Pituitary Tumor-transforming Gene 1 Overexpression Research Articles

PTTG1 induces pancreatic cancer cell proliferation and promotes aerobic glycolysis by regulating c-myc.

This study aimed to clarify the role of pituitary tumor-transforming gene 1 (PTTG1) in proliferation, migration, invasion, and aerobic glycolysis of pancreatic cancer cells, and evaluate the potential of PTTG1 as a therapeutic target. PTTG1 expression in pancreatic cancers was analyzed using the GEPIA databank. In the Panc1 cell with the PTTG1 knockdown or Mia-PaCa2 cells with PTTG1 overexpression, the cell proliferation was evaluated using cell viability curves and colony formation, and wound heal assay and transwell assay were performed to evaluate the migration and invasion, respectively. Furthermore, a western blot was performed to evaluate the expressions of PTTG1, proliferating cell nuclear antigen, E-cadherin, N-cadherin, and c-myc. Meanwhile, the glucose uptake, extracellular acidification rates (ECAR), and oxygen consumption rates (OCR) were analyzed. Our results showed that PTTG1 expression is upregulated in pancreatic cancer, which promoted cell proliferation. Low PTTG1 contributed to higher disease-free survival and overall survival. In Panc1 cell, PTTG1 knockdown resulted in reduced cell viability and colony formation. The migration and invasion abilities of the cells were also reduced in Panc1 with PTTG1 knockdown. Correspondingly, PTTG1 knockdown decreased c-myc expression, glucose uptake, ECAR, and OCR in Panc1 cells. In Mia-PaCa2 cells, PTTG1 overexpression promoted cell proliferation, aerobic glycolysis, and translocation of β-catenin to the nucleus by regulating c-myc. In conclusion, PTTG1 induces proliferation, migration, and invasion, and promotes aerobic glycolysis in pancreatic cancer cells via regulating c-myc, demonstrating the potential of PTTG1 as a therapeutic target.

Upregulated expression of PTTG1 is associated with progression of pancreatic cancer.

Pancreatic cancer (PC) is an aggressive disease with a very poor prognosis. The insidious onset, rapid progression, and resistance to conventional therapies mark the imperious need for novel biomarkers and therapeutic targets. The pituitary tumor transforming gene 1 (PTTG1), implicated in tumorigenesis and cellular transformation, has been studied in various cancers, however, its role and mechanisms in PC remain to be elucidated for better understanding the disease pathology and in enhancing patient management strategies. The present study examined the PTTG1 messenger RNA (mRNA) expression levels and clinical significance through meta-analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) was used to measure PTTG1 protein levels in PC and adjacent non-cancerous tissues. A correlation was observed between PTTG1 expression and some clinical characteristics based on the TCGA and IHC data. Univariate and multivariate Cox regressions were used to identify independent prognostic factors. Kaplan-Meier (KM) survival analysis was performed. The co-expressed genes of PTTG1 were determined by integrating online tools, and the enrichment analyses were performed to determine PTTG1-related pathways and hub co-expressed genes. PTTG1 was highly expressed in PC tissues based on the TCGA, GEO, and IHC data. The combined standard mean difference (SMD) values of PTTG1 expression based on TCGA and GEO databases was 1.02 [95% confidence interval (CI): 0.74-1.30]. The area under the curve (AUC) based on the summary receiver operating characteristic (sROC) curve was 0.93 (95% CI: 0.90-0.95). PTTG1 overexpression was remarkably correlated with an inferior overall survival (OS). A total of 367 genes were identified as co-expressed genes of PTTG1 in PC and were mainly involved in the cell cycle pathway. The four identified core genes were CDK1, CCNA2, CDC20, and MAD2L1. The upregulated expression of PTTG1 plays an essential role in PC's progression as a biomarker.

PTTG1 promotes CD34+CD45+ cells to repair the pulmonary vascular barrier via activating the VEGF-bFGF/PI3K/AKT/eNOS signaling pathway in rats with phosgene-induced acute lung injury

Accidental exposure to phosgene can cause acute lung injury (ALI), characterized by uncontrolled inflammation and impaired lung blood-gas barrier. CD34+CD45+ cells with high pituitary tumor transforming gene 1 (PTTG1) expression were identified around rat pulmonary vessels through single-cell RNA sequencing, and have been shown to attenuate P-ALI by promoting lung vascular barrier repair. As a transcription factor closely related to angiogenesis, whether PTTG1 plays a role in CD34+CD45+ cell repairing the pulmonary vascular barrier in rats with P-ALI remains unclear. This study provided compelling evidence that CD34+CD45+ cells possess endothelial differentiation potential. Rats with P-ALI were intratracheally administered with CD34+CD45+ cells transfected with or without PTTG1-overexpressing and sh-PTTG1 lentivirus. It was found that CD34+CD45+ cells reduced the pulmonary vascular permeability and mitigated the lung inflammation, which could be reversed by knocking down PTTG1. Although PTTG1 overexpression enhanced the ability of CD34+CD45+ cells to attenuate P-ALI, no significant difference was found. PTTG1 was found to regulate the endothelial differentiation of CD34+CD45+ cells. In addition, knocking down of PTTG1 significantly reduced the protein levels of VEGF and bFGF, as well as their receptors, which in turn inhibited the activation of the PI3K/AKT/eNOS signaling pathway in CD34+CD45+ cells. Moreover, LY294002 (PI3K inhibitor) treatment inhibited the endothelial differentiation of CD34+CD45+ cells, while SC79 (AKT activator) yielded the opposite effect. These findings suggest that PTTG1 can promote the endothelial differentiation of CD34+CD45+ cells by activating the VEGF-bFGF/PI3K/AKT/eNOS signaling pathway, leading to the repair of the pulmonary vascular barrier in rats with P-ALI.

A Comprehensive Pan-Cancer Analysis for Pituitary Tumor-Transforming Gene 1.

Pituitary tumor-transforming gene 1 (PTTG1) encodes a multifunctional protein that is involved in many cellular processes. However, the potential role of PTTG1 in tumor formation and its prognostic function in human pan-cancer is still unknown. The analysis of gene alteration, PTTG1 expression, prognostic function, and PTTG1-related immune analysis in 33 types of tumors was performed based on various databases such as The Cancer Genome Atlas database, the Genotype-Tissue Expression database, and the Human Protein Atlas database. Additionally, PTTG1-related gene enrichment analysis was performed to investigate the potential relationship and possible molecular mechanisms between PTTG1 and tumors. Overexpression of PTTG1 may lead to tumor formation and poor prognosis in various tumors. Consequently, PTTG1 acts as a potential oncogene in most tumors. Additionally, PTTG1 is related to immune infiltration, immune checkpoints, tumor mutational burden, and microsatellite instability. Thus, PTTG1 could be potential biomarker for both prognosis and outcomes of tumor treatment and it could also be a promising target in tumor therapy.

SP1-mediated transcriptional activation of PTTG1 regulates the migration and phenotypic switching of aortic vascular smooth muscle cells in aortic dissection through MAPK signaling

Pituitary tumor-transforming gene 1 (PTTG1) has been found to be associated with the process of cell proliferation and invasion, and is highly expressed in aortic dissection (AD). However, its potential role and underlying mechanism in AD remain uncertain. This study aims at elucidating the roles of specificity protein 1 (SP1) and PTTG1 in the migration and phenotypic switching of aortic vascular smooth muscle cells (VSMCs) in AD. Aortic samples were collected from 35 patients with AD for examination of PTTG1 expression in the tissues by qPCR, western blot and immunofluorescence. Human aortic vascular smooth muscle cells (HAVSMCs) were stimulated with platelet-derived growth factor-BB (PDGF-BB) to establish the cellular model of AD. PTTG1 expression in VSMCs was also examined by qPCR and western blot. Cell viability was detected by CCK-8, cell proliferation by EdU staining and cell migration by wound healing and transwell. Western blot was then performed to assay migration-related proteins. After interference with PTTG1, the levels of smooth muscle pthenotypic switch markers smooth muscle protein 22 alpha (SM22-α) and osteopontin (OPN) were detected by qPCR, western blot and immunofluorescence. The binding of SP1 and PTTG1 was verified with dual-luciferase reporter assay and chromatin immunoprecipitation assay (ChIP). PTTG1 overexpression was found in AD patients. Interference with PTTG1 attenuated the proliferation and migration of PDGF-BB-stimulated HAVSMCs, in addition to their switching from contractile phenotype to synthetic phenotype. Transcription factor SP1 was up-regulated in PDGF-BB-stimulated HAVSMCs, combined with PTTG1 promoter sequence and regulated PTTG1 expression, whose overexpression reversed the effects of PTTG1 interference on cell proliferation, migration and phenotypic switching. SP1 transcriptional activation of PTTG1 activated MAPK/ERK signaling pathway. In conclusion, SP1 transcriptional activation of PTTG1 regulates the migration and phenotypic transformation of HAVSMCs in AD by MAPK Signaling.

MiR-362-3p suppresses sinonasal squamous cell carcinoma progression via directly targeting pituitary tumor-transforming gene 1

Background Sinonasal squamous cell carcinoma (SNSCC) is a main subtype of sinonasal malignancy with unclear pathogenesis. microRNAs (miRNAs) are involved in SNSCC progression. Nevertheless, the role and mechanism of miR-362-3p in SNSCC development are unclear. Methods The SNSCC tissues (n = 23) and normal sinonasal samples (n = 13) were harvested. SNSCC cell line RPMI-2650 cells were transfected using Lipofectamine 3000. miR-362-3p and pituitary tumor-transforming gene 1 (PTTG1) were determined by quantitative reverse transcription polymerase chain reaction and western blot. Cell proliferation was analyzed via Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assays. Cell migration and invasion was assessed using wound healing assay and transwell assay. Epithelial-mesenchymal transition (EMT)-associated protein (E-cadherin, N-cadherin and Vimentin) levels were measured via western blot. The binding relationship was analyzed via bioinformatic analysis and dual-luciferase reporter assay. Results miR-362-3p abundance was decreased in SNSCC samples. miR-362-3p addition constrained cell proliferation, migration, invasion and EMT, but miR-362-3p knockdown played an opposite effect. PTTG1 was targeted and negatively modulated by miR-362-3p. PTTG1 abundance was elevated in SNSCC samples. PTTG1 overexpression mitigated miR-362-3p-modulated suppression of cell proliferation, migration, invasion and EMT in SNSCC cells. Conclusion miR-362-3p repressed cell proliferation, migration, invasion and EMT in SNSCC via targeting PTTG1.

Upregulation of PTTG1 is associated with poor prognosis in prostate cancer.

Pituitary tumor-transforming gene 1 (PTTG1) is a regulator of chromosome stability. PTTG1 overexpression had been associated with tumor aggressiveness in several cancer types. To examine its prognostic utility in prostate cancer, a tissue microarray including 12 427 tumors with clinical and molecular data was analyzed by immunohistochemistry. PTTG1 immunostaining was largely absent in normal prostate epithelial cells. In cancers, staining was considered weak in 5.4%, moderate in 5.6% and strong in 0.8%. Strong staining was linked to advanced pT stage, high classical and quantitative Gleason grade, high Ki67-labeling index (all P < 0.0001) and lymph node metastasis (P = 0.0083). The prognostic impact of PTTG1 expression was independent of established preoperative and postoperative prognostic features. Comparison with molecular features revealed that PTTG1 upregulation was associated with nine of 12 common genomic deletions (P < 0.05), p53 alterations and high androgen receptor levels (P < 0.001 each), but was unrelated to the TMPRSS2:ERG fusion status. In conclusion, these data identify PTTG1 as a strong and independent prognostic feature in prostate cancer. PTTG1 measurement, either alone or in combination with other biomarkers might be instrumental for determining prostate cancer aggressiveness.

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.

MiR‑186 functions as a tumor suppressor in osteosarcoma cells by suppressing the malignant phenotype and aerobic glycolysis.

Osteosarcoma (OS) is the most common primary bone malignancy among children and adolescents. Deregulation of microRNAs has been well documented in OS, while the putative effects of miR‑186 have not been identified yet. In the present study, we assessed the expression of miR‑186 in a cohort of 40 OS tissues and explored its effects on OS cells. As expected, miR‑186 was suppressed in OS tissues compared with relative normal tissues. Overexpression of miR‑186 inhibited cell proliferation, arrested the cell cycle progression and suppressed the cell invasion of the HOS and U2 OS cell lines. These results indicated the tumor‑suppressive role of miR‑186 in OS. Among the target genes of miR‑186, we found that pituitary tumor transforming gene1 (PTTG1) may be a target gene of miR‑186 in OS and that the overexpression of PTTG1 could partially abolish miR‑186‑mediated suppressive effects on OS cells. Aerobic glycolysis is the major way of energy supply and is one of the characteristic phenotypes of tumor cells. In addition, we found that overexpression of miR‑186 significantly suppressed the expression of hypoxia‑inducible factor 1 (HIF‑1) and inhibited the glucose uptake and lactate production of OS cells. Collectively, our findings demonstrated that miR‑186 functions as a tumor suppressor in OS cells partially by targeting PTTG1 and that HIF‑1‑mediated suppression of aerobic glycolysis may be also involved in its suppressive effects.

Interleukin-6/signal transducer and activator of transcription 3 promotes prostate cancer resistance to androgen deprivation therapy via regulating pituitary tumor transforming gene 1 expression.

Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration‐resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen‐independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen‐dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen‐deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44+ CD24‐ cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by interleukin‐6 via activated signal transducer and activator of transcription 3 (STAT3) directly binding to the region −500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that interleukin‐6/STAT3 activation can increase PTTG1 expression and, consequently, promote the resistance to ADT in CRPC by inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC.

The clinical value and biological function of PTTG1 in colorectal cancer

Pituitary tumor transforming gene-1 (PTTG1) has been suggested to serve as an oncogene in several types of human tumors, but little is known about the biological function of PTTG1 in colorectal cancer. PTTG1 mRNA and protein expressions in colorectal cancer tissues and cell lines were measured by qRT-PCR, western blot or immunohistochemistry. The association between PTTG1 protein expression and clinicopathological features was analyzed. The function of PTTG1 on colorectal cancer cell proliferation and metastasis were explored through MTT, colony formation, migration and invasion assays. In our results, PTTG1 mRNA and protein expressions were increased in colorectal cancer tissues and cell lines compared with normal colonic tissues and colon epithelial cell line. PTTG1 overexpression positively associated with clinical stage, T classification, N classification, M classification and differentiation. The univariate and multivariate analyses suggested PTTG1 overexpression was an independent poor prognostic factor for colorectal cancer patients. The in vitro experiments showed knocking down PTTG1 inhibited colorectal cancer growth and metastasis. In conclusion, PTTG1 is an independent prognostic factor and acts as an oncogene in colorectal cancer.

PTTG1 regulated by miR-146a-3p promotes bladder cancer migration, invasion, metastasis and growth.

Pituitary tumor-transforming gene 1 (PTTG1) is identified as an oncogene, and overexpresses in many tumors. However, the role of PTTG1 in bladder cancer (BC) hasn't yet been characterized well. In this study, we showed the expression of PTTG1 mRNA and protein were both significantly increased in BC tissues and cells. The PTTG1 protein levels were positive correlated with increased tumor size, tumor–node–metastasis (TNM) stage, lymphatic invasion and distant metastasis of BC. PTTG1 knockdown dramatically suppressed the migration, invasion, metastasis and growth, and induced senescence and cell-cycle arrest at G0/G1 phase of BC cells. We further identified PTTG1 was the direct target of miR-146a-3p through using target prediction algorithms and luciferase reporter assay. miR-146a-3p was low expressed and negatively correlated with PTTG1 levels in BC tissues and cells. miR-146a-3p overexpression inhibited migration, invasion, metastasis and growth, and induced senescence of BC cells. Rescue experiment suggested ectopic expression of miR-146a-3p and PTTG1 suppressed migration, invasion and induced cell cycle arrest and senescence of BC cells compared to PTTG1 overexpression, confirming miR-146a-3p inhibited BC progression by targeting PTTG1. In summary, our study found miR-146a-3p/PTTG1 axis regulated BC migration, invasion, metastasis and growth, and might be a targets for BC therapy.

Pituitary tumor-transforming gene 1 and related skin diseases

With the extensive application of genome-wide association study (GWAS) and other technologies, susceptibility genes of many complex skin diseases have been gradually discovered, which have facilitated the interpretation of pathogenesis of these diseases. Pituitary tumor-transforming gene 1 (PTTG1) is a common protooncogene, and plays an important role in the occurrence and development of many kinds of cancer. PTTG1 is also named securin gene, codes for cyclin, and takes part in the regulation of sister chromatid separation in cell division cycle and transition from metaphase to anaphase in cell cycle. Moreover, the overexpression of PTTG1 can enhance the proliferation of epithelial cells and interfere with cell differentiation, and then result in the occurrence of psoriasis, squamous cell carcinoma and other diseases. Further more, PTTG1 participates in the occurrence of systemic lupus erythematosus through regulation of the interferon signaling pathway. Key words: Skin diseases; Psoriasis; Lupus erythematosus, systemic; Neoplasms, squamous cell; Genes, PTTG1

High expression of pituitary tumor-transforming gene-1 predicts poor prognosis in clear cell renal cell carcinoma.

Pituitary tumor-transforming gene-1 (PTTG1) is a recently identified oncogene involved in the progression of malignant tumors; however, the expression level of PTTG1 in clear cell renal cell carcinoma (ccRCC) and its potential value as a novel prognostic marker for ccRCC remains unclear. In this study, PTTG1 mRNA and protein levels were assessed in 44 paired ccRCC tissues and adjacent normal tissues by quantitative polymerase chain reaction (qPCR) and immunohistochemistry, respectively. Further immunohistochemical analysis was implemented in 192 samples of ccRCC to evaluate the associations between PTTG1 levels and the clinical characteristics in ccRCC. Reverse transcription qPCR and immunohistochemical analysis demonstrated that the PTTG1 mRNA and protein levels were significantly higher in ccRCC compared to normal tissues. In addition, the PTTG1 protein level in 192 ccRCC samples was found to be significantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, whereas it was not associated with age and gender. Patients with low PTTG1 levels exhibited a better survival outcome compared to those with a higher PTTG1 level. PTTG1 expression and N stage were identified as independent prognostic factors for the overall survival of ccRCC patients. The results suggested that the overexpression of PTTG1 indicates a poor prognosis in ccRCC patients and, therefore, PTTG1 may serve as a novel prognostic marker for ccRCC.

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.

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.

PTTG1 inhibits SMAD3 in prostate cancer cells to promote their proliferation

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.

Pituitary Tumor Transforming Gene 1 Induces Tumor Necrosis Factor-α Production from Keratinocytes: Implication for Involvement in the Pathophysiology of Psoriasis

Proliferation and differentiation in the epidermis must be tightly regulated. This regulation is known to involve a range of transcription factors, including pituitary tumor transforming gene 1 (PTTG1), a ubiquitously distributed transcription factor that regulates keratinocyte proliferation and differentiation. Psoriasis is a common but refractory skin disorder, the pathophysiology of which is characterized by hyperproliferation and impaired differentiation in the epidermis. The present study was conducted to clarify the less well-known roles of PTTG1 in the pathophysiology of psoriasis, focusing on its relationship with tumor necrosis factor-α (TNF-α), which is a critical mediator of the disease. The levels of PTTG1 expression were increased in the psoriatic epidermis. Overexpression of PTTG1 resulted in the overproduction of TNF-α, and TNF-α itself had an inductive effect on PTTG1 expression, suggesting that their expression may involve autoinduction. Moreover, overexpression of PTTG1 involved augmented the expression of cyclin A and B1 proteins in both cultured keratinocytes and the psoriatic epidermis. Therefore, enhanced expression of PTTG1 in the psoriatic epidermis may result in aberrant regulation of the cell cycle and impaired differentiation via the interplay between PTTG1 and TNF-α.

Down-Regulation of the Oncogene PTTG1 via the KLF6 Tumor Suppressor during Induction of Myeloid Differentiation

The aberrant expression of proto-oncogenes is involved in processes that are responsible for cellular proliferation and the inhibition of myeloid differentiation in acute myeloid leukemia (AML). Pituitary Tumor-Transforming gene 1 (PTTG1), an oncogenic transcription factor, is abundantly expressed in various human cancers and hematopoietic malignancies. However, its expression in normal leukocytes and most normal tissues is very low or undetectable. The mechanism by which PTTG1 overexpression modifies myeloid cell development and promotes leukemogenesis remain unclear. To investigate the mechanistic links between PTTG1 overexpression and leukemia cell differentiation, we utilized phorbol 12-myristate 13-acetate (PMA), a well-known agent that triggers monocyte/macrophage differentiation, to analyze the expression patterns of PTTG1 in PMA-induced myeloid differentiation. We found that PTTG1 is down-regulated at the transcriptional level in PMA-treated HL-60 and THP1 cells. In addition, we identified a binding site for a tumor suppressor protein, Kruppel-like factor 6 (KLF6), in the PTTG1 promoter. We found that KLF6 could directly bind and repress PTTG1 expression. In HL-60 and THP1 cells, KLF6 mRNA and protein levels are up-regulated with a concordant reduction of PTTG1 expression upon treatment with PMA. Furthermore, KLF6 knockdown by shRNA abolished the suppression of PTTG1 and reduced the activation of the differentiation marker CD11b in PMA-primed cells. The protein kinase C (PKC) inhibitor and the MAPK/ERK kinase (MEK) inhibitor significantly blocked the potentiation of PMA-mediated KLF6 induction and the down-regulation of PTTG1, indicating that PTTG1 is suppressed via the activation of PKC/ERK/KLF6 pathway. Our findings suggest that drugs that increase the KLF6 inhibition of PTTG1 may have a therapeutic application in AML treatment strategies.

Pituitary Tumor-Transforming Gene 1 Enhances Proliferation and Suppresses Early Differentiation of Keratinocytes

The epidermis is a self-renewing tissue, the homeostasis of which is dependent upon the tight balance between proliferation and differentiation based on appropriate regulation of the cell cycle. The cell cycle regulation is dependent on the interactions among a number of cell cycle regulatory molecules, including the pituitary tumor-transforming gene 1 (PTTG1), also known as securin, a regulator of sister chromatid separation and transition from metaphase to anaphase. This study was conducted to clarify the less-known functions of PTTG1 in the epidermis by the use of keratinocytes cultured under two-dimensional (2D) or three-dimensional (3D) conditions. Forced overexpression of PTTG1 caused upregulation of cyclin B1, cyclin-dependent kinase 1 (CDK1), and c-Myc, resulting in enhanced proliferation and suppression of early differentiation without apparent alterations in terminal differentiation, and the exogenous PTTG1 was downregulated in association with cell cycle exit. In contrast, depletion of PTTG1 caused their downregulation and constrained proliferation with retention of differentiation capacity. These findings suggested that PTTG1 could alter the proliferation status by modulating the expression levels of the other cell cycle regulatory proteins, and excess PTTG1 primarily affects early differentiation of keratinocytes under the stability regulation associated with cell cycle exit.

Induction of Dlk1 by PTTG1 Inhibits Adipocyte Differentiation and Correlates with Malignant Transformation

Pituitary tumor-transforming gene-1 (PTTG1) is an oncogene highly expressed in a variety of endocrine, as well as nonendocrine-related cancers. Several tumorigenic mechanisms for PTTG1 have been proposed, one of the best characterized being its capacity to act as a transcriptional activator. To identify novel downstream target genes, we have established cell lines with inducible expression of PTTG1 and a differential display approach to analyze gene expression changes after PTTG1 induction. We identified dlk1 (also known as pref-1) as one of the most abundantly expressed PTTG1 targets. Dlk1 is known to participate in several differentiation processes, including adipogenesis, adrenal gland development, and wound healing. Dlk1 is also highly expressed in neuroendocrine tumors. Here, we show that PTTG1 overexpression inhibits adipogenesis in 3T3-L1 cells and that this effect is accomplished by promoting the stability and accumulation of Dlk1 mRNA, supporting a role for PTTG1 in posttranscriptional regulation. Moreover, both pttg1 and dlk1 genes show concomitant expression in fetal liver and placenta, as well as in pituitary adenomas, breast adenocarcinomas, and neuroblastomas, suggesting that PTTG1 and DLK1 are involved in cell differentiation and transformation.