Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells

Sebastian Griesing, Taisuke Kajino, Mei Chee Tai, Zhuoran Liu, Masahiro Nakatochi, Yukako Shimada, Motoshi Suzuki, Takashi Takahashi

研究成果: Article

11 引用 (Scopus)

抄録

Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma that possesses double-edged sword characteristics. Although evidence from previous studies has steadily accumulated regarding the roles of TTF-1 in transcriptional regulation of protein-coding genes, little is known about its regulatory relationship with microRNAs. Here, we utilized an integrative approach designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro, which identified microRNA (miR)-532-5p as a novel transcriptional target of TTF-1. We found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region located 8 kb upstream of miR-532-5p, which appears to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Furthermore, our results identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wild-type lung adenocarcinoma cell lines. Interestingly, miR-532-5p showed effects on MEK-ERK pathway signaling, specifically in cell lines sensitive to siKRAS treatment, whereas those miR-532-5p-mediated effects were clearly rendered as phenocopies by repressing expression or inhibiting the function of MKL2 regardless of KRAS mutation status. In summary, our findings show that miR-532-5p is a novel transcriptional target of TTF-1 that plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma.

元の言語English
ページ(範囲)1394-1404
ページ数11
ジャーナルCancer science
108
発行部数7
DOI
出版物ステータスPublished - 07-2017

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MicroRNAs
Oncogenes
Apoptosis
Cell Line
thyroid nuclear factor 1
Adenocarcinoma of lung
MAP Kinase Signaling System
Introns
Neoplasms
Proteins
Mutation
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Griesing, S., Kajino, T., Tai, M. C., Liu, Z., Nakatochi, M., Shimada, Y., ... Takahashi, T. (2017). Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells. Cancer science, 108(7), 1394-1404. https://doi.org/10.1111/cas.13271
Griesing, Sebastian ; Kajino, Taisuke ; Tai, Mei Chee ; Liu, Zhuoran ; Nakatochi, Masahiro ; Shimada, Yukako ; Suzuki, Motoshi ; Takahashi, Takashi. / Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells. :: Cancer science. 2017 ; 巻 108, 番号 7. pp. 1394-1404.
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abstract = "Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma that possesses double-edged sword characteristics. Although evidence from previous studies has steadily accumulated regarding the roles of TTF-1 in transcriptional regulation of protein-coding genes, little is known about its regulatory relationship with microRNAs. Here, we utilized an integrative approach designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro, which identified microRNA (miR)-532-5p as a novel transcriptional target of TTF-1. We found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region located 8 kb upstream of miR-532-5p, which appears to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Furthermore, our results identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wild-type lung adenocarcinoma cell lines. Interestingly, miR-532-5p showed effects on MEK-ERK pathway signaling, specifically in cell lines sensitive to siKRAS treatment, whereas those miR-532-5p-mediated effects were clearly rendered as phenocopies by repressing expression or inhibiting the function of MKL2 regardless of KRAS mutation status. In summary, our findings show that miR-532-5p is a novel transcriptional target of TTF-1 that plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma.",
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Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells. / Griesing, Sebastian; Kajino, Taisuke; Tai, Mei Chee; Liu, Zhuoran; Nakatochi, Masahiro; Shimada, Yukako; Suzuki, Motoshi; Takahashi, Takashi.

:: Cancer science, 巻 108, 番号 7, 07.2017, p. 1394-1404.

研究成果: Article

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T1 - Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells

AU - Griesing, Sebastian

AU - Kajino, Taisuke

AU - Tai, Mei Chee

AU - Liu, Zhuoran

AU - Nakatochi, Masahiro

AU - Shimada, Yukako

AU - Suzuki, Motoshi

AU - Takahashi, Takashi

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N2 - Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma that possesses double-edged sword characteristics. Although evidence from previous studies has steadily accumulated regarding the roles of TTF-1 in transcriptional regulation of protein-coding genes, little is known about its regulatory relationship with microRNAs. Here, we utilized an integrative approach designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro, which identified microRNA (miR)-532-5p as a novel transcriptional target of TTF-1. We found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region located 8 kb upstream of miR-532-5p, which appears to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Furthermore, our results identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wild-type lung adenocarcinoma cell lines. Interestingly, miR-532-5p showed effects on MEK-ERK pathway signaling, specifically in cell lines sensitive to siKRAS treatment, whereas those miR-532-5p-mediated effects were clearly rendered as phenocopies by repressing expression or inhibiting the function of MKL2 regardless of KRAS mutation status. In summary, our findings show that miR-532-5p is a novel transcriptional target of TTF-1 that plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma.

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