Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors
Open accessPublished version of a preprint
Abstract
MicroRNAs (miRNAs) act at the posttranscriptional level to control gene expression in virtually every biological process, including oncogenesis. Here, we report the identification of a set of miRNAs that are differentially regulated in childhood adrenocortical tumors (ACT), including miR-99a and miR-100. Functional analysis of these miRNAs in ACT cell lines showed that they coordinately regulate expression of the insulin-like growth factor-mammalian target of rapamycin (mTOR)-raptor signaling pathway through binding sites in their 3'-untranslated regions. In these cells, the active Ser(2448)-phosphorylated form of mTOR is present only in mitotic cells in association with the mitotic spindle and midbody in the G(2)-M phases of the cell cycle. Pharmacologic inhibition of mTOR signaling by everolimus greatly reduces tumor cell growth in vitro and in vivo. Our results reveal a novel mechanism of regulation of mTOR signaling by miRNAs, and they lay the groundwork for clinical evaluation of drugs inhibiting the mTOR pathway for treatment of adrenocortical cancer.
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In pediatric ACCs, miR-483 is significantly upregulated, while a majority of differentially expressed miRNAs are downregulated, most notably miR-99a and miR-100.
“In this study, similar to the adult ACC study, miR-483 was found to be significantly upregulated in pediatric ACCs. However, a majority of the differentially expressed miRNAs were downregulated in ACCs, most notably miR-99a and miR-100.”
From Adrenocortical carcinoma (2014) · cites this paper as [199]
In pediatric adrenal neoplasms, unsupervised clustering of miRNA expression clearly differentiates tumors from normal controls, but cannot differentiate ACA from ACC.
“Unsupervised clustering of the samples according to miRNA expression resulted in clear differentiation of the tumors from the normal controls. Further differentiation between ACA and ACC could not be achieved.”
From Adrenocortical carcinoma (2014) · cites this paper as [199]
miR-99a and miR-100 are bioinformatically predicted to target IGF1R, RPTOR, and FRAP1 (mTOR) and were experimentally confirmed to target several components of the IGF-1 signaling pathway.
“MiR-99a and miR-100 are bioinformatically predicted to target the 3′-untranslated regions of IGF1R, RPTOR, and FRAP1 (mTOR) and were experimentally confirmed to target several components of the IGF-1 signaling pathway (199).”
From Adrenocortical carcinoma (2014) · cites this paper as [199]
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References 44 · Cited by 221
- Authors
- Doghman, M., Wakil, A. E., Cardinaud, B., Thomas, E., Wang, J., Zhao, W., Peralta-Del Valle, M. H. C., Figueiredo, B. C., Zambetti, G. P., & Lalli, E.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Authors' Affiliations: 1Institut de Pharmacologie Moléculaire et Cellulaire; 2Université de Nice-Sophia Antipolis, Valbonne, France; 3Programme Carte d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France; Departments of 4Biochemistry and 5Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee; and 6Instituto de Pesquisa Pelé Pequeno Principe and Faculdades Pequeno Principe, Curitiba PR, Brazil
- Corresponding author
- Lalli, Enzo
- ORCID
- Venue
- Cancer Research
- Published
- 2010-06-01
- Volume
- 70
- Issue
- 11
- Pages
- 4666-4675
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2880211
- OpenAlex
- W2106919258
- Cited by
- 221
- References
- 44
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 14 · 2020: 8 · 2019: 8 · 2018: 17 · 2017: 12 · 2016: 14 · 2015: 26 · 2014: 22 · 2013: 26 · 2012: 23
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Cancer Institute (CA21765, P30CA021765, P01CA071907)
- National Institute of General Medical Sciences (R01GM083159, GM-083159)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- microRNA, insulin-like growth factor, mTOR signaling, raptors, miR-99a, miR-100, 3' untranslated region, mTOR phosphorylation, mitosis, everolimus, adrenocortical carcinoma, tumor cell proliferation
- MeSH terms
- Everolimus, Adrenal Cortex Neoplasms, Animals, Female, Humans, Somatomedins, Transplantation, Heterologous, Mice, SCID, Mice, Inbred NOD, Protein Serine-Threonine Kinases, Adrenocortical Adenoma, Adrenocortical Carcinoma, Sirolimus, MicroRNAs, Intracellular Signaling Peptides and Proteins, Cell Growth Processes, Mice, TOR Serine-Threonine Kinases
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