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

人类乳腺癌HIV-EP2基因异常分析

• 批准号: 14570165
• 负责人: FUJII Hiroaki
• 金额: $ 1.92万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570165/
• 关键词: HIV-EP2; breast cancer; LOH; down-regulation; Tumor suppressor gene; real-time RT-PCR; 5'-RACE; breast cancer; loss of heterozygosity(LOH); real-time PCR; methylation; alternative splicing; Breast cancer; Real-time PCR; Microdissection; mRN

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.

HIV-EP2基因位于6q23-q24，该区域在乳腺癌中经常缺失，属于编码含有转录因子蛋白的大锌指的基因家族。尽管该基因与免疫反应、炎症和细胞增殖的调节有关，但其功能在很大程度上是未知的。在本研究中，我们研究了HIVE。微解剖乳腺癌组织中PZ基因异常。对配对的正常和肿瘤组织进行实时PCR定量分析时，mRNA水平降低了25倍。乳腺癌中总中位表达水平（33例）显著低于正常乳腺组织（归一化中位值为4.49比17.68,p<0.0001）。但其下调与6q、16q、17p、18q的LOR无关。全长5'-RACE （cDNA末端快速扩增）分析在5'-非翻译区（5'-UTR）中发现了多个具有多个转录起始位点的外显子，其中四个位于一个大的CpG岛。通过对5'-UTR外显子的多重RT-PCR分析，没有发现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，仅在其岛的5′区检测到微弱的甲基化，提示生理性、衰老性，无肿瘤特异性甲基化。突变筛选只检测到种系多态性，而没有检测到体细胞突变。因此，HIVEP2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，它的转录可能受到复杂机制的调控，包括与其他因素的相互作用和/或其他遗传/表观遗传机制。

项目成果

Fujii H, Shimoda T, et al.: "Genetic evolution of alpha fetoprotein producing gastric cancer."J Clin Pathol. 56. 942-949 (2003)

Fujii H、Shimoda T 等人：“甲胎蛋白产生胃癌的基因进化。”J Clin Pathol。

藤井博昭: "クローナリティー解析"病理と臨床. 22臨時増刊号. 28-37 (2004)

Hiroaki Fujii：“克隆性分析”病理学和临床研究 22 特刊（2004 年）。

Arakawa A, Eujii H, et al.: "Loss of heterozygosity in the clonal evolution with genetic progression and divergence in spindle cell carcinoma of gallbladder."Hum Pathol. in press. (2004)

Arakawa A、Eujii H 等人：“随着胆囊梭形细胞癌的遗传进展和分化，克隆进化中杂合性的丧失。”Hum Pathol。

分担執筆 藤井博昭, 他: "卵巣腫瘍病理アトラスより分担執筆、[広汎性浮腫]「多嚢胞性卵巣症候群」"文光堂(印刷中). (2004)

合著者 Hiroaki Fujii 等人：“《卵巢肿瘤病理学图谱》的合著者，[播散性水肿]‘多囊卵巢综合征’”Bunkodo（2004 年出版）。

Fujii H, et al.: "Genetic evolution of alpha fetoprotein producing gastric cancer."J Cninical Pathol. 56. 942-949 (2003)

Fujii H 等人：“产生胃癌的甲胎蛋白的基因进化。”J Cninical Pathol。