Identification of driver genes and key pathways of non-functional pituitary adenomas predicts the therapeutic effect of STO-609.

OBJECTIVE: Our study is to identify DEGs (Differentially Expressed Genes), comprehensively investigate hub genes, annotate enrichment functions and key pathways of Non-functional pituitary adenomas (NFPAs), and also to verify STO-609 therapeutic effect. METHODS: The gene expression level of NFPA and normal tissues were compared to identify the DEGs (Differential expressed genes) based on gene expression profiles (GSE2175, GSE26966 and GSE51618). Enrichment functions, pathways and key genes were identified by carrying out GO (Gene Ontology), KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis and PPI (Protein-Protein Interation) network analysis. Moreover, experiments in vitro were conducted to verify the anti-NFPAs effects of STO-609. RESULTS: 169 over-expression genes and 182 low expression genes were identified among 3 datasets. Dopaminergic synapse and vibrio cholerae infection pathways have distinctly changed in NFPA tissues. The Ca2+/CaM pathway played important roles in NFPA. Four hub proteins encoded by genes CALM1, PRDM10, RIPK4 and MAD2L1 were recognized as hub proteins. In vitro, assays showed that STO-609 induced apoptosis of NFPA cells to inhibit the hypophysoma cellular viability, diffusion and migration. CONCLUSION: Four hub proteins, encoded by gene CALM1, PRDM10, RIPK4 and MAD2L1, played important roles in NFPA development. The Ca2+/CaM signaling pathway had significant alternations during NFPA forming process, the STO-609, a selective CaM-KK inhibitor, inhibited NFPA cellular viability, proliferation and migration. Meanwhile, NFPA was closely related to parkinson's disease (PD) in many aspects.

T5224, RSPO2 and AZD5363 are novel drugs against functional pituitary adenoma.

We tested whether the drugs T5224, RSPO2, and AZD5363 exert therapeutic effects against functioning pituitary adenoma (FPA). We analysed the gene expression profiles of four FPA mRNA microarray datasets (GSE2175, GSE26966, GSE36314, and GSE37153) from the Gene Expression Omnibus database and identified genes differentially expressed in FPA vs control tissues. We then carried out Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction network analyses. We also measured the difference in expression of hub genes between human normal pituitary cells and FPA cells using qRT-PCR. Our in vitro colony-formation and MTT assays showed that cell viability, number, and the size of clonogenicities were all lower in the presence of T5224, RSPO2, or AZD536 than in controls. Moreover, flow cytometry experiments showed that the incidence of apoptosis was higher in the presence of T5224, RSPO2, or AZD5363 than among controls, and was increased by increasing the doses of the drugs. This suggests these drugs could be used as therapeutic agents to treat FPA. Finally, we found that cFos, WNT5A, NCAM1, JUP, AKT3, and ADCY1 are abnormally expressed in FPA cells compared to controls, which highlights these genes as potential prognostic and/or therapeutic targets.