Regulation of Estrogen Receptor Alpha through novel function of HMGA1a.-Towards a novel breast cancer therapy-

通过 HMGA1a 的新功能调节雌激素受体 Alpha。-迈向新型乳腺癌疗法-

• 批准号: 21591679
• 负责人: OHE Kenji
• 金额: $ 2.75万
• 依托单位: Fujita Health University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591679/
• 关键词: 内分泌外科学; ストロゲン受容体; 乳癌; エストロゲン受容体; HMGA1a

HMGA1a, known as a DNA-binding transcription factor, was found to induce alternative splicing through novel sequence-specific RNA-binding. We found an HMGA1a RNA-binding site in Estrogen Receptor alpha(ERα) pre-mRNA. HMGA1a binds an RNA sequence 33 nucleotides upstream the 5' splice site of ERα exon 1.Interestingly, HMGA1a induces ERα46 isoform mRNA expression by exon skipping of ERα exon 1, and an RNA decoy of the HMGA1a RNA binding site inhibits ERα46 isoform mRNA expression in cultured MCF-7 mammary carcinoma cells. The HMGA1a RNA binding site in ERα exon 1 is located adjacently upstream a pseudo 5' splice site. Thus, HMGA1a traps U1 snRNP to this upstream 5' splice site and leads to dysfunction of the authentic 5' splice site of ERα exon 1.In this way, exon skipping is induced and consequent expression of ERα46 isoform is achieved through alternative splicing. Confirming the decrease of ERα46 protein expression in MCF-7 cells expressing the RNA decoy of HMGA1a RNA binding site, a stable transfectant of MCF-7 cells was established. This stable transfectant was implanted subcutaneously to ovarectomized nude mice with estrogen pellet, resulting in attenuated growth of the implanted cells. Since ERα46 isoform protein is known to inhibit the estrogen response of full length ERα, the findings shown here "an RNA decoy of HMGA1a improves estrogen response of MCF-7 cells by regulating alternative splicing of ERα" will give us a clue in deciphering the mechanism of estrogen resistance in ERα positive mammary carcinoma.

发现HMGA1A被称为DNA结合转录因子，它通过新型序列特异性RNA结合影响替代剪接。我们在雌激素受体α（ERα）前MRNA中发现了HMGA1A RNA结合位点。 HMGA1a binds an RNA sequence 33 nuclearotides upstream the 5' splice site of ERα exon 1.Interestingly, HMGA1a influences ERα46 isoform mRNA expression by exon skipping of ERα exon 1, and an RNA decoy of the HMGA1a RNA binding site inhibits ERα46 isoform mRNA expression in cultured MCF-7 mammary carcinoma cells. ERα外显子1中的HMGA1A RNA结合位点位于伪5'剪接位点上游。这是HMGA1A将U1 SNRNP诱至该上游5'剪接位点，并导致ERα外显子的真实5'剪接位点的功能障碍1.在这种方式中，通过替代胶带诱导ERα46同工型的外显子跳过。确认了表达HMGA1A RNA结合位点RNA诱饵的MCF-7细胞中ERα46蛋白表达的降低，建立了MCF-7细胞的稳定转化剂。将这种稳定的转化剂皮下植入带有雌激素颗粒的卵巢切除的裸鼠，导致植入细胞的生长减弱。由于已知ERα46同工蛋白可以抑制全长ERα的雌激素反应，因此此处显示的结果“ HMGA1A的RNA诱饵可以通过控制ERα的替代性剪接来改善MCF-7细胞的雌激素反应”，这将为我们提供一个线索，使我们在破译雌激素抗雌激素的机制方面具有依赖eRANIAN阳性乳腺癌的雌激素机制。

项目成果

HMGA1に対する「おとり」RNAは、エストロゲン受容体αの異常スプライシングを是正する

针对 HMGA1 的“诱饵”RNA 可纠正雌激素受体 α 的异常剪接

• 发表时间: 2010
• 作者: 江賢治;内海俊明;前田明
• 通讯作者: 前田明

Alternative use of multiple exons 1 of aromatase gene in cancerous and normal breast tissues from women over the age of 80 years

• DOI: 10.1186/bcr2335
• 发表时间: 2009-01-01
• 期刊: BREAST CANCER RESEARCH
• 影响因子: 7.4
• 作者: Honma, Naoko;Takubo, Kaiyo;Harada, Nobuhiro
• 通讯作者: Harada, Nobuhiro

HMGA1a trapping of U1 snRNP at an authentic 5' splice site induces aberrant exon skipping in sporadic Alzheimer's disease

HMGA1a 在真实的 5 剪接位点捕获 U1 snRNP 诱导散发性阿尔茨海默氏病的异常外显子跳跃

• 发表时间: 2010
• 期刊: Molecular and Cellular Biology (印刷中)
• 作者: 大江賢治;前田明
• 通讯作者: 前田明

HMGA1a induces aberrant splicing of Estrogen Receptor α in MCF-7 breast cancer cells

HMGA1a 诱导 MCF-7 乳腺癌细胞中雌激素受体 α 的异常剪接

• 发表时间: 2010
• 作者: Kenji Ohe;Toshiaki Utsumi;Akila Mayeda
• 通讯作者: Akila Mayeda

Oncogenic Product HMGA1a Might Function as Aberrant Splicing Inducer of Estrogen Receptor α in Breast Cancer

致癌产物 HMGA1a 可能作为乳腺癌中雌激素受体 α 的异常剪接诱导剂

• 发表时间: 2009
• 作者: Kenji Ohe;Toshiaki Utsumi;Akila Mayeda
• 通讯作者: Akila Mayeda