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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-

基本信息

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

项目摘要

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.

HMGA1a是一种DNA结合转录因子，被发现通过新的序列特异性RNA结合诱导选择性剪接。我们在雌激素受体α(ER-α)前体基因中发现了一个HMGA1aRNA结合位点。有趣的是，HMGA1a通过跳过ERα外显子1的外显子来诱导ERα46异构体α的表达，而HMGA1a结合位点的诱骗抑制了培养的乳腺癌细胞ERα46的表达。ERα外显子1的HMGA1aRNA结合位点位于伪5‘剪接位点的上游。因此，HMGA1a将U1SnRNP捕获到这个上游5‘剪接点，导致ERα外显子1真实的5’剪接点功能障碍，从而诱导外显子跳跃，从而通过选择性剪接实现ERα46亚型的表达。证实了表达HMGA1aRNA结合位点诱饵的MCF7细胞ERα46蛋白表达降低，建立了稳定的MCF7细胞转染体。将该稳定的转基因细胞与雌激素颗粒一起植入去卵巢裸鼠皮下，使移植细胞的生长受到抑制。由于已知ERα46亚型蛋白可抑制全长ERα的雌激素反应，本研究的结果将为我们解释ERα阳性乳腺癌的雌激素耐药机制提供线索。