Pituitary Tumor Transforming Gene Research Articles

Gene signatures and prognostic analyses of the Tob/BTG pituitary tumor-transforming gene (PTTG) family in clinical breast cancer patients.

Breast cancer is the most common cancer type in females, and exploring the mechanisms of disease progression is playing a crucial role in the development of potential therapeutics. Pituitary tumor-transforming gene (PTTG) family members are well documented to be involved in cell-cycle regulation and mitosis, and contribute to cancer development by their involvement in cellular transformation in several tumor types. The critical roles of PTTG family members as crucial transcription factors in diverse types of cancers are recognized, but how they regulate breast cancer development still remains mostly unknown. Meanwhile, a holistic genetic analysis exploring whether PTTG family members regulate breast cancer progression via the cell cycle as well as the energy metabolism-related network is lacking. To comprehensively understand the messenger RNA expression profiles of PTTG proteins in breast cancer, we herein conducted a high-throughput screening approach by integrating information from various databases such as Oncomine, Kaplan-Meier Plotter, Metacore, ClueGo, and CluePedia. These useful databases and tools provide expression profiles and functional analyses. The present findings revealed that PTTG1 and PTTG3 are two important genes with high expressions in breast cancer relative to normal breast cells, implying their unique roles in breast cancer progression. Results of our coexpression analysis demonstrated that PTTG family genes were positively correlated with thiamine triphosphate (TTP), deoxycytidine triphosphate (dCTP) metabolic, glycolysis, gluconeogenesis, and cell-cycle related pathways. Meanwhile, through Cytoscape analyzed indicated that in addition to the metastasis markers AURKA, AURKB, and NDC80, many of the kinesin superfamily (KIF) members including KIFC1, KIF2C, KIF4A, KIF14, KIF20A, KIF23, were also correlated with PTTG family transcript expression. Finally, we revealed that high levels of PTTG1 and PTTG3 transcription predicted poor survival, which provided useful insights into prospective research of cancer associated with the PTTG family. Therefore, these members of the PTTG family would serve as distinct and essential prognostic biomarkers in breast cancer.

Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors

Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory Gα protein (Gαs encoded by GNAS) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone-secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were GNAS mutation negative (Gsp- ). The chromosome stable (CS) -group contained Gsp+ somatotropinomas and two totally aneuploidy-free Gsp- tumors. Genes related to the mitotic G1-S-checkpoint transition were differentially expressed in CA- and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct Gsp genotype-specific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Gα (Gαi) signaling is activated in Gsp+ tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp- somatotropinomas, whereas Gsp+ tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Gαi signaling. IMPLICATIONS: These findings provide valuable new information about subtype-specific pituitary tumorigenesis and may help to elucidate the mechanisms of aneuploidy also in other tumor types.

Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation.

Cushing's disease is primarily caused by autonomic hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. In Cushing's disease, mutations in the ubiquitin-specific protease 8 (USP8) have been detected. These mutations are associated with hyperactivation of USP8 that prevent epidermal growth factor receptor (EGFR) degradation. This leads to increased EGFR stability and results in the maintenance of EGFR signaling in Cushing's disease. USP8 inhibitors can suppress the growth of various tumors. In this study, the effects of a potent USP8 inhibitor, DUBs-IN-2, on ACTH production and cell proliferation were examined in mouse corticotroph tumor (AtT-20) cells. Proopiomelanocortin (Pomc) mRNA levels and ACTH levels were decreased in AtT-20 cells by DUBs-IN-2. Further, cell proliferation was inhibited, and apoptosis was induced by DUBs-IN-2. Transcript levels of pituitary tumor-transforming gene 1 (Pttg1), a pituitary tumor growth marker, were increased; and transcript levels of stress response growth arrest and DNA damage-inducible 45 (Gadd45β) and Cdk5 and ABL enzyme substrate 1 (Cables1) mRNA levels were increased in response to the drug. Gadd45β or Cables1 knockdown partially inhibited the DUBs-IN-2-induced decrease in cell proliferation, but not Pomc mRNA levels. Both GADD45β and CABLES1 may be responsible, at least in part, for the USP8-induced suppression of corticotroph tumor cell proliferation. USP-8 may be a new treatment target in Cushing's disease.

PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas.

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

PBF, a Proto-oncogene in Esophageal Carcinoma.

Emerging evidence shows that the pituitary tumour-transforming gene (PTTG)-binding factor (PBF) functions as a proto-oncogene in some tumors. However, the precise functions of PBF in tumorigenesis and its action mechanisms remain largely unknown. Here for the first time we demonstrated that PBF was associated with a tumor-related cell phenotype in esophageal carcinoma (ESCA) and identified the involved signaling pathways. PBF was up-regulated in ESCA tissues (Data from GEPIA) and cells. Then we down-regulated PBF in ESCA cell lines, Eca-109 and TE-1, by using RNAi technology. Cell function analysis suggested that down-regulation of PBF could inhibit tumor-related cell phenotypes, including proliferation, motility, apoptosis and cell cycle, in Eca-109 and TE-1 cells. Mechanism investigation suggested that apoptosis induced by PBF knockdown may be mediated by the activation of the mitochondrial apoptosis pathway and cell cycle arrest. AKT/mTOR and Wnt3a/β-catenin, key pathways in regulating tumor proliferation and metastasis, were found to be inactivated by the down-regulation of PBF in ESCA cells. In conclusion, our study demonstrates that PBF functions as a proto-oncogene in ESCA in vitro, which may be mediated through AKT/mTOR and Wnt3a/β-catenin pathways.

Oral exposure to low-dose bisphenol A induces hyperplasia of dorsolateral prostate and upregulates EGFR expression in adult Sprague-Dawley rats.

Prostate is sensitive to endocrine hormone level, and the synergetic effect of estrogen and androgen is critical in prostate growth. The change of signal pathways caused by the imbalance of estrogen and androgen might function in the occurrence of prostate diseases. As a well-known endocrine disruptor compound, bisphenol A (BPA) can disturb the normal function of endocrine hormone and affect prostate development. This study aims to investigate effects of BPA on the dorsolateral prostate (DLP) and the related gene expression of the tissue in adult Sprague-Dawley (SD) rats and to explore the mechanism for the effect of low-dose BPA on DLP hyperplasia. Three-month-old male SD rats were treated with BPA (10.0, 30.0, or 90.0 µg (kg.day)-1, gavage) or vehicle (gavage) for 4 weeks. BPA significantly increased the DLP weight, the DLP organ coefficient, and the prostate epithelium height (p < 0.01) of rats dose-dependently. Microarray analysis and quantitative real-time polymerase chain reaction showed that BPA significantly upregulated the transcriptional levels of some genes, including pituitary tumor transforming gene 1, epidermal growth factor, Sh3kbp1, and Pcna. Furthermore, the expression of PCNA (p < 0.01), androgen receptor (p < 0.01), and EGF receptor (EGFR) (p < 0.001) in DLP was increased significantly by BPA treatment, and the expression of estrogen receptor alpha was also upregulated. The findings evidenced that low-dose BPA could induce DLP hyperplasia in adult rats, and the upregulated EGF/EGFR pathway that was responsive to estrogen and androgen might play an essential role in the DLP hyperplasia induced by low-dose BPA.

Proteomics evaluation of MDA-MB-231 breast cancer cells in response to RNAi-induced silencing of hPTTG

AimsBreast cancer is the most common cancer in women worldwide. Several genes are up-regulated in breast cancer such as human pituitary tumor transforming gene (hPTTG). This study aims to evaluate cell proliferation and the downstream expression pattern of hPTTG1 gene at the mRNA and protein levels after specific down-regulation of hPTTG1 by siRNA. Main methodsThe human breast cancer MDA-MB-231 cell line was transfected with siRNA against hPTTG1. The mRNA and protein expression levels were examined by Real-time PCR and Western blot, respectively. The cell proliferation was assayed by MTS. To investigate the pattern of protein expression, total cellular protein was analyzed by 2D gel electrophoresis and mass spectroscopy. Subsequently, the possible biological consequences were determined by the bioinformatics databases. Key findingsSubsequent of hPTTG1 silencing in the MDA_MB-231 cells, the proliferation of cells decreased obviously. In response to hPTTG1 silencing, the levels mRNA and protein were effectively down-regulated 80% and 50%, respectively, at 48 h post-transfection. The proteomics evidenced that PTTG1 increased the expression of 5 proteins. The reduced expression of PTTG1 was functionally involved in hypoxia (NPM1, ENO1), cell proliferation and apoptosis (ENO1, NPM1, NME1, STMN1), and metastasis (NPM1, NME1). SignificanceWe identified the hPTTG1-regulated proteins and its molecular mechanism in pathogenesis of breast cancer. Further study emphasis is to understand the association of hPTTG1 with other genes in cancer progression. This novel modality might also consider for identification of targeted drugs, prognosis and follow up in breast cancer gene therapy.

Distinct expression pattern and prognostic values of pituitary tumor transforming gene family genes in non-small cell lung cancer.

Members of the pituitary tumor transforming gene (PTTG) family, including PTTG1, PTTG2 and PTTG3P, exhibit pivotal roles in the onset and progression of certain types of human cancer. However, to the best of our knowledge, a systematic study regarding the expression pattern and the prognostic values of PTTG family genes in non-small cell lung cancer (NSCLC) remains to be performed. The expression levels of PTTG family genes in NSCLC were successively determined using the Gene Expression Profiling Interactive Analysis, UALCAN and Oncomine databases. Subsequently, the Kaplan-Meier plotter database was used to assess the prognostic value of the PTTG family genes in patients with NSCLC, and to determine the associations between PTTG expression levels and the prognosis of patients based on different clinicopathological features, including cancer stage, grade, chemotherapy, radiotherapy, lymph node status, smoking history, and sex. PTTG1 was identified to be significantly upregulated in NSCLC in all three databases, whereas PTTG2 and PTTG3P were significantly upregulated in NSCLC in only the UALCAN database. Patients with NSCLC with higher expression levels of the three PTTG genes demonstrated shorter overall survival times. In summary, the results of the present study suggested that increased expression of PTTG family genes may serve as promising prognostic biomarkers for patients with NSCLC.

Expression of Serum PTTG1 in Laryngeal Carcinoma and Its Correlation to Prognosis.

Objectives.The purpose of this study was to investigate serum pituitary tumor transforming gene (PTTG1) expression in laryngeal carcinoma and its relationship with the clinical pathological characteristics and prognosis.Methods.Expression of serum PTTG1 was measured by enzyme-linked immunosorbent assay in 110 patients with laryngeal carcinoma and 60 patients with vocal cord polyps. Expression of the serum PTTG1 levels relationship with the clinicopathological characteristics and prognosis were analyzed.Results.In laryngeal carcinoma patients’ serum, the PTTG1 median concentration was 141.43 pg/mL (interquartile range [IQR], 111.387 to 160.837 pg/mL), significantly higher than that of the vocal cord polyp group of 94.01 pg/mL (IQR, 81.26 to 108.59 pg/mL), and the difference was statistically significant (z=–6.715, P<0.001). PTTG1 expression with lymph node metastasis, clinical stage, and patients with laryngeal carcinoma was significantly correlated with the tumor differentiation degree (P<0.05). The total survival rate of the PTTG1 high expression group was significantly lower than the low expression group, and the difference of total survival time of the two groups was statistically significant (P<0.001).Conclusion.The PTTG1 expression level can be used as an index for evaluating prognosis of laryngeal cancer. High PTTG1 expression is one of the factors of poor prognosis of laryngeal carcinoma patients.

Integrative genomics analysis of hub genes and their relationship with prognosis and signaling pathways in esophageal squamous cell carcinoma.

The main purpose of the present study was to recognize the integrative genomics analysis of hub genes and their relationship with prognosis and signaling pathways in esophageal squamous cell carcinoma (ESCC). The mRNA gene expression profile data of GSE38129 were downloaded from the Gene Expression Omnibus database, which included 30 ESCC and 30 normal tissue samples. The differentially expressed genes (DEGs) between ESCC and normal samples were identified using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify the functions and related pathways of the genes. The protein-protein interaction (PPI) network of these DEGs was constructed with the Search Tool for the Retrieval of Interacting Genes and visualized with a molecular complex detection plug-in via Cytoscape. The top five important modules were selected from the PPI network. A total of 928 DEGs, including ephrin-A1 (EFNA1), collagen type IV α1 (COL4A1), C-X-C chemokine receptor 2 (CXCR2), adrenoreceptor β2 (ADRB2), P2RY14, BUB1B, cyclin A2 (CCNA2), checkpoint kinase 1 (CHEK1), TTK, pituitary tumor transforming gene 1 (PTTG1) and COL5A1, including 498 upregulated genes, were mainly enriched in the ‘cell cycle’, ‘DNA replication’ and ‘mitotic nuclear division’, whereas 430 downregulated genes were enriched in ‘oxidation-reduction process’, ‘xenobiotic metabolic process’ and ‘cell-cell adhesion’. The KEGG analysis revealed that ‘ECM-receptor interaction’, ‘cell cycle’ and ‘p53 signaling pathway’ were the most relevant pathways. According to the degree of connectivity and adjusted P-value, eight core genes were selected, among which those with the highest correlation were CHEK1, BUB1B, PTTG1, COL4A1 and CXCR2. Gene Expression Profiling Interactive Analysis in The Cancer Genome Atlas database for overall survival (OS) was applied among these genes and revealed that EFNA1 and COL4A1 were significantly associated with a short OS in 182 patients. Immunohistochemical results revealed that the expression of PTTG1 in esophageal carcinoma tissues was higher than that in normal tissues. Therefore, these genes may serve as crucial predictors for the prognosis of ESCC.

PTTG1 is involved in TNF-α-related hepatocellular carcinoma via the induction of c-myc.

Hepatocellular carcinoma (HCC) is a malignant disease caused by a variety of factors. However, the genomic and molecular aberrations in HCC are largely unknown. Herein, pituitary tumor transforming gene 1 (PTTG1) was discovered as a potential inflammation‐related oncogene in HCC, and its functions and molecular mechanisms were investigated. mRNA expression microarray, real‐time polymerase chain reaction (PCR), immunohistochemistry, and western blotting analyses revealed that PTTG1 is upregulated in HCC. Further in vitro and in vivo studies indicated that the proinflammatory cytokine tumor necrosis factor‐α (TNF‐α) induces PTTG1 expression, and PTTG1 was found to upregulate c‐myc, a well‐known oncogene. Downregulation of PTTG1 reduced c‐myc and proliferating cell nuclear antigen (PCNA) expression and inhibited cell proliferation. Interestingly, inhibition of c‐myc by 10058‐F4 did not affect PTTG1, which suggests that PTTG1 regulates c‐myc expression. Furthermore, PTTG1 expression levels are inversely correlated with HCC patient survival, indicating an independent prognostic biomarker for patients with HCC. Our data demonstrate that PTTG1 is involved in TNF‐α‐related HCC via c‐myc induction and that PTTG1 may be a potential therapeutic target for HCC.

Molecular markers of prognosis in canine cortisol-secreting adrenocortical tumours.

Hypercortisolism is caused by a cortisol‐secreting adrenocortical tumour (ACT) in approximately 15%‐20% of cases in dogs. Little is known about which molecular markers are associated with malignant behaviour of canine ACTs. The objective of this study was to identify molecular markers of prognosis, which could be useful to refine prognostic prediction and to identify potential treatment targets. Cortisol‐secreting ACTs were included from 40 dogs, of which follow‐up information was available. The ACTs were classified as low risk of recurrence tumours (LRT; n = 14) or moderate‐high risk of recurrence tumours (MHRT; n = 26), based on the novel histopathological Utrecht score. Normal adrenals (NAs) were included from 11 healthy dogs as reference material. The mRNA expression of 14 candidate genes was analysed in the 40 ACTs and in 11 NAs with quantitative RT‐PCR. The genes' expression levels were statistically compared between NAs, LRTs and MHRTs. Univariate and multivariate analyses were performed to determine the association of the genes' expression levels with survival. Seven genes were differentially expressed between NAs and ACTs, of which pituitary tumour‐transforming gene‐1 (PTTG1) and topoisomerase II alpha (TOP2A) were also differentially expressed between LRTs and MHRTs. In survival analyses, high expression levels of Steroidogenic factor‐1 (SF‐1), PTTG1 and TOP2A were significantly associated with poor survival. In conclusion, we have identified several genes that are part of the molecular signature of malignancy in canine ACTs. These findings can be used to refine prognostic prediction, but also offer insights for future studies on druggable targets.

Diagnosis of Invasive Nonfunctional Pituitary Adenomas by Serum Extracellular Vesicles.

The invasiveness evaluation of nonfunctional pituitary adenoma (NFPAs) is crucial for the prediction of the malignant potential and for making surgical plans of NFPAs. Current invasiveness evaluation of NFPAs is based on neuroimaging, which can hardly predict the invasive potential and dynamically monitor disease progress. Here we used microbead-assisted flow cytometry to detect and analyze the serum extracellular vesicles (EVs) from 30 NFPAs patients (15 invasive and 15 noninvasive). Lower expressions of folate receptor 1 (FOLR1) and epithelial cell adhesion molecule (EpCAM) were found in serum EVs from the invasive NFPAs patients compared to the noninvasive ones [area under the curve (AUC) of 0.94 for FOLR1 and 0.88 for EpCAM]. Meanwhile, increased mRNA expression of vimentin and N-cadherin, two mesenchymal markers, was found in serum EVs from the invasive NFPAs patients compared to the noninvasive ones. Consistent results were observed in the tumor tissue that invasive NFPAs have lower expression of the epithelial markers while higher expression of the mesenchymal markers. These results suggested the possible role of epithelial-mesenchymal transition (EMT) in the invasiveness of NFPAs. Pituitary tumor transforming gene 1 (PTTG1) mRNA in serum EVs was also found to be an indicator for invasive NFPAs and is related with EMT. These results provide a method for the blood-based diagnosis and invasiveness evaluation of NFPAs and would be beneficial to the diagnosis, prognosis prediction, and surgical risk evaluation of NFPAs.

Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer.

Despite the clinical requirement for early diagnosis, the early events in lung cancer and their mechanisms are not fully understood. Pituitary tumor transforming gene 1 binding factor (PTTG1IP) is a tumor-associated gene; however, to the best of our knowledge, its association with lung cancer has not been reported. The present study analyzed PTTG1IP expression in early-stage non-small cell lung cancer (NSCLC) samples and investigated its epigenetic regulatory mechanisms. The results revealed that the mRNA level of PTTG1IP in NSCLC tissues was significantly downregulated by 43% compared with that in adjacent tissues. In addition, overexpression of this gene significantly inhibited cell proliferation. According to data from The Cancer Genome Atlas, a significant negative correlation was identified between the PTTG1IP gene methylation level and expression level in lung adenocarcinoma and lung squamous cell carcinoma cases. Reduced representation bisulfite sequencing (RRBS) analysis of six paired early-stage NSCLC tissue samples indicated that the CpG island shore of the PTTG1IP promoter is hypermethylated in lung cancer tissues, which was further validated in 12 paired early-stage NSCLC samples via bisulfite amplicon sequencing. Following treatment with 5-aza-2′-deoxycytidine to reduce DNA methylation in the promoter region, the PTTG1IP mRNA level increased, indicating that the PTTG1IP promoter DNA methylation level negatively regulates PTTG1IP transcription. In conclusion, in early-stage NSCLC, the PTTG1IP gene is regulated by DNA methylation in its promoter region, which may participate in the development and progression of lung cancer.

The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function.

The percentage of murine hematopoietic stem and progenitor cells, which present with a loss of function upon treatment with the genotoxic agent hydroxyurea, is inversely correlated to the mean lifespan of inbred mice, including the long-lived C57BL/6 and short-lived DBA/2 strains. Quantitative trait locus mapping in BXD recombinant inbred strains identified a region spanning 12.5 cM on the proximal part of chromosome 11 linked to both the percentage of dysfunctional hematopoietic stem and progenitor cells as well as regulation of lifespan. By generating and analyzing reciprocal congenic mice for this locus, we demonstrate that this region indeed determines the sensitivity of hematopoietic stem and progenitor cells to hydroxyurea. These cells do not present, as previously anticipated, with differences in cell cycle distribution, and also not with changes in the frequency of cells undergoing apoptosis, senescence, replication stalling and re-initiation activity, excluding that variations in proliferation, replication or viability underlie the distinct response of these cells from the congenic and parental strains. An epigenetic aging clock in blood cells was accelerated in C57BL/6 mice congenic for the DBA/2 version of the locus. We verified pituitary tumor-transforming gene-1 (pttg1)/securin as the quantitative trait gene regulating the differential response of hematopoietic stem and progenitor cells to hydroxyurea treatment and which might thus likely be linked to the regulation of lifespan.

Identification of the potential therapeutic target gene UBE2C in human hepatocellular carcinoma: An investigation based on GEO and TCGA databases.

Hepatocellular carcinoma (HCC) ranks the third major cause of cancer-associated mortality globally. Numerous studies have attempted to elucidate the underlying mechanisms of HCC using various biomarkers. In the present study, two expression profiles datasets from Gene Expression Omnibus (GSE76427 and GSE84402) and data associated with liver cancer samples from The Cancer Genome Atlas (TCGA) were downloaded for integrated analysis. Five differentially expressed genes (DEGs) exhibiting high expression, including ubiquitin-conjugating enzyme 2C (UBE2C), topoisomerase II α, pituitary tumor transforming gene 1, glypican-3 and polycomb-repressive complex 1, were selected and considered as candidate genes. Enrichment analysis demonstrated that these genes were associated with Gene Ontology terms of cellular components and molecular functions, including regulation of apoptosis, stabilization of p53 and Anaphase Promoting Complex/Cyclosome (APC/C) (APC/C:Cdc20)-mediated degradation of Securin. The expression profiles of these genes in HCC, other human malignancies and different human HCC cell lines were validated using GSE14520, GSE3500 and TCGA data. The results confirmed the upregulation of UBE2C in tissues from patients with HCC or other human malignancies and human liver cancer cell lines, compared with the expression levels in the corresponding adjacent non-tumor tissues and cell lines, respectively. Patients with HCC who exhibited an increased messenger RNA level of UBE2C exhibited a significantly shorter survival time. The results of the present study suggest that the overexpression of UBE2C may be used as a novel prognostic biomarker of HCC.

Gene set enrichment analysis and meta-analysis identified 12 key genes regulating and controlling the prognosis of lung adenocarcinoma.

The aim of the present study was to analyze lung adenocarcinoma-associated microarray data and identify potentially crucial genes. The gene expression profiles were downloaded from the Gene Expression Omnibus database and 6 datasets, of which 2 were discarded and 4 were retained, were preprocessed using packages in the R computing language. Subsequently, Gene Set Enrichment Analysis (GSEA) and meta-analysis was used to screen the common pathways and differentially expressed genes at the transcriptional level. The genes detected from GSEA through The Cancer Genome Atlas databases were subsequently examined, and the crucial genes by survival data were identified. Pathways of the crucial genes were obtained using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the online website Database for Annotation, Visualization and Integrated Discovery (DAVID) tool, and the pathways of crucial genes that were upregulated or downregulated were matched using the Venn method to identify the common crucial pathways. Furthermore, on the basis of the common crucial pathways, key genes that are closely associated with the development and progression of lung adenocarcinoma were identified with the KEGG pathway of DAVID. Additional information was obtained through Gene Ontology annotation. A total of two key pathways, including cell cycle and DNA replication, as well as 12 key genes [DNA polymerase δ subunit 2, DNA replication licensing factor MCM4, MCM6, mitotic checkpoint serine/threonine-protein kinase BUB1, BUB1β, mitotic spindle assembly checkpoint protein MAD2A, dual specificity protein kinase TTK, M-phase inducer phosphatase 1, cell division control protein 45 homolog, cyclin-dependent kinase inhibitor 1C, pituitary tumor-transforming gene 1 protein and polo-like kinase 1] were identified. These key pathways and genes may be studied in future studies involving gene transfection/knockdown, which may provide insights into the prognosis of lung adenocarcinoma. Additional studies are required to confirm their biological function.

Cancer-Associated Fibroblasts Induce Epithelial-Mesenchymal Transition in Endometrial Cancer Cells by Regulating Pituitary Tumor Transforming Gene

Cancer-associated fibroblasts (CAFs) play an important role in the development and progression of cancer by inducing epithelial-mesenchymal transition (EMT). In this study, we investigated the role of CAFs in endometrial cancer (EC) cells. We found that the pituitary tumor transforming gene (PTTG) expression was significantly increased in EC cell lines compared to normal human endometrial epithelial cells. Furthermore, CAFs could induce PTTG over-expression and increase EC cell invasion and migration in vitro. In addition, CAFs also induced EMT in EC cells. This study demonstrated that CAFs induced EMT in endometrial cancer cells by regulating PTTG.

The long non-coding RNA PTTG3P promotes growth and metastasis of cervical cancer through PTTG1.

The outgrowth and metastasis of cervical cancer (CC) contribute to its malignancy. Pituitary Tumor Transforming Gene 1 (PTTG1) is upregulated in many types of cancer, and enhances tumor cell growth and metastasis. However, the activation and regulation of PTTG1 in CC, especially by its pseudogene PTTG3P, have not been shown. Here, we detected significantly higher levels of PTTG1 and PTTG3P in the resected CC tissue, compared to the paired adjacent normal cervical tissue. Interestingly, the PTTG3P levels positively correlated with the PTTG1 levels. High PTTG3P levels were associated with poor patients’ survival. In vitro, PTTG1 were increased by PTTG3P overexpression, but was inhibited by PTTG3P depletion in CC cells. However, PTTG3P levels were not altered by modulation of PTTG1 in CC cells, suggesting that PTTG3P is upstream of PTTG1. Moreover, PTTG3P increased CC cell growth, likely through CCNB1-mediated increase in cell proliferation, rather than through decrease in cell apoptosis. Furthermore, PTTG3P increased CC cell invasiveness, likely through upregulation of SNAIL and downregulation of E-cadherin. Our work thus suggests that PTTG3P may promote growth and metastasis of CC through PTTG1.

In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.