyclinL1的扩增/拷贝数增加及其mRNA谱是一致的。免疫组织化学（IHC）分析显示，在原代CACX细胞系SiHa和HeLa中，cyclinL1在细胞核内有强表达，Western blot进一步证实了这一点。而47%（7/15）的CACX表达高/中等水平的cyclin L1。Kaplan-Meier生存分析表明CyclinL1扩增是患者预后不良的决定因素。肿瘤的放射抵抗性发展的结果CyclinL1扩增。考克斯多因素分析显示，经产（≥ 5）的CACX患者中，CyclinL1基因沿着扩增，且肿瘤分期为III/IV期者预后最差。我们的数据表明CyclinL1在宫颈癌发生中的重要性及其相关途径，即：前体mRNA剪接，细胞周期调节（G（0）/G（1）和G（2）/M）是CACX治疗干预的潜在靶点。(C)2010 Wiley-Liss，Inc.
The chromosomal 3q25.31 region was consistently amplified in primary cancer of cervix (CACX). CyclinL1 is a candidate gene of this region and already have been implicated as an oncogene in head and neck cancers. In this study, we aimed to investigate the involvement of CyclinL1 in cervical carcinogenesis and for this purpose its copy number variation (CNV) was studied in 23 cervical intraepithelial neoplasia (CIN) and 110 CACX samples. In CIN lesions CyclinL1 was not amplified; however, the amplification frequency was 16% (9/56) in stage I/II tumors which remained comparable during subsequent stages of tumorigenesis. This implied association of CyclinL1 amplification with development of early invasiveness. Quantitation of mRNA expression revealed 2.6 +/- 1.53-fold overexpression of this gene in primary CACX. The amplification/copy number gain of CyclinL1 and its mRNA profile were concordant, in tumors. Immunohistochemical (IHC) analysis in primary CACX, cell lines: SiHa and HeLa revealed intense nuclear expression of cyclinL1, which was further confirmed by Western blot in the cell lines. However 47% (7/15) CACX samples expressed high/intermediate level of cyclin L1. Kaplan-Meier survival analysis indicated CyclinL1 amplification as a determinant of poor patient outcome. Tumor radio-resistance developed as a consequence of CyclinL1 amplification. Cox multivariate analysis revealed that multiparous (>= 5) CACX patients with amplified CyclinL1 locus along with advanced tumor stage (III/IV) had worst prognosis. Our data suggest importance of CyclinL1 in cervical carcinogenesis with its associated pathways viz: pre-mRNA splicing, cell-cycle regulation (G(0)/G(1) and G(2)/M) being potential targets of therapeutic interventions in CACX. (C) 2010 Wiley-Liss, Inc.