HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells

Kenji Ohe, Shinsuke Miyajima, Ichiro Abe, Tomoko Tanaka, Yuriko Hamaguchi, Yoshihiro Harada, Yuta Horita, Yuki Beppu, Fumiaki Ito, Takafumi Yamasaki, Hiroki Terai, Masayoshi Mori, Yusuke Murata, Makito Tanabe, Kenji Ashida, Kunihisa Kobayashi, Munechika Enjoji, Toshihiko Yanase, Nobuhiro Harada, Toshiaki UtsumiAkira Maeda

Research output: Contribution to journalArticle

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Abstract

The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

Original languageEnglish
Pages (from-to)21-26
Number of pages6
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume182
DOIs
Publication statusPublished - 01-09-2018

Fingerprint

High Mobility Group Proteins
Estrogen Receptor alpha
Alternative Splicing
Cells
Breast Neoplasms
Tamoxifen
Proteins
RNA
Exons
MCF-7 Cells
Estrogens
Growth
Presenilin-2
Neoplasms
Tumors
Oncogenes
Genes
Nude Mice
Alzheimer Disease
Fibroblasts

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Ohe, Kenji ; Miyajima, Shinsuke ; Abe, Ichiro ; Tanaka, Tomoko ; Hamaguchi, Yuriko ; Harada, Yoshihiro ; Horita, Yuta ; Beppu, Yuki ; Ito, Fumiaki ; Yamasaki, Takafumi ; Terai, Hiroki ; Mori, Masayoshi ; Murata, Yusuke ; Tanabe, Makito ; Ashida, Kenji ; Kobayashi, Kunihisa ; Enjoji, Munechika ; Yanase, Toshihiko ; Harada, Nobuhiro ; Utsumi, Toshiaki ; Maeda, Akira. / HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells. In: Journal of Steroid Biochemistry and Molecular Biology. 2018 ; Vol. 182. pp. 21-26.
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abstract = "The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.",
author = "Kenji Ohe and Shinsuke Miyajima and Ichiro Abe and Tomoko Tanaka and Yuriko Hamaguchi and Yoshihiro Harada and Yuta Horita and Yuki Beppu and Fumiaki Ito and Takafumi Yamasaki and Hiroki Terai and Masayoshi Mori and Yusuke Murata and Makito Tanabe and Kenji Ashida and Kunihisa Kobayashi and Munechika Enjoji and Toshihiko Yanase and Nobuhiro Harada and Toshiaki Utsumi and Akira Maeda",
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Ohe, K, Miyajima, S, Abe, I, Tanaka, T, Hamaguchi, Y, Harada, Y, Horita, Y, Beppu, Y, Ito, F, Yamasaki, T, Terai, H, Mori, M, Murata, Y, Tanabe, M, Ashida, K, Kobayashi, K, Enjoji, M, Yanase, T, Harada, N, Utsumi, T & Maeda, A 2018, 'HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells', Journal of Steroid Biochemistry and Molecular Biology, vol. 182, pp. 21-26. https://doi.org/10.1016/j.jsbmb.2018.04.007

HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells. / Ohe, Kenji; Miyajima, Shinsuke; Abe, Ichiro; Tanaka, Tomoko; Hamaguchi, Yuriko; Harada, Yoshihiro; Horita, Yuta; Beppu, Yuki; Ito, Fumiaki; Yamasaki, Takafumi; Terai, Hiroki; Mori, Masayoshi; Murata, Yusuke; Tanabe, Makito; Ashida, Kenji; Kobayashi, Kunihisa; Enjoji, Munechika; Yanase, Toshihiko; Harada, Nobuhiro; Utsumi, Toshiaki; Maeda, Akira.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 182, 01.09.2018, p. 21-26.

Research output: Contribution to journalArticle

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T1 - HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells

AU - Ohe, Kenji

AU - Miyajima, Shinsuke

AU - Abe, Ichiro

AU - Tanaka, Tomoko

AU - Hamaguchi, Yuriko

AU - Harada, Yoshihiro

AU - Horita, Yuta

AU - Beppu, Yuki

AU - Ito, Fumiaki

AU - Yamasaki, Takafumi

AU - Terai, Hiroki

AU - Mori, Masayoshi

AU - Murata, Yusuke

AU - Tanabe, Makito

AU - Ashida, Kenji

AU - Kobayashi, Kunihisa

AU - Enjoji, Munechika

AU - Yanase, Toshihiko

AU - Harada, Nobuhiro

AU - Utsumi, Toshiaki

AU - Maeda, Akira

PY - 2018/9/1

Y1 - 2018/9/1

N2 - The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

AB - The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

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