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在神经母细胞瘤中，INSM1通过正反馈回路增加N-myc的稳定性并促进肿瘤发生。

INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma.

作者信息

Chen Chiachen, Breslin Mary B, Lan Michael S

机构信息

The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.

Laboratory of Diana Helis Henry Medical Research Foundation, New Orleans, LA 70119, USA.

出版信息

Oncotarget. 2015 Nov 3;6(34):36700-12. doi: 10.18632/oncotarget.5485.

DOI:10.18632/oncotarget.5485
PMID:26456864
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4742205/
Abstract

Insulinoma associated-1 (IA-1/INSM1) gene is exclusively expressed during early embryonic development, but has been found to be re-expressed at high levels in neuroendocrine tumors including neuroblastoma. Using over-expression and knockdown experiments in neuroblastoma cells, we showed that INSM1 is critical for cell proliferation, BME-coated invasion, and soft agar colony formation. Here, we identified INSM1 as a novel target gene activated by N-myc in N-myc amplified neuroblastoma cells. The Sonic hedgehog signaling pathway induced INSM1 by increasing N-myc expression. INSM1 activated PI3K/AKT/GSK3β pathways to suppress N-myc phosphorylation (Thr-58) and inhibited degradation of N-myc. Inversely, N-myc protein bound to the E2-box region of the INSM1 promoter and activated INSM1 expression. The invasion assay and the xenograft nude mouse tumor model revealed that the INSM1 factor facilitated growth and oncogenesis of neuroblastoma. The current data supports our hypothesis that a positive-feedback loop of sonic hedgehog signaling induced INSM1 through N-myc and INSM1 enhanced N-myc stability contributing to the transformation of human neuroblastoma.

摘要

胰岛素瘤相关蛋白1（IA-1/INSM1）基因仅在胚胎发育早期表达，但已发现在包括神经母细胞瘤在内的神经内分泌肿瘤中高水平重新表达。通过在神经母细胞瘤细胞中进行过表达和敲低实验，我们表明INSM1对细胞增殖、BME包被侵袭和软琼脂集落形成至关重要。在此，我们确定INSM1是N-myc在N-myc扩增的神经母细胞瘤细胞中激活的一个新靶基因。音猬因子信号通路通过增加N-myc表达诱导INSM1。INSM1激活PI3K/AKT/GSK3β通路以抑制N-myc磷酸化（苏氨酸-58）并抑制N-myc降解。相反，N-myc蛋白与INSM1启动子的E2-box区域结合并激活INSM1表达。侵袭实验和异种移植裸鼠肿瘤模型显示，INSM1因子促进神经母细胞瘤的生长和肿瘤发生。目前的数据支持我们的假设，即音猬因子信号的正反馈环通过N-myc诱导INSM1，而INSM1增强N-myc稳定性，促进人类神经母细胞瘤的转化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/38dc1d17dd31/oncotarget-06-36700-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/0c8731b8aea0/oncotarget-06-36700-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/b712824f0904/oncotarget-06-36700-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/8686e360e7bb/oncotarget-06-36700-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/966d2a14cb5a/oncotarget-06-36700-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/0faf88b6175c/oncotarget-06-36700-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/01f2ba0ed862/oncotarget-06-36700-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/38dc1d17dd31/oncotarget-06-36700-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/0c8731b8aea0/oncotarget-06-36700-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/b712824f0904/oncotarget-06-36700-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/8686e360e7bb/oncotarget-06-36700-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/966d2a14cb5a/oncotarget-06-36700-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/0faf88b6175c/oncotarget-06-36700-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/01f2ba0ed862/oncotarget-06-36700-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fc8/4742205/38dc1d17dd31/oncotarget-06-36700-g007.jpg

相似文献

[1]
INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma.

Oncotarget. 2015-11-3

[2]
Sonic hedgehog signaling pathway promotes INSM1 transcription factor in neuroendocrine lung cancer.

Cell Signal. 2018-3-1

[3]
5'-Iodotubercidin represses expression, decreases cAMP levels, and suppresses human neuroblastoma cell growth.

J Biol Chem. 2019-2-12

[4]
Repurposing a plant alkaloid homoharringtonine targets insulinoma associated-1 in N-Myc-activated neuroblastoma.

Cell Signal. 2023-9

[5]
MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma.

J Cell Biochem. 2017-7

[6]
Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer.

Am J Pathol. 2015-12

[7]
Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2.

Mol Cancer. 2015-2-21

[8]
MYCN induces neuroblastoma in primary neural crest cells.

Oncogene. 2017-8-31

[9]
Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo.

Int J Cancer. 2011-8-29

[10]
Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction.

Cell Signal. 2014-1-7

引用本文的文献

[1]
Repurposing a plant alkaloid homoharringtonine targets insulinoma associated-1 in N-Myc-activated neuroblastoma.

Cell Signal. 2023-9

[2]
Interplay: The Essential Role between INSM1 and N-Myc in Aggressive Neuroblastoma.

Biology (Basel). 2022-9-20

[3]
MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.

Oncol Lett. 2021-12

[4]
A promoter-driven assay for INSM1-associated signaling pathway in neuroblastoma.

Cell Signal. 2020-12

[5]
Insulinoma-Associated-1: From Neuroendocrine Tumor Marker to Cancer Therapeutics.

Mol Cancer Res. 2019-5-21

[6]
Collaborative ISL1/GATA3 interaction in controlling neuroblastoma oncogenic pathways overlapping with but distinct from MYCN.

Theranostics. 2019-1-30

[7]
5'-Iodotubercidin represses expression, decreases cAMP levels, and suppresses human neuroblastoma cell growth.

J Biol Chem. 2019-2-12

本文引用的文献

[1]
Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction.

Cell Signal. 2014-1-7

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