MiR-15a/miR-16-1 expression inversely correlates with 1 cyclin D1 levels in Men1 pituitary NETs

Kate E Lines, Paul Newey, Christopher J. Yates, Mark Stevenson, Rebecca Dyar, Gerard V. Walls, Mike R Bowl, Rajesh V. Thakker

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Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. miRNAs are non-coding single-stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knockout of the Men1 gene (Men1+/− mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, P < 0.05; 2.1-fold P < 0.01 and 1.6-fold P < 0.05, respectively) of Men1+/− mice, compared to normal WT pituitaries. miR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knockdown of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (P < 0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.

Original languageEnglish
Pages (from-to)41-50
Number of pages10
JournalJournal of Endourology
Volume240
Issue number1
Early online dateSep 2018
DOIs
Publication statusPublished - Jan 2019

Fingerprint

Cyclin D1
MicroRNAs
Multiple Endocrine Neoplasia Type 1
Pituitary Neoplasms
Neoplasms
Down-Regulation
Tumor Suppressor Proteins
Cell Line
Gene Knockout Techniques
Genomic Instability
Islets of Langerhans
Cell Division
Cell Proliferation
RNA
Gene Expression
Mutation
Genes

Keywords

  • Menin
  • MicroRNA
  • Multiple endocrine neoplasia type 1
  • Neuroendocrine tumour

Cite this

Lines, K. E., Newey, P., Yates, C. J., Stevenson, M., Dyar, R., Walls, G. V., ... Thakker, R. V. (2019). MiR-15a/miR-16-1 expression inversely correlates with 1 cyclin D1 levels in Men1 pituitary NETs. Journal of Endourology, 240(1), 41-50. https://doi.org/10.1530/JOE-18-0278
Lines, Kate E ; Newey, Paul ; Yates, Christopher J. ; Stevenson, Mark ; Dyar, Rebecca ; Walls, Gerard V. ; Bowl, Mike R ; Thakker, Rajesh V. / MiR-15a/miR-16-1 expression inversely correlates with 1 cyclin D1 levels in Men1 pituitary NETs. In: Journal of Endourology. 2019 ; Vol. 240, No. 1. pp. 41-50.
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abstract = "Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. miRNAs are non-coding single-stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knockout of the Men1 gene (Men1+/− mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, P < 0.05; 2.1-fold P < 0.01 and 1.6-fold P < 0.05, respectively) of Men1+/− mice, compared to normal WT pituitaries. miR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knockdown of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (P < 0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.",
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note = "This work was supported by: the UK Medical Research Council (MRC) grants G9825289, G1000467 (KEL, PJN, MS, RD, RVT) and G0601423 (PJN); AMEND Research Fund Award (KEL); a Wellcome Trust Senior Investigator Award (RVT); Royal Australasian",
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Lines, KE, Newey, P, Yates, CJ, Stevenson, M, Dyar, R, Walls, GV, Bowl, MR & Thakker, RV 2019, 'MiR-15a/miR-16-1 expression inversely correlates with 1 cyclin D1 levels in Men1 pituitary NETs' Journal of Endourology, vol. 240, no. 1, pp. 41-50. https://doi.org/10.1530/JOE-18-0278

MiR-15a/miR-16-1 expression inversely correlates with 1 cyclin D1 levels in Men1 pituitary NETs. / Lines, Kate E ; Newey, Paul; Yates, Christopher J.; Stevenson, Mark; Dyar, Rebecca ; Walls, Gerard V.; Bowl, Mike R ; Thakker, Rajesh V.

In: Journal of Endourology, Vol. 240, No. 1, 01.2019, p. 41-50.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MiR-15a/miR-16-1 expression inversely correlates with 1 cyclin D1 levels in Men1 pituitary NETs

AU - Lines, Kate E

AU - Newey, Paul

AU - Yates, Christopher J.

AU - Stevenson, Mark

AU - Dyar, Rebecca

AU - Walls, Gerard V.

AU - Bowl, Mike R

AU - Thakker, Rajesh V.

N1 - This work was supported by: the UK Medical Research Council (MRC) grants G9825289, G1000467 (KEL, PJN, MS, RD, RVT) and G0601423 (PJN); AMEND Research Fund Award (KEL); a Wellcome Trust Senior Investigator Award (RVT); Royal Australasian

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N2 - Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. miRNAs are non-coding single-stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knockout of the Men1 gene (Men1+/− mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, P < 0.05; 2.1-fold P < 0.01 and 1.6-fold P < 0.05, respectively) of Men1+/− mice, compared to normal WT pituitaries. miR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knockdown of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (P < 0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.

AB - Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. miRNAs are non-coding single-stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knockout of the Men1 gene (Men1+/− mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, P < 0.05; 2.1-fold P < 0.01 and 1.6-fold P < 0.05, respectively) of Men1+/− mice, compared to normal WT pituitaries. miR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knockdown of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (P < 0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.

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KW - MicroRNA

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KW - Neuroendocrine tumour

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