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Oct-1 induces pituitary tumor transforming gene expression in endocrine tumors.

ABSTRACT: As human pituitary tumor transforming gene (hPTTG1) is upregulated in endocrine tumors, we studied regulatory mechanisms for hPTTG1 expression. We identified Oct-1-binding motifs in the hPTTG1 promoter region and show Oct-1-specific binding to the hPTTG1 promoter using chromatin immunoprecipitation. We overexpressed Oct-1 and observed approximately 2.5-fold activation of hPTTG1 promoter luciferase constructs (-2642/-1 and -1717/-1). Transcriptional activation was abrogated by co-transfection of an inactive Oct-1 form lacking the POU domain or by utilizing mutated hPTTG1 promoters or mutants devoid of two Oct-1-binding motifs (-1717/-1mut, -637/-1 or -433/-1). Using biotin-streptavidin pull-down assays, we confirmed Oct-1 binding to the two octamer motifs in the hPTTG1 promoter (-1669/-1631 and -1401/-1361). Endogenous hPTTG1 mRNA and protein increased up to approximately fourfold in Oct-1 transfectants, as measured by real-time PCR and western blot. In contrast, siRNA-mediated suppression of endogenous Oct-1 attenuated both the hPTTG1 mRNA and protein levels. Using confocal immunofluorescence imaging, Oct-1 and hPTTG1 were concordantly upregulated in pituitary (57 and 62%, n=79, P<0.01) and breast tumor specimens (57 and 42%, n=77, P<0.05) respectively. The results show that Oct-1 transactivates hPTTG1, and both proteins are concordantly overexpressed in endocrine tumors, thus offering a mechanism for endocrine tumor hPTTG1 abundance.

SUBMITTER: Zhou C

PROVIDER: S-EPMC3123374 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Oct-1 induces pituitary tumor transforming gene expression in endocrine tumors.

Zhou Cuiqi C Tong Yunguang Y Wawrowsky Kolja K Bannykh Serguei S Donangelo Ines I Melmed Shlomo S

Endocrine-related cancer 20080611 3

As human pituitary tumor transforming gene (hPTTG1) is upregulated in endocrine tumors, we studied regulatory mechanisms for hPTTG1 expression. We identified Oct-1-binding motifs in the hPTTG1 promoter region and show Oct-1-specific binding to the hPTTG1 promoter using chromatin immunoprecipitation. We overexpressed Oct-1 and observed approximately 2.5-fold activation of hPTTG1 promoter luciferase constructs (-2642/-1 and -1717/-1). Transcriptional activation was abrogated by co-transfection of ...[more]

PMID: 18550719

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Project description:Background and aimAbout a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates.MethodsWe performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis.ResultsEighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression (p = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression (p = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence.ConclusionsPD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.

Project description:BackgroundAlthough evidence regarding pituitary tumor-transforming 3, pseudogene (PTTG3P) involvement in human cancers has been acquired via human and animal model-based molecular studies, there is a lack of pan-cancer analysis of this gene in human tumors.MethodsTumor-causing effects of PTTG3P in 24 human tumors were explored using The Cancer Genome Atlas (TCGA) datasets from different bioinformatics databases and applying in silico tools such as The University of ALabama at Birmingham CANcer (UALCAN), Human Protein Atlas (HPA), Kaplan Meier (KM) plotter, cBioPortal, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Cytoscape, Database for Annotation, Visualization, and Integrated Discovery (DAVID), Tumor IMmune Estimation Resource (TIMER), and Comparative Toxicogenomics Database (CTD). Then, via in vitro experiments, including RNA sequencing (RNA-seq) and targeted bisulfite sequencing (bisulfite-seq), expression and promoter methylation levels of PTTG3P were verified in cell lines.ResultsThe PTTG3P expression was overexpressed across 23 malignancies and its overexpression was further found significantly effecting the overall survival (OS) durations of the esophageal carcinoma (ESCA) and head and neck cancer (HNSC) patients. This important information helps us to understand that PTTG3P plays a significant role in the development and progression of ESCA and HNSC. As for PTTG3P functional mechanisms, this gene along with its other binding partners was significantly concentrated in "Oocyte meiosis", "Cell cycle", "Ubiquitin mediated proteolysis", and "Progesterone-mediated oocyte maturation". Moreover, ESCA and HNSC tissues having the higher expression of PTTG3P were found to have lower promoter methylation levels of PTTG3P and higher CD8+ T immune cells level. Additionally, PTTG3P expression-regulatory drugs were also explored in the current manuscript for designing appropriate treatment strategies for ESCA and HNSC with respect to PTTG3P expression.ConclusionOur pan-cancer based findings provided a comprehensive account of the oncogenic role and utilization of PTTG3P as a novel molecular biomarker of ESCA and HNSC.

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Oct-1 induces pituitary tumor transforming gene expression in endocrine tumors.

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Oct-1 induces pituitary tumor transforming gene expression in endocrine tumors.

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