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Purpose <p>Pituitary neuroendocrine tumors (PitNETs) are usually benign tumors of the anterior lobe of the pituitary gland, but some exhibit invasive behavior. Research increasingly highlights microRNAs (miRs) as promising markers of PitNET invasiveness. Our study aimed to identify and validate miR expression differences in invasive versus noninvasive PitNETs, independent of their hormonal activity.</p> Methods <p>We evaluated the global expression of 754 miRs in 12 human PitNETs (6 invasive and 6 noninvasive) using TaqMan Low-Density Array cards. We further validated the expression of the 9 most dysregulated miRs in an expanded cohort of 75 human PitNETs using quantitative PCR. Moreover, we examined the expression of 6 mRNAs, for which our miRs had potential binding sites. This was followed by in vitro functional validation using colony formation, migration, and invasion assays in the RC-4B/C rat pituitary adenoma cell line.</p> Results <p>Of the 754 miRs, 22 showed significant dysregulation in the initial cohort. In the expanded cohort (<i>n</i> = 75) <i>miR-191-5p</i> was significantly downregulated in invasive PitNETs (<i>p</i> = 0.0062**) across all hormonal activity types, while <i>miR-186-5p</i> was upregulated in gonadotrophs and somatotrophs (<i>p</i> = 0.0264*). In vitro experiments revealed that <i>miR-454-3p</i> and <i>miR-590-5p</i> increased invasiveness of the model cell line RC-4B/C. Coexpression analysis revealed associations between specific miRs and targeted genes such as <i>PTEN</i>,<i> TIMP2</i>, and <i>TGFB1</i>, which may suggest their potential role in PitNETs pathogenesis. Yet, negative correlation among invasive tumors between <i>mir-26a-5p</i> and <i>PTEN</i> expression may suggest its regulatory mechanisms.</p> Conclusions <p>This study identifies <i>miR-191-5p</i> and <i>miR-186-5p</i> as potential biomarkers for invasive PitNETs, while functional studies highlight <i>miR-454-3p</i> and <i>miR-590-5p</i> as potential contributors to tumor invasiveness. Correlations with target genes <i>PTEN</i>, <i>TIMP2</i>, and <i>TGFB1</i> suggest miRs-mediated regulatory pathways in PitNET pathogenesis. These findings provide insights into the molecular mechanisms underlying PitNET invasiveness, with implications for biomarker development and therapeutic targeting.</p>

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MicroRNA signatures of invasiveness in PitNETs: a focus on miR-186-5p, miR-191-5p, miR-454-3p, and miR-590-5p

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Beata Rak-Makowska,
  • Filip Garbicz,
  • Dawid Mehlich,
  • Emir Sajjad,
  • Zofia Kuśmierczyk,
  • Grzegorz Zieliński,
  • Maria Maksymowicz,
  • Sabrina Doboszek,
  • Tomasz M. Grzywa,
  • Paweł Włodarski,
  • Dominika Nowis,
  • Urszula Ambroziak

摘要

Purpose

Pituitary neuroendocrine tumors (PitNETs) are usually benign tumors of the anterior lobe of the pituitary gland, but some exhibit invasive behavior. Research increasingly highlights microRNAs (miRs) as promising markers of PitNET invasiveness. Our study aimed to identify and validate miR expression differences in invasive versus noninvasive PitNETs, independent of their hormonal activity.

Methods

We evaluated the global expression of 754 miRs in 12 human PitNETs (6 invasive and 6 noninvasive) using TaqMan Low-Density Array cards. We further validated the expression of the 9 most dysregulated miRs in an expanded cohort of 75 human PitNETs using quantitative PCR. Moreover, we examined the expression of 6 mRNAs, for which our miRs had potential binding sites. This was followed by in vitro functional validation using colony formation, migration, and invasion assays in the RC-4B/C rat pituitary adenoma cell line.

Results

Of the 754 miRs, 22 showed significant dysregulation in the initial cohort. In the expanded cohort (n = 75) miR-191-5p was significantly downregulated in invasive PitNETs (p = 0.0062**) across all hormonal activity types, while miR-186-5p was upregulated in gonadotrophs and somatotrophs (p = 0.0264*). In vitro experiments revealed that miR-454-3p and miR-590-5p increased invasiveness of the model cell line RC-4B/C. Coexpression analysis revealed associations between specific miRs and targeted genes such as PTEN, TIMP2, and TGFB1, which may suggest their potential role in PitNETs pathogenesis. Yet, negative correlation among invasive tumors between mir-26a-5p and PTEN expression may suggest its regulatory mechanisms.

Conclusions

This study identifies miR-191-5p and miR-186-5p as potential biomarkers for invasive PitNETs, while functional studies highlight miR-454-3p and miR-590-5p as potential contributors to tumor invasiveness. Correlations with target genes PTEN, TIMP2, and TGFB1 suggest miRs-mediated regulatory pathways in PitNET pathogenesis. These findings provide insights into the molecular mechanisms underlying PitNET invasiveness, with implications for biomarker development and therapeutic targeting.