Analysis of the HIV-EP2 gene abnormality in human breast cancer

HIV-EP 2基因位于6 q23-q24上，该区域在乳腺癌中经常缺失，并且属于编码含有转录因子蛋白的大锌指的基因家族。虽然该基因与免疫反应、炎症和细胞增殖的调节有关，但其功能在很大程度上尚不清楚。在本研究中，我们研究了显微切割的乳腺癌组织中HIVE.PZ基因的异常。对于配对的正常组织和肿瘤组织的实时PCR定量分析，mRNA水平降低高达25倍。乳腺癌（33例）的总体中位表达水平显著低于正常乳腺组织（标准化中位值为4.49 vs 17.68 ; p<0.0001）。然而，其下调与6 q、16 q、17 p或18 q的LOR无关。全长5 '-RACE（cDNA末端快速扩增）分析鉴定了5'-非翻译区（5 '-UTR）中具有多个转录起始位点的多个外显子，其中四个位于大的CpG岛上。通过对5 '-UTR外显子的多重RT-PCR分析，未鉴定出转录起始位点的组织特异性或癌症特异性使用模式。在淋巴细胞、正常乳腺和乳腺癌组织中，在其岛的5'区域中仅检测到微弱的甲基化，表明生理、老化和无肿瘤特异性甲基化。突变筛查只检测到生殖系多态性，而不是体细胞突变。因此，HIVEP 2基因的下调经常发生，可能是导致乳腺癌的关键遗传事件之一。然而，它的转录可能受到涉及与其他因子相互作用的复杂机制和/或其他遗传/表观遗传机制的调控。

The HIV-EP2 gene is located on 6q23-q24, the region frequently deleted in breast cancer, and belongs to a family of genes that encodes large zinc finger containing transcription factor proteins. Although this gene has been implicated in the regulation of immune responses, inflammation, and cellular proliferation, its functions are largely unknown. In the present study, we investigated HIVE.PZ gene abnormalities in microdissected breast cancer tissue. For real-time PCR quantitational analysis of paired normal and tumor tissues, mRNA levels were reduced by up to 25 times. The overall median expression level in breast cancer (33 cases) was significantly lower than that in normal breast tissue (normalized median value of 4.49 versus 17.68 ; p<0.0001). However, its down-regulation was not correlated with the LOR of 6q, 16q, 17p, or 18q. Full-length 5'-RACE (rapid amplification of cDNA ends) analysis identified multiple exons in the 5'-untranslated regions (5'-UTR) with multiple transcriptional start sites, four of which were located in a large CpG island. No tissue-specific or cancer-specific usage patterns for the transcription start sites were identified by multiplex RT-PCR analysis of the 5'-UTR exons. Only faint methylation was detected in their 5' region of the island in lymphocytes, normal breast and breast cancer tissue, indicating physiological, aging and no tumor-specific methylation. Mutation screening detected only germline polymorphisms and not somatic mutation. Thus, down-regulation of the HIVEP2 genes frequently occurs and may be one of the critical genetic events responsible for breast cancer. However, its transcription may be regulated by complex mechanisms involving interactions with other factors and/or by other genetic/epigenetic mechanisms.