Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma

Maria Rossing; Rehannah Borup Helweg-Larsen; Ricardo Henao Giraldo; Ole Winther; Jonas Vikeså; Omid Niazi; Christian Godballe; Annelise Krogdahl; Martin Glud; Christian Hjort Sørensen; Katalin Kiss; Finn Noe Bennedbæk; Finn Cilius Nielsen

doi:10.1530/jme-11-0039

Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma

Maria Rossing, Rehannah Borup Helweg-Larsen, Ricardo Henao Giraldo, Ole Winther, Jonas Vikeså, Omid Niazi, Christian Godballe, Annelise Krogdahl, Martin Glud, Christian Hjort Sørensen, Katalin Kiss, Finn Noe Bennedbæk, Finn Cilius Nielsen

69 Citations (Scopus)

Abstract

The molecular determinants of thyroid follicular nodules are incompletely understood and assessment of malignancy is a diagnostic challenge. Since microRNA (miRNA) analyses could provide new leads to malignant progression, we characterised the global miRNA expression in follicular adenoma (FA) and follicular carcinoma (FC). Comparison of carcinoma and adenoma with normal thyroid revealed 150 and 107 differentially expressed miRNAs respectively. Most miRNAs were down-regulated and especially miR-199b-5p and miR-144 which were essentially lost in the carcinomas. Integration of the changed miRNAs with differentially expressed mRNAs demonstrated an enrichment of seed sites among up-regulated transcripts encoding proteins implicated in thyroid tumourigenesis. This was substantiated by the demonstration that pre-miR-199b reduced proliferation when added to cultured follicular thyroid carcinoma cells. The down-regulated miRNAs in FC exhibited a substantial similarity with down-regulated miRNAs in anaplastic carcinoma (AC) and by gene set enrichment analysis, we observed a significant identity between target mRNAs in FC and transcripts up-regulated in AC. To examine the diagnostic potential of miRNA expression pattern in distinguishing malignant from benign nodules we employed a supervised learning algorithm and leave-one-out-cross-validation. By this procedure, FA and FC were identified with a negative predicted value of 83% (data generated by microarray platform) and of 92% (data generated by qRT-PCR platform). We conclude that follicular neoplasia is associated with major changes in miRNA expression that may promote malignant transformation by increasing the expression of transcripts encoding tumourigenic factors. Moreover, miRNA profiling may facilitate the diagnosis of carcinoma vs adenoma.

Original language	English
Journal	Journal of Molecular Endocrinology
Volume	48
Issue number	1
Pages (from-to)	11-23
Number of pages	13
ISSN	0952-5041
DOIs	https://doi.org/10.1530/jme-11-0039
Publication status	Published - Feb 2012

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Rossing, M., Helweg-Larsen, R. B., Henao Giraldo, R., Winther, O., Vikeså, J., Niazi, O., Godballe, C., Krogdahl, A., Glud, M., Sørensen, C. H., Kiss, K., Bennedbæk, F. N., & Nielsen, F. C. (2012). Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma. Journal of Molecular Endocrinology, 48(1), 11-23. https://doi.org/10.1530/jme-11-0039

Rossing, M, Helweg-Larsen, RB, Henao Giraldo, R, Winther, O, Vikeså, J, Niazi, O, Godballe, C, Krogdahl, A, Glud, M, Sørensen, CH, Kiss, K, Bennedbæk, FN & Nielsen, FC 2012, 'Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma', Journal of Molecular Endocrinology, vol. 48, no. 1, pp. 11-23. https://doi.org/10.1530/jme-11-0039

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abstract = "The molecular determinants of thyroid follicular nodules are incompletely understood and assessment of malignancy is a diagnostic challenge. Since microRNA (miRNA) analyses could provide new leads to malignant progression, we characterised the global miRNA expression in follicular adenoma (FA) and follicular carcinoma (FC). Comparison of carcinoma and adenoma with normal thyroid revealed 150 and 107 differentially expressed miRNAs respectively. Most miRNAs were down-regulated and especially miR-199b-5p and miR-144 which were essentially lost in the carcinomas. Integration of the changed miRNAs with differentially expressed mRNAs demonstrated an enrichment of seed sites among up-regulated transcripts encoding proteins implicated in thyroid tumourigenesis. This was substantiated by the demonstration that pre-miR-199b reduced proliferation when added to cultured follicular thyroid carcinoma cells. The down-regulated miRNAs in FC exhibited a substantial similarity with down-regulated miRNAs in anaplastic carcinoma (AC) and by gene set enrichment analysis, we observed a significant identity between target mRNAs in FC and transcripts up-regulated in AC. To examine the diagnostic potential of miRNA expression pattern in distinguishing malignant from benign nodules we employed a supervised learning algorithm and leave-one-out-cross-validation. By this procedure, FA and FC were identified with a negative predicted value of 83% (data generated by microarray platform) and of 92% (data generated by qRT-PCR platform). We conclude that follicular neoplasia is associated with major changes in miRNA expression that may promote malignant transformation by increasing the expression of transcripts encoding tumourigenic factors. Moreover, miRNA profiling may facilitate the diagnosis of carcinoma vs adenoma.",

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AU - Helweg-Larsen, Rehannah Borup

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AU - Winther, Ole

AU - Vikeså, Jonas

AU - Niazi, Omid

AU - Godballe, Christian

AU - Krogdahl, Annelise

AU - Glud, Martin

AU - Sørensen, Christian Hjort

AU - Kiss, Katalin

AU - Bennedbæk, Finn Noe

AU - Nielsen, Finn Cilius

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N2 - The molecular determinants of thyroid follicular nodules are incompletely understood and assessment of malignancy is a diagnostic challenge. Since microRNA (miRNA) analyses could provide new leads to malignant progression, we characterised the global miRNA expression in follicular adenoma (FA) and follicular carcinoma (FC). Comparison of carcinoma and adenoma with normal thyroid revealed 150 and 107 differentially expressed miRNAs respectively. Most miRNAs were down-regulated and especially miR-199b-5p and miR-144 which were essentially lost in the carcinomas. Integration of the changed miRNAs with differentially expressed mRNAs demonstrated an enrichment of seed sites among up-regulated transcripts encoding proteins implicated in thyroid tumourigenesis. This was substantiated by the demonstration that pre-miR-199b reduced proliferation when added to cultured follicular thyroid carcinoma cells. The down-regulated miRNAs in FC exhibited a substantial similarity with down-regulated miRNAs in anaplastic carcinoma (AC) and by gene set enrichment analysis, we observed a significant identity between target mRNAs in FC and transcripts up-regulated in AC. To examine the diagnostic potential of miRNA expression pattern in distinguishing malignant from benign nodules we employed a supervised learning algorithm and leave-one-out-cross-validation. By this procedure, FA and FC were identified with a negative predicted value of 83% (data generated by microarray platform) and of 92% (data generated by qRT-PCR platform). We conclude that follicular neoplasia is associated with major changes in miRNA expression that may promote malignant transformation by increasing the expression of transcripts encoding tumourigenic factors. Moreover, miRNA profiling may facilitate the diagnosis of carcinoma vs adenoma.

AB - The molecular determinants of thyroid follicular nodules are incompletely understood and assessment of malignancy is a diagnostic challenge. Since microRNA (miRNA) analyses could provide new leads to malignant progression, we characterised the global miRNA expression in follicular adenoma (FA) and follicular carcinoma (FC). Comparison of carcinoma and adenoma with normal thyroid revealed 150 and 107 differentially expressed miRNAs respectively. Most miRNAs were down-regulated and especially miR-199b-5p and miR-144 which were essentially lost in the carcinomas. Integration of the changed miRNAs with differentially expressed mRNAs demonstrated an enrichment of seed sites among up-regulated transcripts encoding proteins implicated in thyroid tumourigenesis. This was substantiated by the demonstration that pre-miR-199b reduced proliferation when added to cultured follicular thyroid carcinoma cells. The down-regulated miRNAs in FC exhibited a substantial similarity with down-regulated miRNAs in anaplastic carcinoma (AC) and by gene set enrichment analysis, we observed a significant identity between target mRNAs in FC and transcripts up-regulated in AC. To examine the diagnostic potential of miRNA expression pattern in distinguishing malignant from benign nodules we employed a supervised learning algorithm and leave-one-out-cross-validation. By this procedure, FA and FC were identified with a negative predicted value of 83% (data generated by microarray platform) and of 92% (data generated by qRT-PCR platform). We conclude that follicular neoplasia is associated with major changes in miRNA expression that may promote malignant transformation by increasing the expression of transcripts encoding tumourigenic factors. Moreover, miRNA profiling may facilitate the diagnosis of carcinoma vs adenoma.

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DO - 10.1530/jme-11-0039

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JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

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ER -

Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma

Abstract

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