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

Eur J Endocrinol. 2018 Mar;178(3):295-307. doi: 10.1530/EJE-17-0702. Epub 2017 Dec 19.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenoma / genetics*
  • Adenoma / metabolism
  • 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
  • Membrane Proteins
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Myosin Type I / genetics
  • Nerve Tissue Proteins / genetics
  • Pituitary Neoplasms / genetics*
  • Pituitary Neoplasms / metabolism
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins
  • Receptors, Cell Surface / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleases / genetics
  • Sialoglycoproteins / genetics
  • Time Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • Cell Adhesion Molecules
  • EMCN protein, human
  • GPM6A protein, human
  • Intracellular Signaling Peptides and Proteins
  • MTDH protein, human
  • MYO1B protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • PCDH18 protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Cell Surface
  • SKIL protein, human
  • SPAG9 protein, human
  • Sialoglycoproteins
  • UNC5D protein, human
  • hook1 protein, human
  • Luteinizing Hormone
  • Follicle Stimulating Hormone
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACB protein, human
  • CNOT6L protein, human
  • Ribonucleases
  • Myosin Type I