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.

HMGA1a 被称为 DNA 结合转录因子，被发现可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 (ERα) 前 mRNA 中发现了 HMGA1a RNA 结合位点。 ERα 外显子 1 5' 剪接位点上游 33 个核苷酸。有趣的是，HMGA1a 诱导 ERα46 亚型 mRNA 表达通过 ERα 外显子 1 的外显子跳跃，HMGA1a RNA 结合位点的 RNA 诱饵抑制培养的 MCF-7 乳腺癌细胞中的 ERα46 同工型 mRNA 表达 ERα 外显子 1 中的 HMGA1a RNA 结合位点位于伪 5' 剪接的上游附近。因此，HMGA1a 将 U1 snRNP 捕获到该上游 5' 剪接位点并导致真实功能障碍。 ERα 外显子 1 的 5' 剪接位点。通过这种方式，诱导外显子跳跃，并通过选择性剪接实现 ERα46 同种型的后续表达，证实了表达 HMGA1a RNA 结合位点的 RNA 诱饵的 MCF-7 细胞中 ERα46 蛋白表达的减少。建立了MCF-7细胞的稳定转染子，将该稳定转染子皮下植入卵巢切除的裸鼠体内。雌激素沉淀，导致植入细胞生长减弱。由于已知 ERα46 亚型蛋白会抑制全长 ERα 的雌激素反应，因此此处显示的研究结果“HMGA1a 的 RNA 诱饵通过调节选择性剪接改善 MCF-7 细胞的雌激素反应”。 ERα”将为我们破译ERα阳性乳腺癌雌激素抵抗机制提供线索。

项目成果

Equal contribution to first author and corresponding author. HMGA1a is involved in specific splice site regulation of human immunodeficiency virus type 1

第一作者和通讯作者同等贡献。

• 发表时间: 2011
• 作者: Tsuruno C; Ohe K; Kuramitsu M; Kohma T; Takahama Y; Hamaguchi Y; Hamaguchi I; Okuma K
• 通讯作者: Okuma K

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

芳香酶基因多个外显子 1 在 80 岁以上女性癌性和正常乳腺组织中的替代用途

• 发表时间: 2009
• 影响因子: 7.4
• 作者: Honma N; Takubo K; Sawabe M; Arai T; Akiyama F; Sakamoto G; Utsumi T; Yoshimura N; Harada N
• 通讯作者: Harada N

エストロゲン受容体α46アイソフォーム発現に対するHMGA1aの影響

HMGA1a对雌激素受体α46亚型表达的影响

• 发表时间: 2009
• 作者: 大江賢治

The expression of HMGA1a is increased in lymphoblastoid cell lines from schizophrenia patients

精神分裂症患者的类淋巴母细胞系中 HMGA1a 的表达增加

• 发表时间: 2010
• 影响因子: 4.2
• 作者: Morikawa T; Manabe T; Ito Y; Yamada S; Yoshimi A; Nagai T; Ozaki N; Mayeda A
• 通讯作者: Mayeda A

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
• 作者: 大江賢治; 前田明
• 通讯作者: 前田明