Abstract
Objective
Pituitary adenomas (PAs) can adapt an aggressive phenotype by invading adjacent brain structures with rapid cellular proliferation. Previous studies demonstrated that excessive expression of metalloproteases ADAM12 and MMP-14 is instrumental for the active proliferation and invasiveness of PA cells in vitro and of tumors in vivo. However, the mechanisms regulating ADAM12 and MMP-14 expression in PAs remain unclear.
Methods
Target gene prediction and transcriptomic profiling of invasive vs. noninvasive human PA samples were performed to identify miRNA species potentially involved in the regulation of ADAM12 and MMP14. For cellular analyses of miRNA functions, two mouse PA cell lines (AtT20 and TtT/GF) were transfected with miR-149-3p and miR-149-5p, respectively. The effects of miR-149 (3p and 5p) on expression levels of ADAM12 and MMP14 were determined by Western blotting followed by an analysis of proliferation and colony formation assays, scratch migration assays, and invasion assays.
Results
A significant downregulation of miRNA-149 was observed in invasive vs. noninvasive PA (0.32 vs. 0.09, P<0.0001). In AtT-20 and TtT/GF mouse PAs cells, transfection of mimic miRNA-149 (3p and 5p) caused a significantly reduced cell proliferation and matrigel invasion, whilst the effect on cell migration was less pronounced. Both strands of miRNA-149 (3p and 5p) markedly reduced protein levels of ADAM12 and MMP-14 by at least 40% in both cell lines.
Conclusion
This study proved that the invasiveness of PA cells is, at least partly, regulated by miRNA-149-dependent expression of ADAM12 and MMP-14.
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Acknowledgements
We thank Ulrike Schötz, Department for Radiology, for help with colony formation assays and Kai ZHAO for expert help.
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The authors declare no conflict of interest.
Authors Jörg W. Bartsch and Ting LEI are members of the Editorial Board for Current Medical Science. The paper was handled by other editors and has undergone rigorous peer review process. Authors Jörg W. Bartsch and Ting LEI were not involved in the journal’s review of, or decisions related to, this manuscript.
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This research was funded in part by the ERANET PerMed consortium “PerProGlio” (to J.W.B. and A.S.).
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Zhang, Z., Schäfer, A., Voellger, B. et al. MicroRNA-149 Regulates Proliferation, Migration, and Invasion of Pituitary Adenoma Cells by Targeting ADAM12 and MMP14. CURR MED SCI 42, 1131–1139 (2022). https://doi.org/10.1007/s11596-022-2676-3
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DOI: https://doi.org/10.1007/s11596-022-2676-3
Key words
- pituitary adenoma
- microRNA
- miRNA-149
- ADAM12
- MMP-14
- invasion