Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

Camilla Maria Falch, Arvind Y M Sundaram, Kristin Astrid Øystese, Kjersti Ringvoll Normann, Tove Lekva, Ivars Silamikelis, Alexander Kirkeby Eieland, Marianne Skovsager Andersen, Jens Bollerslev, Nicoleta Cristina Olarescu

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Objective: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Design and methods: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46, P<0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB). MTDH, but not EMCN, demonstrated involvement in cell migration and association with EMT markers. Conclusions: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Endocrinology
Vol/bind178
Udgave nummer3
Sider (fra-til)295-307
ISSN0804-4643
DOI
StatusUdgivet - mar. 2018

Fingeraftryk

Gonadotrophs
Gene Expression Profiling
Adenoma
Growth
Tumor Burden
Transcriptome
RNA Sequence Analysis
Cell Movement
Neoplasms
Down-Regulation

Citer dette

Falch, C. M., Sundaram, A. Y. M., Øystese, K. A., Normann, K. R., Lekva, T., Silamikelis, I., ... Olarescu, N. C. (2018). Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas. European Journal of Endocrinology, 178(3), 295-307. https://doi.org/10.1530/EJE-17-0702
Falch, Camilla Maria ; Sundaram, Arvind Y M ; Øystese, Kristin Astrid ; Normann, Kjersti Ringvoll ; Lekva, Tove ; Silamikelis, Ivars ; Eieland, Alexander Kirkeby ; Andersen, Marianne Skovsager ; Bollerslev, Jens ; Olarescu, Nicoleta Cristina. / Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas. I: European Journal of Endocrinology. 2018 ; Bind 178, Nr. 3. s. 295-307.
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title = "Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas",
abstract = "Objective: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Design and methods: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46, P<0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB). MTDH, but not EMCN, demonstrated involvement in cell migration and association with EMT markers. Conclusions: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.",
keywords = "Adaptor Proteins, Signal Transducing/genetics, Adenoma/genetics, Adult, Aged, Cadherins/genetics, Cell Adhesion Molecules/genetics, Cell Movement/genetics, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics, Epithelial-Mesenchymal Transition/genetics, Female, Follicle Stimulating Hormone/metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, In Vitro Techniques, Intracellular Signaling Peptides and Proteins/genetics, Luteinizing Hormone/metabolism, Male, Membrane Glycoproteins/genetics, Microtubule-Associated Proteins/genetics, Middle Aged, Myosin Type I/genetics, Nerve Tissue Proteins/genetics, Pituitary Neoplasms/genetics, Proto-Oncogene Proteins/genetics, RNA, Messenger/metabolism, Receptors, Cell Surface/genetics, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleases/genetics, Sialoglycoproteins/genetics, Time Factors",
author = "Falch, {Camilla Maria} and Sundaram, {Arvind Y M} and {\O}ystese, {Kristin Astrid} and Normann, {Kjersti Ringvoll} and Tove Lekva and Ivars Silamikelis and Eieland, {Alexander Kirkeby} and Andersen, {Marianne Skovsager} and Jens Bollerslev and Olarescu, {Nicoleta Cristina}",
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year = "2018",
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language = "English",
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pages = "295--307",
journal = "European Journal of Endocrinology",
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Falch, CM, Sundaram, AYM, Øystese, KA, Normann, KR, Lekva, T, Silamikelis, I, Eieland, AK, Andersen, MS, Bollerslev, J & Olarescu, NC 2018, 'Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas', European Journal of Endocrinology, bind 178, nr. 3, s. 295-307. https://doi.org/10.1530/EJE-17-0702

Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas. / Falch, Camilla Maria; Sundaram, Arvind Y M; Øystese, Kristin Astrid; Normann, Kjersti Ringvoll; Lekva, Tove; Silamikelis, Ivars; Eieland, Alexander Kirkeby; Andersen, Marianne Skovsager; Bollerslev, Jens; Olarescu, Nicoleta Cristina.

I: European Journal of Endocrinology, Bind 178, Nr. 3, 03.2018, s. 295-307.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

AU - Falch, Camilla Maria

AU - Sundaram, Arvind Y M

AU - Øystese, Kristin Astrid

AU - Normann, Kjersti Ringvoll

AU - Lekva, Tove

AU - Silamikelis, Ivars

AU - Eieland, Alexander Kirkeby

AU - Andersen, Marianne Skovsager

AU - Bollerslev, Jens

AU - Olarescu, Nicoleta Cristina

N1 - © 2018 European Society of Endocrinology.

PY - 2018/3

Y1 - 2018/3

N2 - Objective: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Design and methods: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46, P<0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB). MTDH, but not EMCN, demonstrated involvement in cell migration and association with EMT markers. Conclusions: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.

AB - Objective: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Design and methods: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46, P<0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB). MTDH, but not EMCN, demonstrated involvement in cell migration and association with EMT markers. Conclusions: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Adenoma/genetics

KW - Adult

KW - Aged

KW - Cadherins/genetics

KW - Cell Adhesion Molecules/genetics

KW - Cell Movement/genetics

KW - Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics

KW - Epithelial-Mesenchymal Transition/genetics

KW - Female

KW - Follicle Stimulating Hormone/metabolism

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Gene Silencing

KW - Humans

KW - In Vitro Techniques

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Luteinizing Hormone/metabolism

KW - Male

KW - Membrane Glycoproteins/genetics

KW - Microtubule-Associated Proteins/genetics

KW - Middle Aged

KW - Myosin Type I/genetics

KW - Nerve Tissue Proteins/genetics

KW - Pituitary Neoplasms/genetics

KW - Proto-Oncogene Proteins/genetics

KW - RNA, Messenger/metabolism

KW - Receptors, Cell Surface/genetics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Ribonucleases/genetics

KW - Sialoglycoproteins/genetics

KW - Time Factors

U2 - 10.1530/EJE-17-0702

DO - 10.1530/EJE-17-0702

M3 - Journal article

VL - 178

SP - 295

EP - 307

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

SN - 0804-4643

IS - 3

ER -