Gene Summary

Gene:TPT1; tumor protein, translationally-controlled 1
Aliases: HRF, p02, p23, TCTP
Summary:This gene encodes a protein that is a regulator of cellular growth and proliferation. Its mRNA is highly structured and contains an oligopyrimidine tract (5'-TOP) in its 5' untranslated region that functions to repress its translation under quiescent conditions. The encoded protein is involved in a variety of cellular pathways, including apoptosis, protein synthesis and cell division. It binds to and stabilizes microtubules, and removal of this protein through phosphorylation is required for progression through mitotic and meiotic cell divisions. This gene is known to play a role in carcinogenesis, and is upregulated in some cancer cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:translationally-controlled tumor protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: TPT1 (cancer-related)

Wu W, Gao H, Li X, et al.
LncRNA TPT1-AS1 promotes tumorigenesis and metastasis in epithelial ovarian cancer by inducing TPT1 expression.
Cancer Sci. 2019; 110(5):1587-1598 [PubMed] Free Access to Full Article Related Publications
Increasing numbers of studies have confirmed that long noncoding RNA (lncRNA) play a critical role in epithelial ovarian cancer (EOC) progression. However, the potential function of the lncRNA tumor protein translationally controlled 1 (TPT1) antisense RNA 1 (TPT1-AS1) in EOC is unclear. In this study, we aimed to uncover the biological roles and regulatory mechanisms of TPT1-AS1 in EOC progression and metastasis. First, TPT1-AS1 expression was significantly higher in EOC metastatic tissue and cell lines than in their respective control counterparts. In addition, ectopic TPT1-AS1 expression was strongly associated with unfavorable EOC clinicopathological features, including FIGO stage, tumor size and tumor differentiation. TPT1-AS1 overexpression remarkably induced cell proliferation, migration and invasion, and significantly attenuated cell adhesion ability in vitro and facilitated nude mouse subcutaneous xenograft growth and intraperitoneal metastasis in vivo, while the downregulation of TPT1-AS1 expression produced the opposite effect in vitro. Mechanistically, TPT1-AS1 was proven to be primarily distributed in EOC cell nuclei and positively modulated TPT1 promoter activity and transcription. Moreover, the oncogenic effects of TPT1-AS1 could be reversed by TPT1 depletion, and the PI3K/AKT signaling pathway downstream of TPT1 was also altered. These results suggested that TPT1-AS1 induced EOC tumor growth and metastasis through TPT1 and downstream PI3K/AKT signaling and that TPT1-AS1 may be a promising therapeutic target for EOC.

Jiang H, Huang G, Zhao N, et al.
Long non-coding RNA TPT1-AS1 promotes cell growth and metastasis in cervical cancer via acting AS a sponge for miR-324-5p.
J Exp Clin Cancer Res. 2018; 37(1):169 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Increasing studies confirmed that abnormal lncRNAs expression play a critical role in cervical cancer (CC) development and progression. LncRNA TPT1-AS1, a novel lncRNA, its role and underlying mechanisms involved in CC remain largely unknown.
METHODS: Colony formation, EdU and Transwell assays were used to determine colony formation, proliferation, migration and invasion in vitro. The subcutaneous tumor model and tail vein injection lung metastasis model were performed to check tumor growth and metastasis in vivo. Luciferase activity and RIP experiment were carried out to determine the interaction between miR-324-5p and TPT1-AS1.
RESULTS: We demonstrated for the first time that TPT1-AS1 expression was up-regulated in CC tissues and cell lines. High TPT1-AS1 was significantly correlated with adverse prognostic characteristics and poor survival. TPT1-AS1 overexpression and knockdown experiments revealed that TPT1-AS1 promoted cell colony formation, proliferation, migration, invasion and EMT progression of CC cells in vitro and in vivo. The underlying mechanism indicated that TPT1-AS1 functioned as an endogenous sponge for miR-324-5p in CC cells. Gain- and loss- experiment confirmed that miR-324-5p inhibited cell colony formation, proliferation, migration, invasion and EMT progression of CC cells, and mediated the biological effects of TPT1-AS1. Further investigations confirmed that SP1 was a direct target of miR-324-5p and mediated the effects of TPT1-AS1 and miR-324-5p in CC.
CONCLUSIONS: We demonstrated for the first time that TPT1-AS1 as an oncogenic lncRNA in CC progression and as a potential target for CC cure.

Zhang L, Wang Q, Wang F, et al.
LncRNA LINC01446 promotes glioblastoma progression by modulating miR-489-3p/TPT1 axis.
Biochem Biophys Res Commun. 2018; 503(3):1484-1490 [PubMed] Related Publications
Accumulating evidence indicates that long noncoding RNA (lncRNA) is implicated in human diseases, including cancers. However, how lncRNA regulates glioblastoma (GBM) progression is poorly understood. Our study revealed a novel lncRNA LINC01446 whose expression was elevated in GBM tissues. Besides, high expression of LINC01446 indicated a poor prognosis in GBM patients. Functionally, LINC01446 knockdown dramatically inhibited GBM cell proliferation, arrested cell-cycle progression and attenuated invasion in vitro. Furthermore, the xenograft mouse model showed that LINC01446 silence led to impaired tumor growth in vivo. Mechanistically, bioinformatics analysis showed that LINC01446 acted as a sponge for miR-489-3p which targeted TPT1. Though inhibiting miR-489-3p availability, LINC01446 promoted TPT1 expression in GBM cells. Rescue experiments demonstrated that restoration of TPT1 could significantly rescued the effects of LINC01446 silence or miR-489-3p overexpression. Taken together, this study demonstrates a novel singling pathway of LINC01446/miR-489-3p/TPT1 cascade that regulates GBM progression.

Bommer UA
The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation.
Results Probl Cell Differ. 2017; 64:69-126 [PubMed] Related Publications
The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein.TCTP is able to interact with a large number of other proteins and is therefore involved in many core cell biological processes, predominantly in the response to cellular stresses, such as oxidative stress, heat shock, genotoxic stress, imbalance of ion metabolism as well as other conditions. Mechanistically, TCTP acts as an anti-apoptotic protein, and it is involved in DNA-damage repair and in cellular autophagy. Thus, broadly speaking, TCTP can be considered a cytoprotective protein. In addition, TCTP facilitates cell division through stabilising the mitotic spindle and cell growth through modulating growth signalling pathways and through its interaction with the proteosynthetic machinery of the cell. Due to its activities, both as an anti-apoptotic protein and in promoting cell growth and division, TCTP is also essential in the early development of both animals and plants.Apart from its involvement in various biological processes at the cellular level, TCTP can also act as an extracellular protein and as such has been involved in modulating whole-body defence processes, namely in the mammalian immune system. Extracellular TCTP, typically in its dimerised form, is able to induce the release of cytokines and other signalling molecules from various types of immune cells. There are also several examples, where TCTP was shown to be involved in antiviral/antibacterial defence in lower animals. In plants, the protein appears to have a protective effect against phytotoxic stresses, such as flooding, draught, too high or low temperature, salt stress or exposure to heavy metals. The finding for the latter stress condition is corroborated by earlier reports that TCTP levels are considerably up-regulated upon exposure of earthworms to high levels of heavy metals.Given the involvement of TCTP in many biological processes aimed at maintaining cellular or whole-body homeostasis, it is not surprising that dysregulation of TCTP levels may promote a range of disease processes, foremost cancer. Indeed a large body of evidence now supports a role of TCTP in at least the most predominant types of human cancers. Typically, this can be ascribed to both the anti-apoptotic activity of the protein and to its function in promoting cell growth and division. However, TCTP also appears to be involved in the later stages of cancer progression, such as invasion and metastasis. Hence, high TCTP levels in tumour tissues are often associated with a poor patient outcome. Due to its multiple roles in cancer progression, TCTP has been proposed as a potential target for the development of new anti-cancer strategies in recent pilot studies. Apart from its role in cancer, TCTP dysregulation has been reported to contribute to certain processes in the development of diabetes, as well as in diseases associated with the cardiovascular system.Since cellular TCTP levels are highly regulated, e.g. in response to cell stress or to growth signalling, and because deregulation of this protein contributes to many disease processes, a detailed understanding of regulatory processes that impinge on TCTP levels is required. The last section of this chapter summarises our current knowledge on the mechanisms that may be involved in the regulation of TCTP levels. Essentially, expression of the TPT1 gene is regulated at both the transcriptional and the translational level, the latter being particularly advantageous when a rapid adjustment of cellular TCTP levels is required, for example in cell stress responses. Other regulatory mechanisms, such as protein stability regulation, may also contribute to the regulation of overall TCTP levels.

Pinkaew D, Fujise K
Fortilin: A Potential Target for the Prevention and Treatment of Human Diseases.
Adv Clin Chem. 2017; 82:265-300 [PubMed] Free Access to Full Article Related Publications
Fortilin is a highly conserved 172-amino-acid polypeptide found in the cytosol, nucleus, mitochondria, extracellular space, and circulating blood. It is a multifunctional protein that protects cells against apoptosis, promotes cell growth and cell cycle progression, binds calcium (Ca

Bizzarri M, Cucina A, Proietti S
Tumor Reversion: Mesenchymal-Epithelial Transition as a Critical Step in Managing the Tumor-Microenvironment Cross-Talk.
Curr Pharm Des. 2017; 23(32):4705-4715 [PubMed] Related Publications
Tumour reversion represents a promising field of investigation. The occurrence of cancer reversion both in vitro and in vivo has been ascertained by an increasing number of reports. The reverting process may be triggered in a wide range of different cancer types by both molecular and physical cues. This process encompasses mandatorily a change in the cell-stroma interactions, leading to profound modification in tissue architecture. Indeed, cancer reversion may be obtained by only resetting the overall burden of biophysical cues acting on the cell-stroma system, thus indicating that conformational changes induced by cell shape and cytoskeleton remodelling trigger downstream the cascade of molecular events required for phenotypic reversion. Ultimately, epigenetic regulation of gene expression (chiefly involving presenilin-1 and translationally controlled tumour protein) and modulation of a few critical biochemical pathways trigger the mesenchymal-epithelial transition, deemed to be a stable cancer reversion. As cancer can be successfully 'reprogrammed' by modifying the dynamical cross-talk with its microenvironment thus the cell-stroma interactions must be recognized as targets for pharmacological intervention. Yet, understanding cancer reversion remains challenging and refinement in modelling such processes in vitro as well as in vivo is urgently warranted. This new approach bears huge implications, from both a theoretical and clinical perspective, as it may facilitate the design of a novel anticancer strategy focused on mimicking or activating the tumour reversion pathway.

Bonhoure A, Vallentin A, Martin M, et al.
Acetylation of translationally controlled tumor protein promotes its degradation through chaperone-mediated autophagy.
Eur J Cell Biol. 2017; 96(2):83-98 [PubMed] Related Publications
Translationally controlled tumor protein (Tpt1/TCTP) is a multi-functional cytosolic protein whose cellular levels are finely tuned. TCTP regulates protein behavior by favoring stabilization of protein partners or on the contrary by promoting degradation of others. TCTP has been shown to be transcriptionally and translationally regulated, but much less is known about its degradation process. In this study, we present evidence that chaperone-mediated autophagy (CMA) contributes to TCTP regulation. CMA allows lysosomal degradation of specific cytosolic proteins on a molecule-by-molecule basis. It contributes to cellular homeostasis especially by acting as a quality control for cytosolic proteins in response to stress and as a way of regulating the level of specific proteins. Using a variety of approaches, we show that CMA degradation of TCTP is Hsc70 and LAMP-2A dependent. Our data indicate that (i) TCTP directly interacts with Hsc70; (ii) silencing LAMP-2A in MEFs using siRNA leads to inhibition of TCTP downregulation; (iii) TCTP is relocalized from a diffuse cytosolic pattern to a punctate lysosomal pattern when CMA is upregulated; (iv) TCTP is degraded in vitro by purified lysosomes. Importantly, using lysine-mutated forms of TCTP, we show that acetylation of Lysine 19 generates a KFERQ-like motif and promotes binding to Hsc70, lysosome targeting and TCTP degradation by CMA. Altogether these results indicate that TCTP is degraded by chaperone-mediated autophagy in an acetylation dependent manner.

Wang W, Yang F, Zhang L, et al.
LncRNA profile study reveals four-lncRNA signature associated with the prognosis of patients with anaplastic gliomas.
Oncotarget. 2016; 7(47):77225-77236 [PubMed] Free Access to Full Article Related Publications
Anaplastic glioma is Grade III and the median overall survival is about 37.6 months. However, there are still other factors that affect the prognosis for anaplastic glioma patients due to variable overall survival. So we screened four-lncRNA signature (AGAP2-AS1, TPT1-AS1, LINC01198 and MIR155HG) from the lncRNA expression profile from the GSE16011, CGGA and REMBRANDT datasets. The patients in low risk group had longer overall survival than high risk group (median OS 2208.25 vs. 591.30 days; P < 0.0001). Moreover, patients in the low risk group showed similar overall survival to Grade II patients (P = 0.1669), while the high risk group showed significant different to Grade IV (P = 0.0005) with similar trend. So based on the four-lncRNA, the anaplastic gliomas could be divided into grade II-like and grade IV-like groups. On the multivariate analysis, it showed the signature was an independent prognostic factor (P = 0.000). The expression of four lncRNAs in different grades showed that AGAP2-AS1, LINC01198 and MIR155HG were increased with tumor grade, while TPT1-AS1 was decreased. Knockdown of AGAP2-AS1 can inhibit the cell proliferation, migration and invasion, while increase the apoptosis cell rates in vitro. In conclusion, our results showed that the four-lncRNA signature has prognostic value for anaplastic glioma. Moreover, clinicians should conduct corresponding therapies to achieve best treatment with less side effects for two groups patients.

Agaësse G, Barbollat-Boutrand L, Sulpice E, et al.
A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion.
Oncogene. 2017; 36(4):446-457 [PubMed] Related Publications
Melanoma is the deadliest form of skin cancer owing to its proclivity to metastasise, and recently developed therapies have not yielded the expected results, because almost all patients relapse. Therefore, understanding the molecular mechanisms that underlie early invasion by melanoma cells is crucial to improving patient survival. We have previously shown that, whereas the Tetraspanin 8 protein (Tspan8) is undetectable in normal skin and benign lesions, its expression arises with the progression of melanoma and is sufficient to increase cell invasiveness. Therefore, to identify Tspan8 transcriptional regulators that could explain the onset of Tspan8 expression, thereby conferring an invasive phenotype, we performed an innovative RNA interference-based screen, which, for the first time, identified several Tspan8 repressors and activators, such as GSK3β, PTEN, IQGAP1, TPT1 and LCMR1. LCMR1 is a recently identified protein that is overexpressed in numerous carcinomas; its expression and role, however, had not previously been studied in melanoma. The present study identified Tspan8 as the first LCMR1 target that could explain its function in carcinogenesis. LCMR1 modulation was sufficient to positively regulate endogenous Tspan8 expression, with concomitant in vitro phenotypic changes such as loss of melanoma cell-matrix adherence and increase in invasion, and Tspan8 expression promoted tumourigenicity in vivo. Moreover, LCMR1 and Tspan8 overexpression were shown to correlate in melanoma lesions, and both proteins could be downregulated in vitro by vemurafenib. In conclusion, this study highlights the importance of Tspan8 and its regulators in the control of early melanoma invasion and suggests that they may be promising new therapeutic targets downstream of the RAF-MEK-ERK signalling pathway.

Prates J, Franco-Salla GB, Dinarte Dos Santos AR, et al.
ANXA1Ac₂₋₂₆ peptide reduces ID1 expression in cervical carcinoma cultures.
Gene. 2015; 570(2):248-54 [PubMed] Related Publications
Cervical cancer is the second most frequent cancer in women worldwide and is associated with genetic alterations, infection with human papilloma virus (HPV), angiogenesis and inflammatory processes. The idea that inflammation is involved in tumorigenesis is supported by the frequent appearance of cancer in areas of chronic inflammation. On the other hand, the inflammatory response is controlled by the action of anti-inflammatory mediators, among these mediators, annexin A1 (ANXA1), a 37 kDa protein was detected as a modulator of inflammatory processes and is expressed by tumor cells. The study was carried out on the epithelial cancer cell line (SiHa) treated with the peptide of annexin A1 (ANXA1Ac2-26). We combined subtraction hybridization approach, Ingenuity Systems software and quantitative PCR, in order to evaluate gene expression influenced by ANXA1. We observed that ANXA1Ac2-26 inhibited proliferation in SiHa cells after 72h. In these cells, 55 genes exhibited changes in expression levels in response to peptide treatment. Six genes were selected and the expression results of 5 up-regulated genes (TPT1, LDHA, NCOA3, HIF1A, RAB13) and one down-regulated gene (ID1) were research by real time quantitative PCR. Four more genes (BMP4, BMPR1B, SMAD1 and SMAD4) of the ID1 pathway were investigated and only one (BMPR1B) shows the same down regulation. The data indicate the involvement of ANXA1Ac2-26 in the altered expression of genes involved in tumorigenic processes, which could potentially be applied as a therapeutic indicator of cervical cancer.

Bommer UA, Iadevaia V, Chen J, et al.
Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway.
Cell Signal. 2015; 27(8):1557-68 [PubMed] Related Publications
Translationally controlled tumour protein TCTP (gene symbol: TPT1) is a highly-conserved, cyto-protective protein implicated in many physiological and disease processes, in particular cancer, where it is associated with poor patient outcomes. To understand the mechanisms underlying the accumulation of high TCTP levels in cancer cells, we studied the signalling pathways that control translation of TCTP mRNA, which contains a 5'-terminal oligopyrimidine tract (5'-TOP). In HT29 colon cancer cells and in HeLa cells, serum increases the expression of TCTP two- and four-fold, respectively, and this is inhibited by rapamycin or mTOR kinase inhibitors. Polysome profiling and mRNA quantification indicate that these effects occur at the level of mRNA translation. Blocking this pathway upstream of mTOR complex 1 (mTORC1) by inhibiting Akt also prevented increases in TCTP levels in both HeLa and HT29 colon cancer cells, whereas knockout of TSC2, a negative regulator of mTORC1, led to derepression of TCTP synthesis under serum starvation. Overexpression of eIF4E enhanced the polysomal association of the TCTP mRNA, although it did not protect its translation from inhibition by rapamycin. Conversely, expression of a constitutively-active mutant of the eIF4E inhibitor 4E-BP1, which is normally inactivated by mTORC1, inhibited TCTP mRNA translation in HEK293 cells. Our results demonstrate that TCTP mRNA translation is regulated by signalling through the PI3-K/Akt/mTORC1 pathway. This explains why TCTP levels are frequently increased in cancers, since mTORC1 signalling is hyperactive in ~80% of tumours.

Zhang F, Liu B, Wang Z, et al.
A novel regulatory mechanism of Pim-3 kinase stability and its involvement in pancreatic cancer progression.
Mol Cancer Res. 2013; 11(12):1508-20 [PubMed] Related Publications
UNLABELLED: Translationally controlled tumor protein (TCTP/TPT1) was identified from a yeast 2-hybrid screen and shown to interact with Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity. TCTP was aberrantly expressed in human pancreatic cancer cells and malignant ductal epithelial cells, but not in normal pancreatic duct epithelial cells adjacent to tumor foci of human pancreatic cancer tissue. Moreover, TCTP colocalized with Pim-3 both in human pancreatic cancer cells and in clinical tissues. Mapping studies revealed that the interaction between Pim-3 and TCTP occurred through the C-terminal region of Pim-3 and N-terminal region of TCTP. Although Pim-3 had no effect on TCTP expression or phosphorylation, overexpression of TCTP increased the amount of Pim-3 in a dose-dependent manner. Interestingly, RNAi-mediated ablation of TCTP expression reduced Pim-3 protein but not mRNA, through a mechanism involving the ubiquitin-proteasome degradation system. As a consequence of Pim-3 instability and subsequent degradation, tumor growth in vitro and in vivo was inhibited by arresting cell-cycle progression and enhancing apoptosis. Furthermore, TCTP and Pim-3 expression were significantly correlated in pancreatic adenocarcinoma specimens, and patients with highly expressed TCTP and Pim-3 presented with a more advanced tumor stage. These observations indicate that TCTP enhances Pim-3 stability to simultaneously promote and prevent cell-cycle progression and apoptosis, respectively. Hence, TCTP and Pim-3 serve a pivotal role in human pancreatic cancer with important ramifications for clinical diagnostic and therapeutic implications.
IMPLICATIONS: The present study provides a new idea and experimental evidence for recognizing TCTP/Pim-3 pathway as a target for therapy in human pancreatic cancer.

Shaheed SU, Rustogi N, Scally A, et al.
Identification of stage-specific breast markers using quantitative proteomics.
J Proteome Res. 2013; 12(12):5696-708 [PubMed] Related Publications
Matched healthy and diseased tissues from breast cancer patients were analyzed by quantitative proteomics. By comparing proteomic profiles of fibroadenoma (benign tumors, three patients), DCIS (noninvasive cancer, three patients), and invasive ductal carcinoma (four patients), we identified protein alterations that correlated with breast cancer progression. Three 8-plex iTRAQ experiments generated an average of 826 protein identifications, of which 402 were common. After excluding those originating from blood, 59 proteins were significantly changed in tumor compared with normal tissues, with the majority associated with invasive carcinomas. Bioinformatics analysis identified relationships between proteins in this subset including roles in redox regulation, lipid transport, protein folding, and proteasomal degradation, with a substantial number increased in expression due to Myc oncogene activation. Three target proteins, cofilin-1 and p23 (increased in invasive carcinoma) and membrane copper amine oxidase 3 (decreased in invasive carcinoma), were subjected to further validation. All three were observed in phenotype-specific breast cancer cell lines, normal (nontransformed) breast cell lines, and primary breast epithelial cells by Western blotting, but only cofilin-1 and p23 were detected by multiple reaction monitoring mass spectrometry analysis. All three proteins were detected by both analytical approaches in matched tissue biopsies emulating the response observed with proteomics analysis. Tissue microarray analysis (361 patients) indicated cofilin-1 staining positively correlating with tumor grade and p23 staining with ER positive status; both therefore merit further investigation as potential biomarkers.

Chen W, Wang H, Tao S, et al.
Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival.
Cell Cycle. 2013; 12(14):2321-8 [PubMed] Free Access to Full Article Related Publications
Tumor suppressor p53 maintains genome stability by differentially activating target genes that control diverse cellular responses, such as the antioxidant response, cell cycle arrest and apoptosis. Despite the fact that many p53 downstream genes have been well characterized, novel p53 target genes are continuously being identified. Here, we report that Tpt1 is a direct target gene of p53. We found that p53 upregulates the transcription of Tpt1 and identified a p53-responsive element in the promoter of the mouse Tpt1 gene. Furthermore, p53-dependent induction of Tpt1 was able to reduce oxidative stress, minimize apoptosis, and promote cell survival in response to H 2O2 challenge. In addition, a positive correlation between the expression of p53 and Tpt1 only existed in normal lung tissues, not in lung tumors. Such positive correlation was also found in lung cell lines that contain wild-type p53, but not mutated p53. Based on the important role of Tpt1 in cancer development, chemoresistance, and cancer reversion, identification of Tpt1 as a direct target gene of p53 not only adds to the complexity of the p53 network, but may also open up a new avenue for cancer prevention and intervention.

Amson R, Karp JE, Telerman A
Lessons from tumor reversion for cancer treatment.
Curr Opin Oncol. 2013; 25(1):59-65 [PubMed] Related Publications
PURPOSE OF REVIEW: Tumor reversion is the biological process by which highly tumorigenic cells lose at great extent or entirely their malignant phenotype. The purpose of our research is to understand the molecular program of tumor reversion and its clinical application. We first established biological models of reversion, which was done by deriving revertant cells from different tumors. Secondly, the molecular program that could override the malignant phenotype was assessed. Differential gene-expression profiling showed that at least 300 genes are implicated in this reversion process such as SIAH-1, PS1, TSAP6, and, most importantly, translationally controlled tumor protein (TPT1/TCTP). Decreasing TPT1/TCTP is key in reprogramming malignant cells, including cancer stem cells.
RECENT FINDINGS: Recent findings indicate that TPT1/TCTP regulates the P53-MDM2-Numb axis. Notably, TPT1/TCTP and p53 are implicated in a reciprocal negative-feedback loop. TPT1/TCTP is a highly significant prognostic factor in breast cancer. Sertraline and thioridazine interfere with this repressive feedback by targeting directly TPT1/TCTP and inhibiting its binding to MDM2, restoring wildtype p53 function. Combining sertraline with classical drugs such as Ara-C in acute myeloid leukemia may be also beneficial.
SUMMARY: In this review, we discuss some of these reversion pathways and how this approach could open a new route to cancer treatment.

Lo WY, Wang HJ, Chiu CW, Chen SF
miR-27b-regulated TCTP as a novel plasma biomarker for oral cancer: from quantitative proteomics to post-transcriptional study.
J Proteomics. 2012; 77:154-66 [PubMed] Related Publications
We combined an iTRAQ-based quantitative proteomic analysis and the miRNA determination to profile potentially novel biomarker from oral cancer. There are 757 and 674 unique proteins identified from proteomic analysis, and 13 proteins displayed consistent underexpression (<0.67 fold) in normal tissues in comparison with the corresponding tumor tissues. After preliminary screening, EGFR, OAT, TPT1, ITGA6, G3BP1 and CB39L were the six genes validated in the 37 oral cancer patients (T1, n=10; T2, n=10; T3, n=10 and T4, n=7). The TPT1, ITGA6 and CAB39L genes were displayed the higher transcriptions level in the tumor tissues and the TPT1, ITGA6 and CAB39L proteins were also shown overexpression in the tumor tissues from the same patients. The miR-19a, 19b, 27a, 27b, 186, 203 and 377 transcripts were predicted and the miR-27b level was shown to significantly reduce in the tumor tissues and the plasma of OSCC patients. In the in vitro study, the overexpression of miR-27b only significantly decreased TCTP protein and gene levels in both HSC-3 and Cal-27 cell lines. Our results demonstrate that human miR-27b regulates the expression of the TCTP tumor protein, and circulating miR-27b may be useful as a biomarker for oral cancer research.

Fu J, Bian L, Zhao L, et al.
Identification of genes for normalization of quantitative real-time PCR data in ovarian tissues.
Acta Biochim Biophys Sin (Shanghai). 2010; 42(8):568-74 [PubMed] Related Publications
Increased attention has been paid to the determination of the potential biomarker and therapeutic target for ovarian cancer in recent years. However, the normalization of quantitative real-time PCR is important to obtain accurate gene expression data. We investigated the stability of 20 reference genes in ovarian tissues under different conditions to determine the most adequate for this application. The study characterized the expression of 20 possible reference genes among 52 ovarian tissue samples involving the normal, non-malignant, and primary ovarian carcinomas. One-way analysis of variance (ANOVA) method was used to compare the candidate gene changes brought about by the disease progression. The stability and suitability of the genes with no statistic difference were further validated employing geNorm and NormFinder softwares. Results showed that the expression levels of the 20 reference genes varied, while the RPL4, RPLP0, HSPCB, TPT1, RPL13A, 18S rRNA, PPIA, TBP, and GUSB kept statistic stability despite different ovarian tissue conditions. RPL4, RPLP0, and HSPCB were demonstrated as the most stable reference genes and the combination of the RPLP0 and RPL4 should be recommended as a much more reliable normalization strategy.

Hsieh SY, Hsu CY, He JR, et al.
Identifying apoptosis-evasion proteins/pathways in human hepatoma cells via induction of cellular hormesis by UV irradiation.
J Proteome Res. 2009; 8(8):3977-86 [PubMed] Related Publications
Evading apoptosis is pivotal in both of carcinogenesis and resistance to anticancer therapy. We investigated the molecules and pathways of apoptosis evasion in human hepatoma cells by irradiating hepatoma cells with optimized UV (so-called "hormetic responses"). Proteins and pathways related to hormetic responses were identified via proteomic approaches followed by reconstruction of function-networks. Of the 2326 defined protein spots, 42 distinct proteins significantly changed their expression. Eleven hormetic response proteins (HINT1, PHB, CTSD, ANXA1, LGASL1, TPT1, NPM, PRDX2, UCHL1, CERK, and C1QBP) were involved in 5 death-regulatory pathways, including the p53-dependent apoptotic pathway, protein ubiquinization, cellular redox, calcium-mediated signaling pathway, and sphingomyelin-metabolism pathway. Knockdown of HINT1 expression via RNA interference increased tumor cell resistance to apoptosis induction, while silencing NPM, UCHL1, or CERK greatly sensitized tumor cells to apoptosis induction. In conclusion, NPM, UCHL1, and CERK act as apoptosis-evasion proteins that may serve as therapeutic targets for hepatoma. Silencing their expression would increase therapeutic efficacy, thereby reducing the corresponding doses and side-effects of anticancer therapy. This model of induction of cellular hormetic responses to identify apoptosis-evasion molecules/pathways via proteomic approaches can be applied to other modalities of anticancer therapy.

Ciotti M, Marzano V, Giuliani L, et al.
Proteomic investigation in A549 lung cell line stably infected by HPV16E6/E7 oncogenes.
Respiration. 2009; 77(4):427-39 [PubMed] Related Publications
BACKGROUND: Data have accumulated implicating the involvement of oncogenic human papillomaviruses (HPVs) in bronchial carcinogenesis. We recently described the presence of oncogenic HPV transcripts in non-small cell lung cancers.
OBJECTIVE: To investigate the role of oncogenic HPVs in lung carcinogenesis.
MATERIAL AND METHODS: The lung cell line A549 stably infected with HPV16E6, HPV16E7 and HPVE6/E7 constructs was used to investigate the protein profile changes associated with the expression of these oncogenes. Replicated two-dimensional gel electrophoresis gels from uninfected and stably HPV16E6-, E7-, and E6/E7-infected A549 cells were compared for changes in protein profile. Protein identification was achieved by peptide mass fingerprinting by MALDI-TOF-MS and nLC-ESI-Q-TOF-MS/MS peptide ladder sequencing.
RESULTS: We identified 17 different polypeptides whose average normalized spot intensity was statistically significant (p < 0.05) and differed by 2-fold. Relationships between differentially expressed proteins and the HPV-induced infection mechanism have been clustered by knowledge-base database functional association network analysis.
CONCLUSION: The impact of Hsp27, annexin III, annexin IV, Gp96 and TPT1 on the cellular response mechanism to HPV infection is presented and discussed.

Sun Y, Yi H, Zhang PF, et al.
Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis.
FEBS Lett. 2007; 581(1):131-9 [PubMed] Related Publications
Although mutation of p53 tumor-suppressor gene is rare in nasopharyngeal carcinoma (NPC), NPC has a high frequency of overexpression of p53 protein. There seem to be complex mechanisms of inactivation and stabilization of p53 in NPC. To detect proteins associated with the function of p53 in high throughout screening, we succeeded in establishing p53 knockdown human NPC CNE2 cell line (CNE2sip53) using stable RNA interference, and compared the proteomic changes between CNE2sip53 and control cell line CNE2/pSUPER using two-dimensional gel electrophoresis. Twenty-two differentially expressed proteins between the two cell lines were identified by both matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and electrospray ionization tandem mass spectrometry, some of which are known to be associated with the p53 function (HSP27, hnRNP K, 14-3-3sigma, etc.), and others may be novel proteins associated with p53 function (eIF4B, TPT1, hnRNP H3, SFRS1 etc.). Furthermore, several differential proteins including HSP27, HSP70, GRP75 and GRP78 were verified as p53 interacting proteins in NPC by immunoprecipitation and Western blot analysis, and the suppression of HSP27 expression by HSP27 antisense oligonucleotides could decrease the p53 protein level. Our data suggest that these differential proteins may be associated with the function of p53 in NPC, and provide new clues to elucidate the mechanisms of inactivation and stabilization of p53 in NPC.

Zhou FL, Zhang WG, Chen G, et al.
Serological identification and bioinformatics analysis of immunogenic antigens in multiple myeloma.
Cancer Immunol Immunother. 2006; 55(8):910-7 [PubMed] Related Publications
Identifying appropriate tumor antigens is critical to the development of successful specific cancer immunotherapy. Serological analysis of tumor antigens by a recombinant cDNA expression library (SEREX) allows the systematic cloning of tumor antigens recognized by the spontaneous autoantibody repertoire of cancer patients. We applied SEREX to the cDNA expression library of cell line HMy2, which led to the isolation of six known characterized genes and 12 novel genes. Known genes, including ring finger protein 167, KLF10, TPT1, p02 protein, cDNA FLJ46859 fis, and DNMT1, were related to the development of different tumors. Bioinformatics was performed to predict 12 novel MMSA (multiple myeloma special antigen) genes. The prediction of tumor antigens provides potential targets for the immunotherapy of patients with multiple myeloma (MM) and help in the understanding of carcinogenesis. Crude lysate ELISA methodology indicated that the optical density value of MMSA-3 and MMSA-7 were significantly higher in MM patients than in healthy donors. Furthermore, SYBR Green real-time PCR showed that MMSA-1 presented with a high number of copy messages in MM. In summary, the antigens identified in this study may be potential candidates for diagnosis and targets for immunotherapy in MM.

Andersen CL, Jensen JL, Ørntoft TF
Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets.
Cancer Res. 2004; 64(15):5245-50 [PubMed] Related Publications
Accurate normalization is an absolute prerequisite for correct measurement of gene expression. For quantitative real-time reverse transcription-PCR (RT-PCR), the most commonly used normalization strategy involves standardization to a single constitutively expressed control gene. However, in recent years, it has become clear that no single gene is constitutively expressed in all cell types and under all experimental conditions, implying that the expression stability of the intended control gene has to be verified before each experiment. We outline a novel, innovative, and robust strategy to identify stably expressed genes among a set of candidate normalization genes. The strategy is rooted in a mathematical model of gene expression that enables estimation not only of the overall variation of the candidate normalization genes but also of the variation between sample subgroups of the sample set. Notably, the strategy provides a direct measure for the estimated expression variation, enabling the user to evaluate the systematic error introduced when using the gene. In a side-by-side comparison with a previously published strategy, our model-based approach performed in a more robust manner and showed less sensitivity toward coregulation of the candidate normalization genes. We used the model-based strategy to identify genes suited to normalize quantitative RT-PCR data from colon cancer and bladder cancer. These genes are UBC, GAPD, and TPT1 for the colon and HSPCB, TEGT, and ATP5B for the bladder. The presented strategy can be applied to evaluate the suitability of any normalization gene candidate in any kind of experimental design and should allow more reliable normalization of RT-PCR data.

Grdisa M
Sensitivity of B-cell chronic lymphocytic leukemia to Rituximab and Campath-1H and correlation with the expression of cell cycle regulatory proteins.
Croat Med J. 2004; 45(2):136-41 [PubMed] Related Publications
AIM: To assess the effect of monoclonal antibodies anti-CD20 (Rituximab) and anti-CD52 (Campath-1H) on the viability of B cells from patients with B cell chronic lymphocytic leukemia (B-CLL) in comparison with a cytotoxic drug fludarabine (Fluda), and to determine the influence of these agents on the expression of cell cycle regulatory proteins in vitro.
METHODS: B-CLL cells were incubated in vitro in the presence of Rituximab, Campath-1H, and Fluda. The viability of the cells was measured by MTT test (3-(4,5-dimethylthiazol-2-yl)-2,5-dyphenyltetrazolium bromide). Gel electrophoresis and Western blotting were used to determine the effect of these agents on the expression of cell cycle regulatory proteins in vitro.
RESULTS: Both monoclonal antibodies, Rituximab and Campath-1H, were less toxic than Fluda to B-CLL cells. Combination of Campath-1H or Rituximab with Fluda did not have a stronger effect on the cells than Fluda alone. Both antibodies decreased the expression of p27 protein and increased the expression of p23; Fluda had a similar effect. The extent of cyclin D3 and cyclin E expression did not change significantly. The expression of cyclin D2 was slightly increased in the presence of Campath-1H, but in the presence of Rituximab it either decreased slightly or remained the same. Treatment of B-CLL cells with Fluda alone induced significant decrease in cyclin D2 expression.
CONCLUSION: These results demonstrated that monoclonal antibodies Campath-1H and Rituximab antibodies, as well as a cytotoxic drug fludarabine, had cytotoxic effects on B-CLL cells. They most likely induce apoptosis of B-CLL cells, but their activity is mediated through different pathways.

Tuynder M, Susini L, Prieur S, et al.
Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.
Proc Natl Acad Sci U S A. 2002; 99(23):14976-81 [PubMed] Free Access to Full Article Related Publications
Tumor reversion is the process by which some cancer cells lose their malignant phenotype. This study was aimed at defining some of the molecular and phenotypic properties of this process. Biological models of tumor reversion were isolated from human leukemia and breast cancer cell lines by using the H-1 parvovirus as a selective agent. Differential gene expression analysis was performed between the parental malignant cells and their revertants or alternatively between these parental cells and their SIAH-1 transfectant counterparts. These SIAH-1 transfectants have a suppressed malignant phenotype and were used as a control for a viral-free system. Two hundred sixty-three genes were found to be either activated or inhibited during the reversion process, as confirmed by Northern blot analysis or quantitative PCR. Of these, 32% were differentially expressed in all systems, irrespective of whether parvovirus-selected, SIAH-1 overexpressing, or p53 mutant or wild-type cell lines were used, suggesting the existence of a universal mechanism underlying tumor reversion. Translationally Controlled Tumor Protein (tpt1/TCTP) has the strongest differential expression, down-regulated in the reversion of U937- and SIAH-1-overexpressing cells. Inhibition of TCTP expression by anti-sense cDNA or small interfering RNA molecules results in suppression of the malignant phenotype and in cellular reorganization, similar to the effect of SIAH-1. Hence, tumor reversion can be defined at the molecular level, not just as the reversal of malignant transformation, but as a biological process in its own right involving a cellular reprogramming mechanism, overriding genetic changes in cancer, by triggering an alternative pathway leading to suppression of tumorigenicity.

Bommer UA, Lazaris-Karatzas A, De Benedetti A, et al.
Translational regulation of the mammalian growth-related protein P23: involvement of eIF-4E.
Cell Mol Biol Res. 1994; 40(7-8):633-41 [PubMed] Related Publications
Synthesis of the mammalian growth-related protein P23 is rapidly induced after serum stimulation of mouse fibroblasts and Ehrlich ascites tumour cells. This induction occurs at the translational level. Growth-induction leads also to an increase in phosphorylation of the rate-limiting initiation factor eIF-4E. Here, we present the following evidence indicating the involvement of eIF-4E in the regulation of P23 synthesis: 1) P23 synthesis is induced by the same mitogenic stimuli which lead to enhanced eIF-4E phosphorylation. 2) Upon heat shock treatment of Ehrlich ascites cells (which results in immediate dephosphorylation and concomitant inactivation of eIF-4E), P23 synthesis is rapidly shut off. 3) In control NIH 3T3 cells, P23 synthesis is readily induced by growth stimulation. This response is strongly diminished in cells overexpressing eIF-4E, and the basal level of P23 synthesis is elevated in these cells. Overexpression of a nonfunctional mutant of eIF-4E diminishes the basal level of P23 synthesis as well as the serum-response of the cells with respect to P23 induction. 4) Cells transformed by overexpression of the ras or src genes in which eIF-4E is highly phosphorylated do not show any inducibility of P23 synthesis. 5) HeLa cells expressing antisense RNA of eIF-4E, have reduced levels of eIF-4E/F and show reduced rates of growth and protein synthesis. In these cells the total amount of P23 protein is about 50% compared with control cells. The results suggest that P23 is one of the gene products, the synthesis of which is regulated by eIF-4E activity.

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