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      Correlations of Pituitary Tumor Transforming Gene Expression with Human Pituitary Adenomas: A Meta-Analysis

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          Abstract

          Objective

          Pituitary tumor transforming gene (PTTG) is an important paracrine growth factor involved in early lactotrope transformation and early onset of angiogenesis in pituitary hyperplasia. Emerging evidences have shown that PTTG expression may contribute to the etiology of pituitary adenomas; but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the correlations of PTTG expression with human pituitary adenomas.

          Methods

          A range of electronic databases were searched: MEDLINE (1966∼2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013) and the Chinese Biomedical Database (CBM) (1982∼2013) without language restrictions. Meta-analysis was performed using the STATA 12.0 software. Crude odds ratio (OR) or standard mean difference (SMD) with its corresponding 95% confidence interval (95%CI) were calculated.

          Results

          Twenty-four clinical cohort studies were included with a total of 1,464 pituitary adenomas patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of non-invasive patients (OR  = 6.68, 95%CI  = 3.72–11.99, P<0.001). We also found a significant difference in microvessel density between invasive and non-invasive patients (SMD  = 1.81, 95%CI  = 0.39–3.23, P = 0.013). However, there were no significant difference in PTTG expression between functional and non-functional patients with pituitary adenomas (OR  = 1.11, 95%CI  = 0.58–2.10, P = 0.753). No publication bias was detected in this meta-analysis (all P>0.05).

          Conclusion

          This present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas, while no correlations with functional status was found.

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          Most cited references28

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          CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009.

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            Pathogenesis of pituitary tumors.

            Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. Despite their high prevalence in the general population, these tumors are invariably benign and exhibit features of differentiated pituitary cell function as well as premature proliferative arrest. Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. Altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins or loss of pituitary suppressor factors may be associated with aberrant growth factor signaling. Considerable information on the etiology of these tumors has been derived from transgenic animal models, which may not accurately and universally reflect human tumor pathophysiology. Understanding subcellular mechanisms that underlie pituitary tumorigenesis will enable development of tumor aggression markers as well as novel targeted therapies.
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              Isolation and characterization of a pituitary tumor-transforming gene (PTTG).

              Pathogenesis of tumor formation in the anterior pituitary has been intensively studied, but the common mechanism involved in pituitary cell transformation and tumorigenesis remains elusive. In this study, we used mRNA differential display PCR to identify mRNAs that are differentially expressed in rat pituitary tumor cells compared with normal pituitary tissue. An mRNA exclusively expressed in pituitary tumor but not in normal pituitary was characterized. Using this pituitary tumor-specific PCR product as a probe to screen a cDNA library constructed from rat pituitary tumor GH4 cells, a cDNA of 974 bp was isolated. This cDNA encodes a novel protein of 199 amino acids, which contains no well characterized functional motifs. The mRNA of this cDNA is detected in normal adult testis and in embryonic liver, where the transcript is about 300 bp shorter and expressed at a much lower level than that detected from pituitary tumor cells. Overexpression of this protein in mouse 3T3 fibroblasts shows that it inhibits cell proliferation and induces cell transformation in vitro. Injection of transfected 3T3 cells into athymic nude mice resulted in tumor formation within 3 weeks in all animals. These results indicate that pituitary tumor cells express a unique and potent transforming gene (PTTG), which may play a role in pituitary tumorigenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                4 March 2014
                : 9
                : 3
                : e90396
                Affiliations
                [1 ]Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
                [2 ]Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
                Harvard Medical School, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RZW FF. Performed the experiments: JQX XHL. Analyzed the data: BH YY KD. Contributed reagents/materials/analysis tools: MF BX WL. Wrote the paper: JQX XHL.

                Article
                PONE-D-13-42249
                10.1371/journal.pone.0090396
                3942425
                0546de73-9053-45a1-bcdc-a1da947050e7
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 October 2013
                : 29 January 2014
                Page count
                Pages: 10
                Funding
                This study was supported by National Natural Science Foundation of China (Grant No. 81072084 and 81100869). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Molecular Cell Biology
                Gene Expression
                Medicine
                Anatomy and Physiology
                Endocrine System
                Endocrine Physiology
                Pituitary
                Clinical Genetics
                Clinical Research Design
                Meta-Analyses
                Endocrinology
                Endocrine Physiology
                Pituitary
                Pituitary
                Neurology
                Oncology
                Cancers and Neoplasms
                Endocrine Tumors
                Neurological Tumors
                Radiology
                Women's Health

                Uncategorized
                Uncategorized

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