Phosphatidylinositol Promotes Pituitary Adenoma Cell Proliferation and Invasion by Regulating POU1F1 Expression

Background

Pituitary adenoma (PA) is one of the most common primary intracranial tumors, accounting for approximately 15% of all intracranial tumors. Although most pituitary adenomas are benign, about 30% of them are invasive, known as invasive pituitary adenomas (IPA). Invasive pituitary adenomas are typically larger in size and exhibit invasive growth, leading to poor response to drugs and radiotherapy, and higher patient mortality. Therefore, exploring the molecular mechanisms of invasive pituitary adenomas is crucial for early diagnosis and improving patient survival rates.

In recent years, advancements in metabolomics and proteomics have provided new perspectives for tumor research. Metabolic reprogramming is considered a key mechanism underlying tumor cell proliferation, invasion, and metastasis. Phosphatidylinositol (PI), an important component of cell membrane phospholipids, plays a critical role in intracellular signaling. However, the role and mechanisms of phosphatidylinositol in pituitary adenoma invasiveness remain poorly understood.

Source of the Study

This study was conducted by researchers including Tongjiang Xu and Xiaodong Zhai from the Provincial Hospital affiliated with Shandong First Medical University in China. It was published in Cancer & Metabolism in 2025. The study was supported by the Natural Science Foundation of Shandong Province (No. ZR2023MH271) and the Provincial Hospital Foundation (No. YW002).

Research Process and Results

1. Proteomic Analysis

The study first compared the differential protein expression between invasive pituitary adenoma (IPA) and non-invasive pituitary adenoma (NIPA) tissues using TMT-labeled quantitative proteomics. The results showed that the significantly upregulated proteins in IPA tissues included AD021, C2orf15, PLCXD3, HIST3H2BB, and POU1F1, while the downregulated proteins included AIPL1, CALB2, GLUD2, SLC4A10, and GTF2I. Among these, POU1F1, a pituitary-specific transcription factor, is closely associated with the progression of pituitary adenomas.

2. Metabolomic Analysis

The study further analyzed metabolite differences in the venous blood of IPA and NIPA patients using untargeted metabolomics. The results revealed that serum levels of phosphatidylinositol (PI) were significantly elevated in IPA patients, while melibiose levels were significantly reduced. The phosphatidylinositol signaling pathway may play a key role in the invasiveness of IPA.

3. Effects of Phosphatidylinositol on Pituitary Adenoma Cells

The research team then investigated the effects of phosphatidylinositol on pituitary adenoma cells (GH3 cells) in vitro. The results showed that phosphatidylinositol stimulation significantly increased the expression of PITPNM1, POU1F1, C2orf15, and LDHA, and promoted the phosphorylation of AKT and ERK. Additionally, phosphatidylinositol significantly enhanced the proliferation, migration, and invasion capabilities of GH3 cells. By knocking down PITPNM1, the researchers found that phosphatidylinositol-induced expression of POU1F1, C2orf15, and LDHA, as well as the phosphorylation of AKT and ERK, were all suppressed.

4. Regulatory Role of POU1F1

The study further explored the role of POU1F1 in phosphatidylinositol-induced pituitary adenoma cell invasion. The results showed that POU1F1 knockdown significantly inhibited the expression of C2orf15 and LDHA and reduced the invasive capability of GH3 cells. Through chromatin immunoprecipitation (ChIP) and luciferase reporter assays, the researchers confirmed that POU1F1 directly binds to and positively regulates the transcription of C2orf15 and LDHA.

5. In Vivo Validation

Finally, the research team validated the effects of phosphatidylinositol on pituitary adenoma cell metastasis using a mouse model. The results showed that phosphatidylinositol treatment significantly accelerated lung metastasis of GH3 cells and increased the expression of PITPNM1, POU1F1, and C2orf15.

Conclusions and Significance

This study revealed the molecular mechanism by which phosphatidylinositol promotes pituitary adenoma cell proliferation and invasion through the PITPNM1/AKT/ERK/POU1F1 signaling axis. Specifically, phosphatidylinositol increases the expression of PITPNM1, promoting the accumulation and transport of intracellular phosphatidylinositol, thereby activating the AKT and ERK signaling pathways. The phosphorylation of AKT and ERK further upregulates the expression of POU1F1, which positively regulates the transcription of C2orf15 and LDHA, promoting the invasion and metastasis of pituitary adenoma cells.

This discovery not only provides new insights into the molecular mechanisms of invasive pituitary adenomas but also offers potential therapeutic targets for future treatments. For example, inhibitors targeting PITPNM1 or POU1F1 may become effective strategies for treating invasive pituitary adenomas.

Research Highlights

1. Innovative Discovery: First to reveal the molecular mechanism by which phosphatidylinositol promotes pituitary adenoma cell invasion through the PITPNM1/AKT/ERK/POU1F1 signaling axis.
2. Multi-Omics Integration: Comprehensive analysis of the molecular characteristics of invasive pituitary adenomas using proteomics and metabolomics.
3. In Vitro and In Vivo Validation: Validated the critical role of phosphatidylinositol in pituitary adenoma invasion through in vitro cell experiments and in vivo mouse models.
4. Potential Therapeutic Targets: PITPNM1 and POU1F1 may serve as new targets for treating invasive pituitary adenomas.

Additional Valuable Information

The research team also developed an LC-MS-based metabolomics analysis method capable of rapidly and accurately detecting changes in serum metabolites. This method is not only applicable to pituitary adenoma research but can also be widely used for metabolomic analysis of other tumors.

This study provides new insights into the molecular mechanisms of invasive pituitary adenomas and offers potential therapeutic targets for future treatments, holding significant scientific value and clinical application prospects.