Rosty Christophe, Sheffer Michal, Tsafrir Dafna, Stransky Nicolas, Tsafrir Ilan, Peter Martine, de Crémoux Patricia, de La Rochefordière Anne, Salmon Rémy, Dorval Thierry, Thiery Jean Paul, Couturier Jérôme, Radvanyi François, Domany Eytan, Sastre-Garau Xavier
Département de Biologie des Tumeurs, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Oncogene. 2005 Oct 27;24(47):7094-104. doi: 10.1038/sj.onc.1208854.
Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a 'cervical cancer proliferation cluster' composed of 163 highly correlated transcripts. Most of these transcripts corresponded to E2F pathway genes controlling cell division or proliferation, whereas none was known as TP53 primary target. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P = 0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus provide a biological marker useful for prognosis assessment and specific therapy of the disease.
特定的人乳头瘤病毒（HPV）DNA序列与90%以上的子宫颈浸润癌相关。病毒E6和E7癌基因通过破坏TP53和RB通路，成为细胞转化的关键介质。为了研究子宫颈浸润癌进展过程中涉及的分子机制，我们根据病毒和临床参数对病例进行了基因表达研究。使用双向聚类耦合和将点排序到邻域的方法，我们鉴定出一个由163个高度相关转录本组成的“宫颈癌增殖簇”。这些转录本大多对应于控制细胞分裂或增殖的E2F通路基因，而没有一个是已知的TP53主要靶点。该簇基因的平均表达水平在早期复发的肿瘤中高于病程良好的肿瘤（P = 0.026）。此外，我们发现E6/E7 mRNA表达水平与该簇基因的表达水平以及病毒DNA载量呈正相关。这些发现表明，HPV E6/E7表达水平通过调控控制肿瘤细胞增殖的细胞基因，在子宫颈浸润癌的进展中起关键作用。因此，HPV表达水平可能为该疾病的预后评估和特异性治疗提供一个有用的生物学标志物。
