Gene Summary

Gene:PTTG1; pituitary tumor-transforming 1
Summary:The encoded protein is a homolog of yeast securin proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC. The gene product has transforming activity in vitro and tumorigenic activity in vivo, and the gene is highly expressed in various tumors. The gene product contains 2 PXXP motifs, which are required for its transforming and tumorigenic activities, as well as for its stimulation of basic fibroblast growth factor expression. It also contains a destruction box (D box) that is required for its degradation by the APC. The acidic C-terminal region of the encoded protein can act as a transactivation domain. The gene product is mainly a cytosolic protein, although it partially localizes in the nucleus. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PTTG1 (cancer-related)

Wang F, Liu Y, Chen Y
Pituitary tumor transforming gene-1 in non-small cell lung cancer: Clinicopathological and immunohistochemical analysis.
Biomed Pharmacother. 2016; 84:1595-1600 [PubMed] Related Publications
Pituitary tumor transforming gene-1 (PTTG1) is a novel oncogene and overexpressed in a wide variety of human cancers. However, the clinical and prognostic significance of PTTG1 in non-small cell lung cancer (NSCLC) is still unknown. The expression status of PTTG1 in NSCLC at the publicly available GEO databases (GSE19804) was observed. The mRNA and protein expression of PTTG1 in NSCLC tissues and cell lines was detected by qRT-PCR and Western blot, and the association between PTTG1 expression and clinicopathological factors was analyzed by immunohistochemistry. In our Results, PTTG1 was one of genes overexpressed in NCSLC samples compared with paired adjacent normal lung samples in microarray data (GSE19804). PTTG1 mRNA and protein expressions were increased in NSCLC tissues and cell lines. PTTG1 protein expression was correlated with malignant status and poor prognosis of NSCLC patients. In conclusion, PTTG1 is correlated with NSCLC progression and as an independent poor prognostic factor in NSCLC patients.

Wierzbicka-Tutka I, Sokołowski G, Bałdys-Waligórska A, et al.
PTTG and Ki-67 expression in pituitary adenomas.
Przegl Lek. 2016; 73(2):53-8 [PubMed] Related Publications
INTRODUCTION: The unpredictable biology of pituitary adenomas makes it a therapeutic challenge. Moreover ,histopathology of pituitary carcinomas and locally invasive adenomas are indistinguishable from benign tumors and a new marker which would enable to differentiate those lesions is vital. The aim of the study was to evaluate Ki-67 and PTTG (pituitary tumour--transforming gene) expression in pituitary adenomas and their applicationas markers of tumour aggressiveness.
MATERIAL AND METHODS: A retrospective analysis of 55 patients: 32 females(58%) and 23 males (42%), mean age 50 ± 16 years who underwent pituitary tumor surgery between 2003-2012. Ki-67 and PTTG indices were determined by immunohistochemical staining. Magnetic resonance imaging or computed tomography was performed beforehand and one year after surgery to figure a potential tumour progression, tumour size and correlation to adjacent tissues.
RESULTS: The expression of Ki-67and PTTG was revealed in cell nucleiin 88% and 85% of adenomas, respectively. The median Ki-67 and PTTG indices were 1.4 and 1.0, respectively(p = 0.006). In the group with macroadenoma as compared with the group with microadenoma, median Ki-67 index was higher (1.4% vs. 1.03%; p = 0.02). We did not find correlation between both Ki-67 and PTTG indices and tumour progression. Tumours with positive immunostaining towards FSH revealed lower Ki-67 and PTTG indices than the rest with a negative one (0.6% vs.1.84%, p = 0.0004 and 0.67% vs 1.23%,p = 0.047; respectively). However, PTTG index was higher in the group with acromegaly as compared to the group with clinically non-functioning pituitary adenoma (NFPA) (1.28% vs.0.35%; p = 0.02).
CONCLUSIONS: Positive nuclear expression of Ki-67 and PTTG was observed in the majority of pituitary adenomas. Only higher Ki-67 expression was related to the tumour invasiveness found on MRI/CT. Tumour progressionwas not related to both Ki-67 and PTTG expression.

Xiea Y, Wangb R
Pttg1 Promotes Growth of Breast Cancer through P27 Nuclear Exclusion.
Cell Physiol Biochem. 2016; 38(1):393-400 [PubMed] Related Publications
BACKGROUND/AIMS: A role of Pituitary Tumor Transforming Gene 1 (Pttg1) in the carcinogenesis has been shown in some cancers, but not in BC (BC).
METHODS: We compared the levels of Pttg1 in the resected BC tissue with the adjacent normal breast tissue from the same patient. We modified Pttg1 levels in a BC cell line, MCF7, by either a Pttg1 transgene, or a Pttg1 shRNA. The cell growth was measured in an MTT assay. The cell apoptosis was measured by apoptosis assay. The nuclear protein of cell-cycle-related genes was examined in Pttg1-modifed BC cells. Co-immunoprecipitation was performed to examine the association of Pttg1 and p27.
RESULTS: We detected significantly higher levels of Pttg1 in the resected BC tissue, compared to the adjacent normal breast tissue from the same patient. Overexpression or depletion of Pttg1 in MCF7 significantly increased or inhibited cell growth, respectively. Changes in Pttg1 levels, however, did not alter cell apoptosis, suggesting that Pttg1 increases cell growth through augmented cell proliferation, rather than decreased cell apoptosis. Among all examined cell-cycle-related proteins in Pttg1-modifed BC cells, only nuclear p27 levels were significantly affected. Further, co-immunoprecipitation showed that Pttg1 directly associated with p27.
CONCLUSION: Pttg1 may increase BC cell growth through nuclear exclusion of p27, which highlights a novel molecular regulatory machinery in tumorigenesis of BC.

Wang LQ, Zhao LH, Qiao YZ
Identification of potential therapeutic targets for lung cancer by bioinformatics analysis.
Mol Med Rep. 2016; 13(3):1975-82 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to identify potential therapeutic targets for lung cancer and explore underlying molecular mechanisms of its development and progression. The gene expression profile datasets no. GSE3268 and GSE19804, which included five and 60 pairs of tumor and normal lung tissue specimens, respectively, were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) between lung cancer and normal tissues were identified, and gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the DEGs was performed. Furthermore, protein‑protein interaction (PPI) networks and a transcription factor (TF) regulatory network were constructed and key target genes were screened. A total of 466 DEGs were identified, and the PPI network indicated that IL‑6 and MMP9 had key roles in lung cancer. A PPI module containing 34 nodes and 547 edges was obtained, including PTTG1. The TF regulatory network indicated that TFs of FOSB and LMO2 had a key role. Furthermore, MMP9 was indicated to be the target of FOSB, while PTTG1 was the target of LMO2. In conclusion, the bioinformatics analysis of the present study indicated that IL‑6, MMP9 and PTTG1 may have key roles in the progression and development of lung cancer and may potentially be used as biomarkers or specific therapeutic targets for lung cancer.

Sapochnik M, Nieto LE, Fuertes M, Arzt E
Molecular Mechanisms Underlying Pituitary Pathogenesis.
Biochem Genet. 2016; 54(2):107-19 [PubMed] Related Publications
During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors.

Gatalica Z, Vranic S, Ghazalpour A, et al.
Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.
Oncotarget. 2016; 7(2):1707-16 [PubMed] Free Access to Full Article Related Publications
Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

Wang X, Duan W, Li X, et al.
PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway.
Oncotarget. 2015; 6(38):40959-69 [PubMed] Free Access to Full Article Related Publications
Human pituitary tumor-transforming gene (PTTG) is a proto-oncogene involved in the development, invasion, and metastasis of many types of cancer, including ovarian cancer. However, little is known about the role of PTTG in the metabolic shift of ovarian cancer cells. In our study, we show that PTTG expression was positively correlated with the differentiation degree of ovarian cancer tissue. In addition, PTTG suppression by specific shRNA could inhibit the proliferation of ovarian cancer cells A2780 and SKOV-3. Furthermore, aerobic glycolysis was suppressed and oxidative phosphorylation was increased in ovarian cancer cells after PTTG suppression. We further found that the expression of c-myc and several crucial enzymes involved in aerobic glycolysis (e.g., PKM2, LDHA, and glucose transporter 1 (GLUT-1)) were downregulated by PTTG knockwown. Overexpression of c-myc could prevent the metabolic shift induced by PTTG knockwown. Together, our findings suggest that the oncogene PTTG promotes the progression of ovarian cancer cells, and its loss resists tumor development, in part, by regulating cellular metabolic reprogramming that supports cell growth and proliferation via c-myc pathway.

Liang HQ, Wang RJ, Diao CF, et al.
The PTTG1-targeting miRNAs miR-329, miR-300, miR-381, and miR-655 inhibit pituitary tumor cell tumorigenesis and are involved in a p53/PTTG1 regulation feedback loop.
Oncotarget. 2015; 6(30):29413-27 [PubMed] Free Access to Full Article Related Publications
Deregulation of the pituitary tumor transforming gene (PTTG1), a newly discovered oncogene, is a hallmark of various malignancies, including pituitary tumors. However, the mechanisms regulating PTTG1 expression are still needed to be explored. MicroRNAs (miRNAs) are a novel class of small RNA molecules that act as posttranscriptional regulators of gene expression and can play a significant role in tumor development. Here, we identified a series of miRNAs, namely, miR-329, miR-300, miR-381 and miR-655, which could target PTTG1 messenger RNA and inhibit its expression. Interestingly, all four miRNAs significantly that are downregulated in pituitary tumors were mapped to the 14q32.31 locus, which acts as a tumor suppressor in several cancers. Functional studies show that the PTTG1-targeting miRNAs inhibit proliferation, migration and invasion but induce apoptosis in GH3 and MMQ cells. Furthermore, overexpression of a PTTG1 expression vector lacking the 3'UTR partially reverses the tumor suppressive effects of these miRNAs. Next, we identified the promoter region of PTTG1-targeting miRNAs with binding sites for p53. In our hands, p53 transcriptionally activated the expression of these miRNAs in pituitary tumor cells. Finally, we found that PTTG1 could inhibit p53 transcriptional activity to the four miRNAs. These data indicate the existence of a feedback loop between PTTG1 targeting miRNAs, PTTG1 and p53 that promotes pituitary tumorigenesis. Together, these findings suggest that these PTTG1-targeting miRNAs are important players in the regulation of pituitary tumorigenesis and that these miRNAs may serve as valuable therapeutic targets for cancer treatment.

Zheng Y, Guo J, Zhou J, et al.
FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion.
BMC Med Genomics. 2015; 8:49 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis is the major cause of cancer-related death. Forkhead Box M1 (FoxM1) is a master regulator of tumor metastasis. This study aims to identify new FoxM1 targets in regulating tumor metastasis using bioinformatics tools as well as biological experiments.
METHODS: Illumina microarray was used to profile WT and PTTG1 knockout HCT116 cells. R2 Genomics Analysis was used to identify PTTG1 as a potential FoxM1 targeted gene. Luciferase reporter array, EMSA and Chromatin Immunoprecipitation (ChIP) were used to determine the binding of FoxM1 to PTTG1 promoter. Boyden chamber assay was used to evaluate the effects of FoxM1-PTTG1 on cell migration and invasion. Splenic-injection induced liver metastasis model was used to evaluate the effects of FoxM1-PTTG1 on liver metastasis of colorectal cancer.
RESULTS: Analyses of multiple microarray datasets derived from human colorectal cancer indicated that correlation levels of FoxM1 and pituitary tumor transforming gene (PTTG1) are highly concordant (R = 0.68 ~ 0.89, p = 2.1E-226 ~ 9.6E-86). FoxM1 over-expression increased and knock-down decreased PTTG1 expression. Luciferase reporter assay identified that the -600 to -300 bp region of PTTG1 promoter is important for FoxM1 to enhance PTTG1 promoter activity. EMSA and ChIP assays confirmed that FoxM1 directly binds to PTTG1 promoter at the -391 to -385 bp region in colorectal cancer cells. Boyden chamber assay indicated that both FoxM1 and PTTG1 regulate migration and invasion of HCT116 and SW620 colorectal cancer cells. Further in vivo assays indicated that PTTG1 knock out decreased the liver metastasis of FoxM1 over-expressing HCT116 cells. Microarray analyses identified 662 genes (FDR < 0.05) differentially expressed between WT and PTTG1(-/-) HCT116 cells. Among them, dickkopf homolog 1 (DKK1), a known WNT pathway inhibitor, was suppressed by PTTG1 and FoxM1.
CONCLUSIONS: PTTG1 is a FoxM1 targeted gene. FoxM1 binds to PTTG1 promoter to enhance PTTG1 transcription, and FoxM1-PTTG1 pathway promotes colorectal cancer migration and invasion.

Cui L, Xu S, Song Z, et al.
Pituitary tumor transforming gene: a novel therapeutic target for glioma treatment.
Acta Biochim Biophys Sin (Shanghai). 2015; 47(6):414-21 [PubMed] Related Publications
Glioma which has strong proliferation and angiogenesis ability is the most common and malignant primary tumor in central nervous system. Pituitary tumor transforming gene (PTTG) is found in pituitary tumor, and plays important role in cell proliferation, cell cycle, cell apoptosis, and angiogenesis. However, the role of PTTG in glioma is still incompletely investigated. Here, we explored the correlation between PTTG and glioma grade, as well as micro-vessel density (MVD). In addition, siRNA was used to silence PTTG expression in glioma cell lines including U87MG, U251, and SHG44. Cell proliferation, apoptosis, invasion, and angiogenesis were studied both in vitro and in vivo. Our results demonstrated that PTTG expression was significantly up-regulated in glioma, and had positive correlation with glioma grade and MVD. Silencing of PTTG inhibited glioma cell proliferation, migration/invasion, and angiogenesis, induced cell apoptosis, suppressed cell invasion, and arrested cell cycle at G0/G1 stage. Silencing of PTTG could also inhibit tumor growth, invasion, and angiogenesis in vivo. Our data indicated that PTTG might be a potential target for glioma treatment.

Chen B, Hou Z, Li C, Tong Y
MiRNA-494 inhibits metastasis of cervical cancer through Pttg1.
Tumour Biol. 2015; 36(9):7143-9 [PubMed] Related Publications
Many cervical cancer (CC) patients experience early cancer metastasis, resulting in poor therapeutic outcome after resection of primary cancer. Hence, there is a compelling requirement for understanding of the molecular mechanisms underlying the invasiveness control of CC. Pituitary tumor-transforming gene 1 (Pttg1) has been recently reported to promote cancer cell growth and metastasis in a number of various tumors. However, its regulation by microRNAs (miRNAs) as well as its role in CC have not been clarified. Here, we reported significantly higher levels of Pttg1 and significantly lower levels of miR-494 in the resected CC tissue, compared with the adjacent normal cervical tissue from the same patient. Interestingly, Pttg1 levels inversely correlated with miR-494 levels. In vitro, Pttg1 levels determined CC cell invasiveness and were inhibited by miR-494 levels. However, miR-494 levels were not affected by Pttg1 levels. Furthermore, miR-494 inhibited Pttg1 expression in CC cells, through directly binding and inhibition on 3'-UTR of Pttg1 mRNA. Together, our data suggest that Pttg1 may increase CC cell metastasis, which is negatively regulated by miR-494. Our work thus highlights a novel molecular regulatory machinery in metastasis of CC.

Liang M, Liu J, Ji H, et al.
A Aconitum coreanum polysaccharide fraction induces apoptosis of hepatocellular carcinoma (HCC) cells via pituitary tumor transforming gene 1 (PTTG1)-mediated suppression of the P13K/Akt and activation of p38 MAPK signaling pathway and displays antitumor activity in vivo.
Tumour Biol. 2015; 36(9):7085-91 [PubMed] Related Publications
In this study, we observed that a Aconitum coreanum polysaccharide (CACP) exhibited an effective inhibitory effect on H22 cell growth in vitro and in vivo via the induction of apoptosis. Further, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting assays revealed that the expression of pituitary tumor transforming gene 1 (PTTG1), one proto-oncogene, was evidently suppressed in both transcript and protein levels in H22 cell model or mice after CACP treatment. Particularly, CACP (40 μg/ml) treatment or transfection with PTTG1 small interfering RNA (siRNA) could greatly reduce the phosphorylation of Akt (p-Akt) but increase phospho-p38 mitogen-activated protein kinase (p-p38 MARK) protein levels in H22 cells as compared with vehicle-treated cells. Likewise, following treatment of H22-tumor-bearing mice with CACP (100 mg/kg), doxorubicin (DOX, 3 mg/kg), and their combination, tumor tissues showed an attenuated p-Akt protein expression, but a striking p-p38 MARK level when compared with those in model mice. Taken together, we demonstrated here the inhibitory effect of CACP on the growth of H22 cells in vitro and in vivo, which may be through, at least partly, repression of PTTG1 and then followed by the inactivation of P13/Akt and activation of p38 MARK signaling pathways. These findings offered a novel approach for the treatment of hepatocellular carcinoma (HCC) in the future.

Haji Amousha MR, Sabetkish N, Sabet Kish N, et al.
Expression of the pituitary tumor transforming gene (PTTG1) in pheochromocytoma as a potential marker for distinguishing benign versus malignant tumors.
Acta Med Iran. 2015; 53(4):236-41 [PubMed] Related Publications
The Distinction between malignant and benign pheochromocytoma has always been a diagnostic challenge over the last decades. To date, the only reliable criterion is metastasis. The aim of the present study was to investigate the possible expression of pituitary-tumor transforming gene (PTTG1) and retinoblastoma (Rb) in benign and malignant pheochromocytoma. Paraffin blocks of 44 and 11 patients diagnosed with benign and malignant pheochromocytoma were collected. Parameters such as sex, age, tumor size, necrosis, and histological features were compared between the benign and malignant groups as well as immunohistochemical labeling using specific antibodies. PTTG1 showed negative expression in all (44) benign and 9 out of 11 (81.8%) malignant tumors with only 2 out of 11 (18.2%) malignant tumors showed positive reactivity for PTTG1 (P: 0.037) with spindle cell histological pattern in both of them (P: 0.013). Although Rb expression in malignant tumors (81.8%) was slightly more than the benign ones (52.3%), no statistically significant correlation was observed (P: 0.087). These results suggest that PTTG1 immunostaining may play a key role in distinguishing between benign and malignant phaeochromocytoma. However, larger studies are necessary to confirm the outcomes of the present study.

Mirandola L, Figueroa JA, Phan TT, et al.
Novel antigens in non-small cell lung cancer: SP17, AKAP4, and PTTG1 are potential immunotherapeutic targets.
Oncotarget. 2015; 6(5):2812-26 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the CTAs, Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in cancer samples, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes from patients' peripheral blood mononuclear cells. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in lung cancer patients.

Kakar SS, Kakar C
Generation of transgenic mouse model using PTTG as an oncogene.
Methods Mol Biol. 2015; 1267:395-411 [PubMed] Related Publications
The close physiological similarity between the mouse and human has provided tools to understanding the biological function of particular genes in vivo by introduction or deletion of a gene of interest. Using a mouse as a model has provided a wealth of resources, knowledge, and technology, helping scientists to understand the biological functions, translocation, trafficking, and interaction of a candidate gene with other intracellular molecules, transcriptional regulation, posttranslational modification, and discovery of novel signaling pathways for a particular gene. Most importantly, the generation of the mouse model for a specific human disease has provided a powerful tool to understand the etiology of a disease and discovery of novel therapeutics. This chapter describes in detail the step-by-step generation of the transgenic mouse model, which can be helpful in guiding new investigators in developing successful models. For practical purposes, we will describe the generation of a mouse model using pituitary tumor transforming gene (PTTG) as the candidate gene of interest.

Xu MD, Dong L, Qi P, et al.
Pituitary tumor-transforming gene-1 serves as an independent prognostic biomarker for gastric cancer.
Gastric Cancer. 2016; 19(1):107-15 [PubMed] Related Publications
BACKGROUND: Pituitary tumor-transforming gene-1 (PTTG1) is a transcription factor that can affect transcriptional activity, angiogenesis, and cell senescence. We examined PTTG1 mRNA and protein expression in gastric cancer (GC) cell lines and tissues to determine its value as a biomarker for GC diagnosis and therapy.
METHODS: PTTG1 mRNA expression from 78 GC cases and paired adjacent normal mucosa (PCR cohort) as well as from five gastric cell lines was assessed using qRT-PCR. Nuclear and cytoplasmic RNA were extracted from two gastric cell lines to determine PTTG1 mRNA localization. PTTG1 protein expression from 98 GC cases, their paired adjacent normal mucosa, and 23 gastric intraepithelial neoplasia (GIN) cases was examined using immunohistochemistry (IHC cohort). The correlation between PTTG1 mRNA and protein expression and GC clinicopathological parameters was analyzed.
RESULTS: PTTG1 mRNA expression in GC tissues and cell lines was significantly increased compared with adjacent normal gastric mucosa and normal gastric mucous cell lines (p < 0.05). PTTG1 expression was nuclear and cytoplasmic, with higher cytoplasmic expression. PTTG1 immunostaining significantly differed in GC (95.66 ± 20.65), GIN (84.00 ± 34.16), and normal adjacent mucosa (28 ± 22.25) (p < 0.001). Multivariate Cox regression analysis revealed that PTTG1 mRNA and protein expression are independent prognostic factors for GC patient survival.
CONCLUSION: Our results suggest that PTTG1 is a promising target for GC diagnosis and therapy.

Cai SQ, Dou TT, Li W, et al.
Involvement of pituitary tumor transforming gene 1 in psoriasis, seborrheic keratosis, and skin tumors.
Discov Med. 2014; 18(101):289-99 [PubMed] Related Publications
Accumulating evidence suggests that pituitary tumor transforming gene 1 (PTTG1) is a potential biomarker for cancer malignancy and a cell-cycle regulatory protein. This investigation was performed to address the subcellular localization of PTTG1 and its possible involvement in proliferative skin diseases. In vitro primary-cultured keratinocytes and skin samples from psoriasis, seborrheic keratosis (SK), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) were investigated by immunofluorescence and real-time PCR. In normal skin, PTTG1 is localized predominantly in 10% of basal keratinocytes, while 30-40% in basal and suprabasal psoriatic keratinocytes. PTTG1 mRNA in psoriatic epidermis is about 5-fold more than that in normal one (P<0.01). PTTG1 is localized in cytoplasm in primary-cultured normal and psoriatic keratinocytes, and PTTG1 in HaCaT cells is distributed throughout the cytoplasm of metaphase cells. PTTG1 is seen at both G2 and M phases, and highest PTTG1 expression correlates with highest cyclin B1 expression and highest degree of nuclear pleomorphism at M phase. The positive rate of PTTG1 in SK, BCC, and SCC is about 10%, 20%, and more than 80%, respectively. PTTG1 siRNA, which knocks down the expression of PTTG1, reduced the invasive capacity of A431 cells. In conclusion, PTTG1 is a marker for proliferative skin diseases associated with cell cycle regulation and may aid in detection of aggressive cancers.

Li J, Zhai X, Wang H, et al.
Bioinformatics analysis of gene expression profiles in childhood B-precursor acute lymphoblastic leukemia.
Hematology. 2015; 20(7):377-83 [PubMed] Related Publications
OBJECTIVES: To explore the underlying molecular mechanisms of childhood B-precursor acute lymphoblastic leukemia (ALL) by bioinformatics analysis and find potential targets for childhood ALL diagnosis and treatment.
METHODS: Gene expression profile GSE28460 was downloaded from the Gene Expression Omnibus, including 49 diagnostic and relapse bone marrow samples with childhood B-precursor ALL. The differentially expressed genes (DEGs) were identified by paired t-test. Pathway enrichment analysis of DEGs and transcription factors (TFs) enrichment analysis were performed, followed by construction of co-expressed, DEGs, and susceptibility gene protein-protein interaction (PPI) network. Based on these three networks, relevant regulatory network modules and the important DEGs in the modules were identified.
RESULTS: Total of 947 DEGs were identified. Up-regulated DEGs enriched 20 pathways including cell cycle, and down-regulated DEGs significantly enriched Jak-STAT signaling pathways. CDK1 and BRCA1 were found to have more hubs in both co-expressed network and PPI network. Besides, total of five modules in INTS10, MCM, BRCA1, GYPA, and VCAN1 families were identified and a pathway of INTS10-INTS6-POLR2A-MAGI2 was selected.
CONCLUSION: Cell cycle and Jak-STAT signaling pathway were closely associated with relapse of childhood B-precursor ALL. The DEGs, such as PTTG1, PIK3CA, CDK1, and BRCA1 may be the potential targets for childhood ALL diagnosis and treatment.

Read ML, Seed RI, Modasia B, et al.
The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.
Mol Carcinog. 2016; 55(1):15-26 [PubMed] Related Publications
The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

Bouchet A, Sakakini N, Atifi ME, et al.
Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy.
Int J Cancer. 2015; 136(11):2705-16 [PubMed] Related Publications
Synchrotron microbeam radiation therapy (MRT) relies on the spatial fractionation of a synchrotron beam into parallel micron-wide beams allowing deposition of hectogray doses. MRT controls the intracranial tumor growth in rodent models while sparing normal brain tissues. Our aim was to identify the early biological processes underlying the differential effect of MRT on tumor and normal brain tissues. The expression of 28,000 transcripts was tested by microarray 6 hr after unidirectional MRT (400 Gy, 50 µm-wide microbeams, 200 µm spacing). The specific response of tumor tissues to MRT consisted in the significant transcriptomic modulation of 431 probesets (316 genes). Among them, 30 were not detected in normal brain tissues, neither before nor after MRT. Areg, Trib3 and Nppb were down-regulated, whereas all others were up-regulated. Twenty-two had similar expression profiles during the 2 weeks observed after MRT, including Ccnb1, Cdc20, Pttg1 and Plk1 related to the mitotic role of the Polo-like kinase (Plk) pathway. The up-regulation of Areg expression may indicate the emergence of survival processes in tumor cells triggered by the irradiation; while the modulation of the "mitotic role of Plk1" pathway, which relates to cytokinetic features of the tumor observed histologically after MRT, may partially explain the control of tumor growth by MRT. The identification of these tumor-specific responses permit to consider new strategies that might potentiate the antitumoral effect of MRT.

Zhang G, Zhao Q, Yu S, et al.
Pttg1 inhibits TGFβ signaling in breast cancer cells to promote their growth.
Tumour Biol. 2015; 36(1):199-203 [PubMed] Related Publications
Increased expression of Pituitary Tumor Transforming Gene 1 (Pttg1) has been shown in various tumor cells, including breast cancer (BC). However, the precise role of Pttg1 in the tumorigenesis is not clarified yet. Here, we examined BC from the patients and detected significant increases and correlation in Pttg1 and phosphorylated SMAD3 (pSMAD3), a key effector of activated transforming growth factor β (TGFβ) receptor signaling pathway. Pttg1 levels were then modulated by transgene or small hairpin RNA (shRNA) in a human BC cell line, BT474, respectively. We found that Pttg1 overexpression increased the proliferation of BC cells in vitro and in vivo, while Pttg1 inhibition decreased proliferation of BC cells in vitro and in vivo. Moreover, phosphorylation of SMAD3 by TGFβ1 was significantly inhibited by Pttg1 overexpression, suggesting that Pttg1 may promote growth of BC cells by inhibiting pSMAD3-mediated cell-growth inhibition. Thus, Pttg1 appears to be a novel therapeutic target for controlling the tumorigenesis of BC.

Castilla C, Flores ML, Medina R, et al.
Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1.
Mol Cancer Ther. 2014; 13(10):2372-83 [PubMed] Related Publications
PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting.

Zhang W, Gong W, Ai H, et al.
Gene expression analysis of lung adenocarcinoma and matched adjacent non-tumor lung tissue.
Tumori. 2014 May-Jun; 100(3):338-45 [PubMed] Related Publications
AIMS AND BACKGROUND: The aim of this study was to find disease-associated genes and gene functions in lung adenocarcinoma and matched adjacent non-tumor lung tissues with DNA microarray.
METHODS: We downloaded the gene expression profile GSE32863 from the Gene Expression Omnibus database including 58 lung adenocarcinoma and 58 adjacent non-tumor lung tissue samples. Data were preprocessed and the differentially expressed genes (DEGs) were identified using packages in the R computing language. The selected DEGs were further analyzed with bioinformatics methods. After the coexpression network of DEGs was constructed by STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), we analyzed gene functions with DAVID (The Database for Annotation, Visualization and Integrated Discovery) and WebGestalt (WEB-based Gene Set Analysis Toolkit).
RESULTS: A total of 1429 genes were filtered as DEGs, including 873 downregulated genes and 556 upregulated genes, and the DEGs including CDC45, CCNB2, CDC20, MCM2, PTTG1, MCM4 and FEN1 were most significantly related to cell cycle and DNA replication.
CONCLUSION: The discovery of featured genes which were significantly related to cell cycle and DNA replication has potential for use in the clinic for the diagnosis of lung adenocarcinoma in the future. However, further experiments will be needed to confirm our result.

Zhang H, Du R, Huang YH, et al.
Characterization of pituitary tumor transforming gene in meningiomas.
Clin Neurol Neurosurg. 2014; 122:120-3 [PubMed] Related Publications
BACKGROUND: Pituitary tumor transforming gene (PTTG) is an oncogene and has been detected in several tumors of unrelated histological origin. However, its role in meningiomas is unknown so far. We aim to investigate PTTG expression in intracranial meningiomas, and clarify the relationship between PTTG and the histopathological types of tumors.
MATERIALS AND METHODS: Over a 7-year period, 195 meningioma specimens were collected from 195 patients. Seventeen nonneoplastic meningeal tissues were used as controls. We analyze PTTG expression by tissue microarray with immunohistochemistry.
RESULTS: Immunoexpression of PTTG was identified in 172 of 195 meningiomas, accounting for 88.2%. All of immunoexpression of tumors were found to be cytoplasmic, and no nuclear expression was observed. In the control group, there were 3 of 17 specimens (17.6%) with positive PTTG expression. The percentage of high expression WHO subtypes of meningiomas ranged from 0% to 95.7%. We further stratified the tumors into 3 subgroups based on pathological grading (WHO grade I, WHO grade II and III, control), and there was significant intergroup difference in PTTG expression (p<0.001).
CONCLUSION: This study demonstrated that PTTG was expressed in most of meningioma tissues, and the degree of PTTG immunostaining was variable in the subtypes of tumors. Further investigations into PTTG expression are required to broaden the pathogenesis research of meningiomas.

Zhang E, Liu S, Xu Z, et al.
Pituitary tumor-transforming gene 1 (PTTG1) is overexpressed in oral squamous cell carcinoma (OSCC) and promotes migration, invasion and epithelial-mesenchymal transition (EMT) in SCC15 cells.
Tumour Biol. 2014; 35(9):8801-11 [PubMed] Related Publications
Pituitary tumor-transforming gene 1 (PTTG1) is an important oncogenic transcription factor implicated in various malignancies, including oral squamous cell carcinoma (OSCC), a common malignancy of head and neck. Although PTTG1 is reportedly overexpressed in OSCC tissues, its role in human OSCC remains elusive. Thus, this study was conducted to explore the correlation between PTTG1 expression and tumorigenesis of OSCC. We first examined PTTG1 mRNA and protein expression in 28 pairs of OSCC tissues and adjacent non-tumor tissues. PTTG1 protein levels in 98 OSCC specimens were also evaluated by using immunohistochemistry. Our data showed that both mRNA and protein expression levels of PTTG1 in OSCC tissue specimens were markedly higher than that in the corresponding non-tumor tissue samples. A high level of PTTG1 protein expression was found in 74 out of 98 cases (75.51 %) and it was correlated with lymph node metastasis (P = 0.002) and tumor-node-metastasis (TNM) stage (P = 0.007) of patients with OSCC. Moreover, forced overexpression of PTTG1 enhanced SCC15 cell migration and invasion, whereas knockdown of PTTG1 resulted in reverse phenomena. In addition, elevated PTTG1 also increased the activities and expressions of matrix metalloproteinase (MMP)-2, and enhanced epithelial-mesenchymal-transition (EMT) process in SCC15 cells. The EMT changes were accompanied by downregulation of epithelial cadherin (E-cadherin) protein expression and upregulation of snail and vimentin. In summary, our results illustrate that PTTG1 may contribute to the development and progression of human OSCC.

Pierconti F, Milardi D, Martini M, et al.
Pituitary-tumour-transforming-gene 1 expression in testicular cancer.
Andrologia. 2015; 47(4):427-32 [PubMed] Related Publications
Genomic instability is a feature of germ cell tumours. The pituitary-tumour-transforming-gene 1 (PTTG1) is the major effector of chromosome segregation during mitosis, protecting the cell from aneuploidy. The protein expression of this gene has been evaluated in testicular tumours by immunohistochemistry. Formalin-fixed and paraffin-embedded specimens of testicular tissues from 83 patients undergoing therapeutic orchidectomy for seminomas (n = 53), embryonal carcinoma (n = 10), yolk sac tumour (n = 10) and teratoma (n = 10) were examined. Seminoma was associated with in situ carcinoma (CIS) in 23 samples. PTTG1 immunostaining was performed using rabbit anti-PTTG1 as a primary antibody. In CIS, only isolated cells showed nuclear staining for PTTG1. In the peripheral area of seminoma, PTTG1 was mostly detected as localised in the nucleus; in the central area of seminoma, PTTG1 staining was more intense in cytoplasm. PTTG1-positive cells were also present in the areas of seminoma infiltration. On the other hand, in embryonal carcinoma, cells had a diffuse positive immunostaining, mainly cytoplasmatic, while we did not observe an expression of PTTG1 in yolk sac tumour and mature teratoma. We firstly identified the PTTG1 expression pattern in normal testis, CIS and testicular cancer. Further investigation is needed to clarify the functional activity of PTTG1 in testicular oncogenesis.

Huang S, Liao Q, Li L, Xin D
PTTG1 inhibits SMAD3 in prostate cancer cells to promote their proliferation.
Tumour Biol. 2014; 35(7):6265-70 [PubMed] Related Publications
Increased expression of pituitary tumor-transforming gene 1 (PTTG1) occurs during mitosis-related sister chromatid segregation, and characterizes various tumor cells, including prostate cancer. Whereas the mechanism remains unclarified. Here, the PTTG1 levels in a prostate cancer cell line, PC3, were modulated by the expression of PTTG1 transgene or shRNA, showing that the PTTG1 levels affected the proliferation of prostate cancer cells, in vitro and in vivo. Moreover, a significant decrease in mothers against decapentaplegic homolog 3 (SMAD3), a key component of transforming growth factor β (TGFβ) signaling pathway, was induced by PTTG1 overexpression. Since SMAD3 is a ubiquitous cell-cycle inhibitor, our data suggest that PTTG1 may promote the proliferation of prostate cancer cells by inhibiting SMAD3-mediated TGFβ signaling. To identify a causal link, we expressed SMAD3 in PTTG1-overexpressing PC3 cells and found that SMAD3 expression inhibited the augmented cancer cell proliferation by PTTG1 overexpression. Furthermore, SMAD3 inhibition by short hairpin RNA (ShRNA) completely rescued the cancer cell proliferation in PTTG1 ShRNA-treated PC3 cells. Taken together, our data suggest that PTTG1 promotes the proliferation of prostate cancer cells via the inhibition of SMAD3. SMAD3 thus appears to be a novel therapeutic target for suppressing the growth of prostate cancer.

Li Y, Zhou LP, Ma P, et al.
Relationship of PTTG expression with tumor invasiveness and microvessel density of pituitary adenomas: a meta-analysis.
Genet Test Mol Biomarkers. 2014; 18(4):279-85 [PubMed] Related Publications
AIMS: Many existing studies have demonstrated that pituitary tumor transforming gene (PTTG) expression may contribute to the development of pituitary adenomas (PAs), but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the relationships of PTTG expression with tumor invasiveness and microvessel density of pituitary adenomas.
METHODS: We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through September 1st, 2013. Meta-analysis was performed using the STATA 12.0 software. The crude odds ratio (OR) with 95% confidence interval (CI) was calculated.
RESULTS: Fifteen clinical cohort studies were included with a total of 752 pituitary adenoma patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of noninvasive patients (OR=6.68, 95% CI=3.72-11.99, p<0.001). We also found a significant difference in the microvessel density between invasive and noninvasive patients (OR=1.81, 95% CI=0.39-3.23, p<0.001). No publication bias was detected in this meta-analysis (all p>0.05).
CONCLUSION: The present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas. Thus, detection of PTTG expression may be useful for the prediction of malignancy degree in pituitary adenomas.

Xiao JQ, Liu XH, Hou B, et al.
Correlations of pituitary tumor transforming gene expression with human pituitary adenomas: a meta-analysis.
PLoS One. 2014; 9(3):e90396 [PubMed] Free Access to Full Article Related Publications
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.

Read ML, Seed RI, Fong JC, et al.
The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.
Endocrinology. 2014; 155(4):1222-34 [PubMed] Free Access to Full Article Related Publications
The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a protooncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity-ligation assays, we show that PBF binds specifically to p53 in thyroid cells and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF overexpression (transgenic PBF mice), which had significantly increased genetic instability as indicated by fluorescent inter simple sequence repeat-PCR analysis. Consistent with this, approximately 40% of all DNA repair genes examined were repressed in transgenic PBF primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51, and Xrcc3. Our data also revealed that PBF induction resulted in up-regulation of the E2 enzyme Rad6 in murine thyrocytes and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the protooncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, in which PBF is generally overexpressed and p53 mutations are rare compared with other tumor types.

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