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Integrating single-cell and bulk RNA sequencing data reveals RGS4 as a functional driver in a proliferative subgroup
Changxi Han1, Qiuyue Fang1, Bo Zhang2
1Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Introduction:
The molecular determinants underlying the heterogeneity and proliferative behavior of Steroidogenic Factor-1 (SF-1) lineage Pituitary Neuroendocrine Tumors (PitNETs) remain insufficiently defined.
Methods:
We performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic datasets from SF-1 lineage PitNETs to identify molecular subgroups and their defining biomarkers. The functional significance of the top candidate gene, Regulator of G-protein Signaling 4 (RGS4), was examined using gain- and loss-of-function approaches and pharmacological inhibition in pituitary adenoma cell lines. Mechanistic studies were conducted using protein interaction and stability assays.
Results:
We identified a previously unrecognized SF-1 lineage subgroup characterized by markedly elevated RGS4 expression, which correlated with larger tumor size and higher MIB-1 proliferation index. Functional experiments demonstrated that Rgs4 enhances tumor cell proliferation and inhibits apoptosis. Mechanistically, RGS4 promotes p53 ubiquitination, resulting in its destabilization and proteasomal degradation.
Conclusion:
This study defines a new SF-1 lineage PitNETs subgroup characterized by high-RGS4 expression. RGS4 promotes tumor proliferation by destabilizing p53, highlighting the RGS4-p53 axis as a promising therapeutic target.
Insights
Researchers identified a new subgroup of Steroidogenic Factor-1 (SF-1) lineage pituitary neuroendocrine tumors (PitNETs) with high Regulator of G-protein Signaling 4 (RGS4) expression. RGS4 promotes tumor growth by degrading the p53 protein.
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.
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