Ndisang D, Faulkes D J, Gascoyne D, Lee S A, Ripley B J, Sindos M, Singer A, Budhram-Mahadeo V, Cason J, Latchman D S
Medical Molecular Biology Unit, Institute of Child Health, University College London, and Department of Women's and Children's Health, The Whittington Hospital, London, UK.
Oncogene. 2006 Jan 5;25(1):51-60. doi: 10.1038/sj.onc.1209006.
The Brn-3a POU family transcription factor is overexpressed in human cervical carcinoma biopsies and is able to activate expression of the human papilloma virus type 16 (HPV-16) upstream regulatory region (URR), which drives the expression of the E6 and E7 oncoproteins. Inhibition of Brn-3a expression in human cervical cancer cells inhibits HPV gene expression and reduces cellular growth and anchorage independence in vitro as well as the ability to form tumours in vivo. Here, we show that Brn-3a differentially regulates different HPV-16 variants that have previously been shown to be associated with different risks of progression to cervical carcinoma. In human cervical material, Brn-3a levels correlate directly with HPV E6 levels in individuals infected with a high risk variant of HPV-16, whereas this is not the case for a low-risk variant. Moreover, the URRs of high- and intermediate-risk variants are activated by Brn-3a in transfection assays, whereas the URR of a low-risk variant is not. The change of one or two bases in a low-risk variant URR to their equivalent in a higher-risk URR can render the URR responsive to Brn-3a and vice versa. These results help explain why the specific interplay between viral and cellular factors necessary for the progression to cervical carcinoma only occurs in a minority of those infected with HPV-16.
Brn-3a POU家族转录因子在人宫颈癌活检组织中过表达，并且能够激活16型人乳头瘤病毒（HPV-16）上游调控区（URR）的表达，该调控区驱动E6和E7癌蛋白的表达。抑制人宫颈癌细胞中Brn-3a的表达可抑制HPV基因表达，并降低体外细胞生长和锚定非依赖性以及体内形成肿瘤的能力。在此，我们表明，Brn-3a对不同的HPV-16变体有不同的调控作用，这些变体先前已被证明与宫颈癌进展的不同风险相关。在人宫颈组织中，对于感染高危HPV-16变体的个体，Brn-3a水平与HPV E6水平直接相关，而对于低危变体则不然。此外，在转染实验中，高危和中危变体的URR被Brn-3a激活，而低危变体的URR则未被激活。低危变体URR中的一两个碱基改变为高危URR中的等效碱基可使URR对Brn-3a产生反应，反之亦然。这些结果有助于解释为什么只有少数感染HPV-16的人会出现宫颈癌进展所需的病毒和细胞因子之间的特定相互作用。
