Integrating single-cell and bulk RNA sequencing data reveals RGS4 as a functional driver in a proliferative subgroup...

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Steroidogenic Factor-1 (SF-1) lineage pituitary neuroendocrine tumors (PitNETs) exhibit heterogeneity and variable proliferative behavior.
• Molecular drivers of PitNET heterogeneity and proliferation are not fully understood.

Purpose of the Study:

• To identify molecular subgroups within SF-1 lineage PitNETs.
• To define biomarkers for these subgroups.
• To investigate the functional role of candidate genes in PitNET progression.

Main Methods:

• Integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic data from SF-1 lineage PitNETs.
• Gain- and loss-of-function studies of Regulator of G-protein Signaling 4 (RGS4) in pituitary adenoma cell lines.
• Protein interaction and stability assays to elucidate RGS4 mechanisms.

Main Results:

• A novel SF-1 lineage PitNET subgroup with significantly elevated RGS4 expression was identified.
• High RGS4 expression correlated with larger tumor size and increased proliferation (MIB-1 index).
• RGS4 was found to enhance tumor cell proliferation and inhibit apoptosis by promoting p53 destabilization and degradation.

Conclusions:

• A new SF-1 lineage PitNET subgroup characterized by high RGS4 expression is defined.
• The RGS4-p53 axis represents a potential therapeutic target for promoting tumor proliferation in PitNETs.