Patterns of Gene Expression in Pituitary Carcinomas and Adenomas Analyzed by High-Density Oligonucleotide Arrays, Reverse Transcriptase-Quantitative PCR, and Protein Expression

Abstract

Very few of the genes that are important in pituitary tumor initiation, progression, and metastasis have been identified to date. To identify potential genes that may be important in pituitary tumor progression and carcinoma development, we used Affymetrix GeneChip HGU-133A-oligonucleotide arrays, which contain more than 15,000 characterized genes from the human genome to study gene expression in an ACTH pituitary carcinoma metastatic to the liver and four pituitary adenomas. Reverse-transcriptase real-time quantitative- PCR (RT-qPCR) was then used to analyze 4 nonneoplastic pituitaries, 19 adenomas, and the ACTH carcinoma. A larger series of pituitary adenomas and carcinomas were also analyzed for protein expression using tissue microarrays (TMA) (n = 233) and by Western blotting (n = 18). There were 4298 genes that were differentially expressed among the adenomas compared to the carcinoma, with 2057 genes overexpressed and 2241 genes underexpressed in the adenomas. The beta-galactoside binding protein galactin-3 was underexpressed in some adenomas compared to the carcinomas. Prolactin (PRL) and ACTH tumors had the highest levels of expression of galectin-3. The human achaetescute homolog-1 ASCL1 (hASH-1) gene was also underexpressed in some adenomas compared to the carcinoma. Prolactin and ACTH tumors had the highest levels of expression of hASH-1. ID2, which has an important role in cell development and tumorigenesis, was underexpressed in some adenomas compared to the carcinomas. Transducin-like enhancer of split four/ Groucho (TLE-4) was over-expressed in adenomas compared to the ACTH carcinoma. The differential expression of these genes was validated by RT-qPCR, by immunohistochemistry using TMA and by Western blotting. These results indicate that the LGALS3, hASH1, ID2, and TLE-4 genes may have important roles in the development of pituitary carcinomas.

The role of TLE1 in synovial sarcoma

“…13 Although most of these related studies reported that the Groucho/TLE family of corepressors inhibits gene expression and the signaling pathway, it also enhances the gene expression including the macrophage colony stimulating factor receptor, 14 Notch ligand Jagged1, 15 and Wnt pathway mediator plakoglobin. 16 The Groucho/ TLE family of corepressors was also suggested to be an oncogene because the over-expression of Gro/TLE family members is associated with lung adenocarcinoma, 17 grade 1 astrocytomas, 18 higher-grade meningiomas, 19 pituitary adenomas, 20,21 and synovial sarcomas, 7,22 which is consistent with our results.…”

Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival

“…Our studies demonstrating low levels of TLE1 and TLE4 expression in myeloid cell lines and subsets of AML samples, and potential tumor suppressor-like activities of the Gro/TLEs, stand in contrast to recent reports that overexpression of various Gro/TLE family members is seen in grade 1 astrocytomas, 61 higher-grade meningiomas, 62 pituitary adenomas, 63,64 and synovial sarcomas. 65,66 In addition, overexpression of murine Tle1/Grg1 in a transgenic model predisposed to the development of lung adenocarcinoma.…”

Growth hormone-secreting adenomas: pathology and cell biology

“…Several studies have used microarraybased, high-throughput gene profiling for identification of candidate genes and pituitary-specific signaling pathways that may be participate in pituitary tumorigenesis, including studies analyzing GH-secreting adenomas. 19,20,36,43 Except for genes linked to adenoma subtype, including GH and GHRH-R, 36,43 the majority of identified genes with potential tumorigenic effect are not unique to GH-secreting adenomas and seem to contribute to the pathogenesis of most adenomas (Table 1).…”