Gene Summary

Gene:TPX2; TPX2 microtubule nucleation factor
Aliases: DIL2, p100, DIL-2, HCTP4, FLS353, HCA519, REPP86, C20orf1, C20orf2, GD:C20orf1
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:targeting protein for Xklp2
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (17)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Survival Rate
  • Gene Expression Profiling
  • Extracellular Matrix Proteins
  • Tubulin
  • Gene Knockdown Techniques
  • Breast Cancer
  • Cell Proliferation
  • Disease Progression
  • Cancer Gene Expression Regulation
  • Immunohistochemistry
  • Microtubule-Associated Proteins
  • Non-Small Cell Lung Cancer
  • Squamous Cell Carcinoma
  • Young Adult
  • Chromosome 20
  • Gene Regulatory Networks
  • Adenocarcinoma
  • Neoplasm Proteins
  • Gene Amplification
  • Messenger RNA
  • Cell Cycle Proteins
  • Disease-Free Survival
  • Cell Survival
  • Lung Cancer
  • Nuclear Proteins
  • Western Blotting
  • Estrogen Receptors
  • Cell Cycle
  • Oligonucleotide Array Sequence Analysis
  • Biomarkers, Tumor
  • siRNA
  • RNA Interference
  • Pregnancy
  • Aurora Kinase A
  • Protein-Serine-Threonine Kinases
  • p53 Protein
  • Apoptosis
  • Computational Biology
  • Cell Movement
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

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

Latest Publications: TPX2 (cancer-related)

Heo SK, Noh EK, Jeong YK, et al.
Radotinib inhibits mitosis entry in acute myeloid leukemia cells via suppression of Aurora kinase A expression.
Tumour Biol. 2019; 41(5):1010428319848612 [PubMed] Related Publications
Aurora kinases play critical roles in regulating several processes pivotal for mitosis. Radotinib, which is approved in South Korea as a second-line treatment for chronic myeloid leukemia, inhibits the tyrosine kinase BCR-ABL and platelet-derived growth factor receptor. However, the effects of radotinib on Aurora kinase expression in acute myeloid leukemia are not well studied. Interestingly, the cytotoxicity of acute myeloid leukemia cells was increased by radotinib treatment. Radotinib significantly decreased the expression of cyclin-dependent kinase 1 and cyclin B1, the key regulators of G2/M phase, and inhibited the expression of Aurora kinase A and Aurora kinase B in acute myeloid leukemia cells. In addition, radotinib decreased the expression and binding between p-Aurora kinase A and TPX2, which are required for spindle assembly. Furthermore, it reduced Aurora kinase A and polo-like kinase 1 phosphorylation and suppressed the expression of α-, β-, and γ-tubulin in acute myeloid leukemia cells. Furthermore, radotinib significantly suppressed the key regulators of G2/M phase including cyclin B1 and Aurora kinase A in a xenograft animal model. Therefore, our results suggest that radotinib can abrogate acute myeloid leukemia cell growth both in vitro and in vivo and may serve as a candidate agent or a chemosensitizer for treating acute myeloid leukemia.

Zhao ZM, Yost SE, Hutchinson KE, et al.
CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer.
BMC Cancer. 2019; 19(1):96 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance.
METHODS: Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets.
RESULTS: Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC.
CONCLUSIONS: CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.

Xu J, Hua X, Jin H, et al.
NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR-145/Sp1/USP8-dependent axis.
Mol Carcinog. 2019; 58(5):777-793 [PubMed] Related Publications
Although overexpression of the non-canonical NFκB subunit p52 has been observed in several tumors, the function and mechanism of p52 in bladder cancer (BC) are less well understood. Here, we aimed at understanding the role and mechanism underlying p52 regulation of BC invasion. Human p52 was stably knockdown with shRNA targeting p52 in two bladder cancer cell lines (T24 and UMUC3). Two constitutively expressing constructs, p52 and p100, were stably transfected in to T24 or UMUC3, respectively. The stable transfectants were used to determine function and mechanisms responsible for p52 regulation of BC invasion. We demonstrate that p52 mediates human BC invasion. Knockdown of p52 impaired bladder cancer invasion by reduction of rhogdiβ mRNA stability and expression. Positively regulation of rhogdiβ mRNA stability was mediated by p52 promoting AUF1 protein degradation, consequently resulting in reduction of AUF1 binding to rhogdiβ mRNA. Further studies indicated that AUF1 protein degradation was mediated by upregulating USP8 transcription, which was modulated by its negative regulatory transcription factor Sp1. Moreover, we found that p52 upregulated miR-145, which directly bound to the 3'-UTR of sp1 mRNA, leading to downregulation of Sp1 protein translation. Our results reveal a comprehensive pathway that p52 acts as a positive regulator of BC invasion by initiating a novel miR-145/Sp1/USP8/AUF1/RhoGDIβ axis. These findings provide insight into the understanding of p52 in the pathology of human BC invasion and progression, which may be useful information in the development of preventive and therapeutic approaches for using p52 as a potential target.

Zhang MY, Liu XX, Li H, et al.
Elevated mRNA Levels of AURKA, CDC20 and TPX2 are associated with poor prognosis of smoking related lung adenocarcinoma using bioinformatics analysis.
Int J Med Sci. 2018; 15(14):1676-1685 [PubMed] Free Access to Full Article Related Publications

Chen M, Zhang H, Zhang G, et al.
Targeting TPX2 suppresses proliferation and promotes apoptosis via repression of the PI3k/AKT/P21 signaling pathway and activation of p53 pathway in breast cancer.
Biochem Biophys Res Commun. 2018; 507(1-4):74-82 [PubMed] Related Publications
Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein required for mitosis and spindle assembly. Previous studies showed that TPX2 is overexpressed in various human cancers and promotes cancer progression. In this study, the differentially expressed genes including TPX2 were screened in GEO database for gene expression microarray of breast cancer. The TPX2 expression level was significantly increased in breast cancer cells and the breast malignant tissues compared with those controls. In vitro experiment further confirmed that knockdown of TPX2 by small hairpin RNA inhibited breast cancer cell proliferatio, migration, and induced cell apoptosis. TPX2 silencing decreased the expression of PI3K and extent of AKT phosphorylation, as well as increased expression of p53 and p21. Taken together, our findings indicate that TPX2 silencing negatively regulates the PI3K/AKT and activates p53 signaling pathway by which breast cancer cells proliferation were inhibited whereas cellulars apoptosis were accelerated, suggesting that TPX2 may be a potential target for anticancer therapy in breast cancer.

Liu L, Shi M, Wang Z, et al.
A molecular and staging model predicts survival in patients with resected non-small cell lung cancer.
BMC Cancer. 2018; 18(1):966 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The current TNM staging system is far from perfect in predicting the survival of individual non-small cell lung cancer (NSCLC) patients. In this study, we aim to combine clinical variables and molecular biomarkers to develop a prognostic model for patients with NSCLC.
METHODS: Candidate molecular biomarkers were extracted from the Gene Expression Omnibus (GEO), and Cox regression analysis was performed to determine significant prognostic factors. The survival prediction model was constructed based on multivariable Cox regression analysis in a cohort of 152 NSCLC patients. The predictive performance of the model was assessed by the Area under the Receiver Operating Characteristic Curve (AUC) and Kaplan-Meier survival analysis.
RESULTS: The survival prediction model consisting of two genes (TPX2 and MMP12) and two clinicopathological factors (tumor stage and grade) was developed. The patients could be divided into either high-risk group or low-risk group. Both disease-free survival and overall survival were significantly different among the diverse groups (P < 0.05). The AUC of the prognostic model was higher than that of the TNM staging system for predicting survival.
CONCLUSIONS: We developed a novel prognostic model which can accurately predict outcomes for patients with NSCLC after surgery.

Yao Y, Zuo J, Wei Y
Targeting of TRX2 by miR-330-3p in melanoma inhibits proliferation.
Biomed Pharmacother. 2018; 107:1020-1029 [PubMed] Related Publications
OBJECTIVE: This study is intended to identify the key gene from gene expression profile and validate its role and regulatory mechanism in melanoma.
METHODS: Gene expression profile of GSE3189 from GEO database was selected among which 7 are normal skin samples, 18 are benign skin lesion samples, and 45 are melanoma samples. The present study examined the 7 normal skin samples and the 45 melanoma samples. Differentially expressed genes (DEGs) between melanoma patients and health people were performed using Morpheus online tool. The 100 most differentially expressed genes (50 upregulated genes and 50 downregulated genes) were selected as hub genes. Then, expression levels and survival analysis of hub genes were conducted via GEPIA tool to choose target gene. The expression of target gene in melanoma cell lines was examined by RT-qPCR and western blotting. The biological function of target gene on cell proliferation in melanoma was measured in vitro. The predicted target of target gene was validated by dual-luciferase reporter assay and rescue experiment. The gene expression in clinical samples were determined by RT-qPCR, immunohistochemistry (IHC) and in situ hybridization (ISH). The tumor formation study was conducted in vivo.
RESULTS: Targeting protein for Xklp2 (TPX2) was identified as key gene in melanoma. TPX2 could promote the proliferation of melanoma cells. The dual luciferase reporter assay confirmed that miR-330-3p targets TPX2. In rescue experiment, it was proved that miR-330-3p inhibits the proliferation of melanoma cells by negatively regulating the expression of TPX2. The results in vitro were also confirmed in vivo. miR-330-3p/TPX2 pathway expressed differently between melanoma patients and health people. These differences were statistically significant (P < 0.05).
CONCLUSION: Inhibiting TPX2 by miR-330-3p suppresses the proliferation of melanoma cell lines. miR-330-3p/TPX2 pathway could be a potential therapeutic target in melanoma.

van Gijn SE, Wierenga E, van den Tempel N, et al.
TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells.
Oncogene. 2019; 38(6):852-867 [PubMed] Free Access to Full Article Related Publications
Genomic instability is a hallmark feature of cancer cells, and can be caused by defective DNA repair, for instance due to inactivation of BRCA2. Paradoxically, loss of Brca2 in mice results in embryonic lethality, whereas cancer cells can tolerate BRCA2 loss. This holds true for multiple DNA repair genes, and suggests that cancer cells are molecularly "rewired" to cope with defective DNA repair and the resulting high levels of genomic instability. In this study, we aim to identify genes that genomically unstable cancer cells rely on for their survival. Using functional genomic mRNA (FGmRNA) profiling, 16,172 cancer samples were previously ranked based on their degree of genomic instability. We analyzed the top 250 genes that showed a positive correlation between FGmRNA levels and the degree of genomic instability, in a co-functionality network. Within this co-functionality network, a strong cluster of 11 cell cycle-related genes was identified, including TPX2. We then assessed the dependency on these 11 genes in the context of survival of genomically unstable cancer cells, induced by BRCA2 inactivation. Depletion of TPX2 or its associated kinase Aurora-A preferentially reduced cell viability in a panel of BRCA2-deficient cancer cells. In line with these findings, BRCA2-depleted and BRCA2-mutant human cell lines, or tumor cell lines derived from Brca2

Dong Z, Zhang H, Zhan T, Xu S
Integrated analysis of differentially expressed genes in esophageal squamous cell carcinoma using bioinformatics.
Neoplasma. 2018; 65(4):523-531 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is a deadly disease. To identify key genes in esophageal squamous cell carcinoma, we followed a strategy utilizing the laiurger microarray dataset (GSE38129) as the training set and another independent microarray dataset (GSE20347) as the validation set. Following quality control, differentially expressed genes (DEGs) were obtained using R software. Functional enrichment analysis was performed using DAVID database and the DEG co-expression network was established with Weighted Gene Co-Expression Network Analysis (WGCNA) and visualized by Cytoscape. The prognosis-related hub genes were then identified by Kaplan-Meier analysis based on the TCGA database. A total of 188 DEGs were obtained; 88 up-regulated genes and 100 down-regulated. The up-regulated DEGs were significantly associated with extracellular matrix organization and disassembly while down-regulated DEGs were significantly related to keratinocyte differentiation. Blue and turquoise co-expression modules were established and 18 hub genes were identified. The blue module was associated with mitotic nuclear division, cell division and mitotic cytokinesis and the turquoise module was associated with collagen catabolic process, extracellular matrix organization and keratinocyte differentiation. We established that the TPX2, CDK1 and CEP55 blue module hub genes were associated with relapse-free survival, and our overall results not only identify key genes but also provide potential novel biomarkers for ESCC diagnosis and treatment.

Jiang XF, Ding L, Tian Y, et al.
Interaction of STAT3 and RelB modulates MMP-1 in colon cancer.
Chem Biol Interact. 2018; 293:94-99 [PubMed] Related Publications
BACKGROUND: MMP-1 (Matrix metalloproteinase-1) promotes carcinogenesis and distant metastasis in different cancers. Regulation of MMP-1 could occur at multiple levels: epigenetically, post-transcriptionally, or post-translationally. An increasing body of evidence supports that the cytoplasmic transcription factor STAT3 (signal transducer and activator of transcription 3) is activated constitutively in a variety of cancers wherein it significantly affects the growth of tumors and also facilitates metastasis. In addition, STAT3 has been found to regulate nuclear activity pro-inflammatory transcriptional factor, NF-κB signaling, especially, the alternative one (RelB/p100) by directly interacting with them METHOD AND RESULTS: In this proof of concept study, we tested the hypothesis that STAT3 interacts with RelB to promote tumor invasion by positively regulating MMP-1 in colon cancer. We found that RelB and STAT3 were constitutively localized in the nucleus of colon cancer in surgically-resected specimens with use of Western blot analysis, which was further confirmed by immunofluorescence (IF) staining in colon carcinoma cell line HT29. We further observed that STAT3/RelB knockdown resulted in reduced MMP-1. Our results from chromatin immunoprecipitation studies further established that association between RelB and MMP-1 promoter decreased when STAT3 was depleted, and conversely, STAT3 association with MMP-1 decreased with the knockdown of RelB.
CONCLUSION: These results suggest that STAT3 and ReB constitute a minimal activator complex for positive regulation of MMP-1 in colon cancer.

Ma S, Rong X, Gao F, et al.
TPX2 promotes cell proliferation and migration via PLK1 in OC.
Cancer Biomark. 2018; 22(3):443-451 [PubMed] Related Publications
BACKGROUND: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated proteinrequired for mitosis and spindle assembly. It has been revealed that TPX2 is overexpressedin various human cancers and promotes cancer progression.
METHODS: The expression of TPX2 was examined in ovarian cancer (OC) tissues and by Western blotting, quantitative real-time reverse transcription PCR (qRT-PCR) and immunohistochemistry. The effects of TPX2 on proliferation and migration of two OC cell lines SKOV3and RMG1 were analyzed using the methylthiazol tetrazolium (MTT) assay, flow cytometry and transwell assay. The mechanisms underlying the effects of TPX2 on OC cells were explored by qRT-PCR and Western blot.
RESULTS: In this study, we found that TPX2 was upregulated in OC tissues. We observed knockdown of TPX2 inhibited the expression of Polo-like kinase 1 (PLK1), which has an important role in the regulation of M phase of the cell cycle, and the activity of Cdc2, induced cell arrested at the G2/M phase and decreased proliferation. Moreover, our data revealed that the levels of PLK1, β-catenin, MMP7 and MMP9 were inhibited following TPX2 knockdown, leading to decrease of cell migration. Finally, we showed that the restoration of PLK1 expression attenuated the anti-proliferation and anti-migration effects of TPX2 knockdown in OC cells.
CONCLUSIONS: TPX2 promotes the proliferation and migration of human OC cells by regulating PLK1 expression.

Zhou Z, Cheng Y, Jiang Y, et al.
Ten hub genes associated with progression and prognosis of pancreatic carcinoma identified by co-expression analysis.
Int J Biol Sci. 2018; 14(2):124-136 [PubMed] Free Access to Full Article Related Publications
Since the five-year survival rate is less than 5%, pancreatic ductal adenocarcinoma (PDAC) remains the 4th cause of cancer-related death. Although PDAC has been repeatedly researched in recent years, it is still predicted to be the second leading cause of cancer death by year 2030. In our study, the differentially expressed genes in dataset GSE62452 were used to construct a co-expression network by WGCNA. The yellow module related to grade of PDAC was screened. Combined with co-expression network and PPI network, 36 candidates were screened. After survival and regression analysis by using GSE62452 and TCGA dataset, we identified 10 real hub genes (

Aushev VN, Lee E, Zhu J, et al.
Novel Predictors of Breast Cancer Survival Derived from miRNA Activity Analysis.
Clin Cancer Res. 2018; 24(3):581-591 [PubMed] Free Access to Full Article Related Publications

Wang LL, Jin XH, Cai MY, et al.
AGBL2 promotes cancer cell growth through IRGM-regulated autophagy and enhanced Aurora A activity in hepatocellular carcinoma.
Cancer Lett. 2018; 414:71-80 [PubMed] Related Publications
AGBL2 has been reported to catalyze α-tubulin detyrosination, by which it promotes tumorigenesis and cancer progression. However, its potential role in the pathogenesis of hepatocellular carcinoma (HCC) has not been revealed yet. In the present study, AGBL2 was frequently found being overexpressed in HCC tissues and cell lines. In a large cohort of clinical HCC tissues, high expression of AGBL2 was positively associated with tumor size, tumor multiplicity and advanced clinical stage (p < 0.05), and it was an independent prognostic factor for HCC patients. In HCC cell lines, ectopic overexpression of AGBL2 substantially enhanced HCC cells survival and proliferation in vitro and promoted tumor growth in vivo. In addition, we demonstrated that overexpression of AGBL2 in HCC cells notably inhibited apoptosis by enhancing IRGM-regulated autophagy. Meanwhile, AGBL2 could up-regulate the expression of TPX2 and Aurora A activity to promote cell proliferation in HCC cells. In summary, our findings suggest that up-regulation of AGBL2 plays a critical oncogenic role in the pathogenesis of HCC through modulation on autophagy and Aurora A activity, and it could be a candidate for prognostic marker and therapeutic target in HCC.

Zhou D, Li Z, Bai X
BRAFV600E and RET/PTC Promote Proliferation and Migration of Papillary Thyroid Carcinoma Cells In Vitro by Regulating Nuclear Factor-κB.
Med Sci Monit. 2017; 23:5321-5329 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Papillary thyroid carcinoma (PTC) is associated with mutations of BRAFV600E and RET/PTC and high levels of expression of nuclear factor-κB (NF-κB). However, few studies have focused on the association between NF-κB expression and mutations in BRAFV600E and RET/PTC, especially regarding PTC cell proliferation and migration. The aim of this in vitro study was to investigate the effect of BRAFV600E or RET/PTC on NF-κB expression, cell proliferation and cell migration in four established PTC cell lines. MATERIAL AND METHODS Four cell lines included TPC-1 (BRAFWT/WT), BCPAP (BRAFV600E/V600E), PCCL3, and PTC3-5 (RET/PTC), were grown in culture in vitro with or without suppression of NF-κB using pyrrolidine dithiocarbamate (PDTC), and cell proliferation, and cell migration were evaluated. RESULTS Expression of the BRAF gene was increased in the BCPAP cell line when compared with the TPC-1 cells. Expression of the RET gene was increased in the PTC3-5 cell line when compared with the PCCL3 cells. In the BCPAP and PTC3-5 cell lines, the relative expression of NF-κB protein, including phosphorylated p100/52, phosphorylated p65, phosphorylated IKKa/b, phosphorylated IκBα, and p65 nuclear translocation were increased compared with the TPC-1 and PCCL3 cells. Proliferation and migration of BCPAP and PTC3-5 cells were increased compared with the TPC-1 and PCCL3 cells. Suppression of NF-κB reduced NF-κB protein expression and inhibited the proliferation of cells in the TPC-1, BCPAP, PCCL3 and PTC3-5 cell lines, and migration of the BCPAP and PTC3-5 cells. CONCLUSIONS BRAFV600E and RET/PTC and the expression of NF-κB promote the proliferation and migration of papillary thyroid carcinoma cells in vitro.

Orth M, Unger K, Schoetz U, et al.
Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2.
Oncogene. 2018; 37(1):52-62 [PubMed] Related Publications
Taxane-based radiochemotherapy is a central treatment option for various cancer entities in locally advanced stages. The therapeutic synergism of this combined modality approach due to taxane-mediated radiosensitization of cancer cells is well-known. However, the underlying molecular mechanisms remain largely elusive, and mechanism-derived predictive markers of taxane-based radiochemotherapy are currently not available. Here, we show that clinically relevant doses of Paclitaxel, the prototype taxane, stimulate a tripolar mode of mitosis leading to chromosomal missegregation and aneuploidization rather than interfering with cell cycle progression. This distinct mitotic phenotype was interlinked with Paclitaxel-mediated radiosensitization via overexpression of mitotic Aurora kinase A (AURKA) and its cofactor TPX2 whose knockdown rescued the bipolar mode of cell division and largely attenuated the radiosensitizing effects of Paclitaxel. In the cancer genome atlas (TCGA) lung adenocarcinoma cohort, high expression levels of AURKA and TPX2 were associated with specifically improved overall survival upon taxane-based radiochemotherapy, but not in case of non-taxane-based radiochemotherapy, chemo- or radiotherapy only. Thus, our data provide insights into Paclitaxel-mediated radiosensitization on a mechanistic and molecular level and identify AURKA and TPX2 as the first potential mechanism-based, predictive markers of taxane-based radiochemotherapy.

Yan L, Li Q, Yang J, Qiao B
TPX2-p53-GLIPR1 regulatory circuitry in cell proliferation, invasion, and tumor growth of bladder cancer.
J Cell Biochem. 2018; 119(2):1791-1803 [PubMed] Related Publications
The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is associated with the metastasis and prognosis of bladder cancer. p53 is closely related to the progression of bladder cancer. Human glioma pathogenesis-related protein 1 (GLIPR1) is a p53 target gene with antitumor activity. This study aims to explore the interplay between TPX2, p53, and GLIPR1 and its correlation with cell proliferation, invasion, and tumor growth in bladder cancer. Here, Western blot and qRT-PCR analysis revealed that TPX2 at both mRNA and protein levels was up-regulated in bladder carcinoma tissues compared to their paired adjacent normal tissues. Additionally, tissues expressing high TPX2 level exhibited high p53 level and low GLIPR1 level. The expressions of TPX2 and p53 in non-muscle-invasive bladder cancer cells (KK47 and RT4) were lower than those in muscle-invasive bladder cancer cells (T24, 5637, and UM-UC-3), while GLIPR1 showed the converse expression pattern. Further investigation revealed that TPX2 activated the synthesis of p53; and GLIPR1 is up-regulated by wild-type (wt)-p53 but not affected by mutated p53; Additionally, GLIPR1 inhibited TPX2. These data suggested a TPX2-p53-GLIPR1 regulatory circuitry. Meanwhile, TPX2 overexpression promoted while overexpression of GLIPR1 or p53 inhibited bladder cancer growth. Interestingly, in T24 cells with mutated p53, p53 silence suppressed bladder cancer growth. This study identified a novel TPX2-p53-GLIPR1 regulatory circuitry which modulated cell proliferation, migration, invasion, and tumorigenicity of bladder cancer. Our findings provide new insight into underlying mechanisms of tumorigenesis and novel therapeutic options in bladder cancer.

Yang J, Gao F, Xu X, et al.
Targeting protein for Xenopus kinesin-like protein 2 knockdown enhances radiation sensitivity of human lung squamous carcinoma cell.
Clin Exp Pharmacol Physiol. 2017; 44(10):1060-1068 [PubMed] Related Publications
The targeting protein for Xenopus kinesin-like protein 2 (TPX2) has been demonstrated to be associated with the tumourigenesis of many cancers. In the present study, we investigated the role and preliminary mechanism of TPX2 in the resistance of lung squamous carcinoma to radiation therapy. The results showed that SK-MES-1R and NCI-H226R cells were more resistant to X-ray irradiation than the parental cells (SK-MES-1 and NCI-H226). Moreover, TPX2 was upregulated in the radioresistant cells compared with the parental cells. TPX2 knockdown significantly decreased TPX2 expression in SK-MES-1 cells, while TPX2 overexpression increased TPX2 expression in NCI-H226 cells compared with the corresponding control cells. TPX2 knockdown enhanced the radiosensitivity of SK-MES-1 and promoted cell apoptosis following exposure to irradiation, whereas TPX2 overexpression decreased the radiosensitivity of NCI-H226 and inhibited cell apoptosis. In in vivo studies, the combination of TPX2 knockdown and irradiation significantly inhibited tumour growth, decreased tumour weight, downregulated TPX2 expression in tumour tissue and induced cell apoptosis in nude mice, while TPX2 overexpression exerted an opposite effect. Our results indicated that TPX2 was correlated with cell radioresistance and it might be served as a therapeutic target to enhance cell radiosensitivity in the radiation therapy of lung squamous carcinoma.

Guo X, Koff JL, Moffitt AB, et al.
Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.
Oncogene. 2017; 36(29):4224-4232 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

Shinmura K, Kato H, Kawanishi Y, et al.
WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma.
Mol Carcinog. 2017; 56(8):1984-1991 [PubMed] Related Publications
Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC (n = 64) using a QRT-PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC (P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC (n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC (P < 0.0001, Mann-Whitney U test). A Kaplan-Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival (P = 0.0378, log-rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071-3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62-overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.

Gu Y, Lu L, Wu L, et al.
Identification of prognostic genes in kidney renal clear cell carcinoma by RNA‑seq data analysis.
Mol Med Rep. 2017; 15(4):1661-1667 [PubMed] Free Access to Full Article Related Publications
The present study aimed to analyze RNA-seq data of kidney renal clear cell carcinoma (KIRC) to identify prognostic genes. RNA‑seq data were downloaded from The Cancer Genome Atlas. Feature genes with a coefficient of variation (CV) >0.5 were selected using the genefilter package in R. Gene co‑expression networks were constructed with the WGCNA package. Cox regression analysis was performed using the survive package. Furthermore, a functional enrichment analysis was conducted using Database for Annotation, Visualization and Integrated Discovery tools. A total of 533 KIRC samples were collected, from which 6,758 feature genes with a CV >0.5 were obtained for further analysis. The KIRC samples were divided into two sets: The training set (n=319 samples) and the validation set (n=214 samples). Subsequently, gene co‑expression networks were constructed for the two sets. A total of 12 modules were identified, and the green module was significantly associated with survival time. Genes from the green module were revealed to be implicated in the cell cycle and p53 signaling pathway. In addition, a total of 11 hub genes were revealed, and 10 of them (CCNA2, CDC20, CDCA8, GTSE1, KIF23, KIF2C, KIF4A, MELK, TOP2A and TPX2) were validated as possessing prognostic value, as determined by conducting a survival analysis on another gene expression dataset. In conclusion, a total of 10 prognostic genes were identified in KIRC. These findings may help to advance the understanding of this disease, and may also provide potential biomarkers for therapeutic development.

Ludwig R, Teran FJ, Teichgraeber U, Hilger I
Nanoparticle-based hyperthermia distinctly impacts production of ROS, expression of Ki-67, TOP2A, and TPX2, and induction of apoptosis in pancreatic cancer.
Int J Nanomedicine. 2017; 12:1009-1018 [PubMed] Free Access to Full Article Related Publications
So far, the therapeutic outcome of hyperthermia has shown heterogeneous responses depending on how thermal stress is applied. We studied whether extrinsic heating (EH, hot air) and intrinsic heating (magnetic heating [MH] mediated by nanoparticles) induce distinct effects on pancreatic cancer cells (PANC-1 and BxPC-3 cells). The impact of MH (100 µg magnetic nanoparticles [MNP]/mL; H=23.9 kA/m; f=410 kHz) was always superior to that of EH. The thermal effects were confirmed by the following observations: 1) decreased number of vital cells, 2) altered expression of pro-caspases, and 3) production of reactive oxygen species, and 4) altered mRNA expression of Ki-67, TOP2A, and TPX2. The MH treatment of tumor xenografts significantly (

Yeo SK, French R, Spada F, Clarkson R
Opposing roles of Nfkb2 gene products p100 and p52 in the regulation of breast cancer stem cells.
Breast Cancer Res Treat. 2017; 162(3):465-477 [PubMed] Related Publications
PURPOSE: Nuclear factor-kappa B (NF-κB) signalling has been shown to regulate properties of breast cancer stem cells. However, the specific contribution of the non-canonical NF-κB pathway, components of which are elevated in aggressive breast cancer has not been addressed.
METHODS: Through shRNA silencing of the Nfkb2 gene, the role of p100/p52 in 4T1 and N202.1A cell lines were assessed by NF-κB reporter, invasion, tumoursphere and orthotopic transplantation assays. The processing of p100 into p52 was also inhibited with a p97 ATPase inhibitor, NMS-873, and its effects on tumoursphere formation was assessed.
RESULTS: Knockdown of Nfkb2 led to opposing changes in NF-κB-dependent transcription. NF-κB activity was elevated in 4T1 cells and this resulted in increased motility, cancer stem cell (CSC) activity and tumourigenicity in vivo. Conversely, depletion of Nfkb2 in N202.1a cells decreased NF-κB activity, CSC properties and tumourigenicity in vivo. By selectively overexpressing the p52 subunit in Nfkb2 depleted cells, we found that the increased malignancy in 4T1 cells could not be reverted in the presence of p52, whereas the decreased tumourigenicity of N202.1a cells could be rescued by p52. These results indicate that p100 and its subunit p52 have opposing effects on breast CSC activity. Accordingly, inhibition of an upstream regulator of p100 processing was effective in reducing tumoursphere formation of N202.1A and SKBR3 (ErbB2
CONCLUSION: These findings indicate that inhibiting the processing of p100 may be a potential therapeutic strategy to suppress CSC activity in a subset of breast tumours.

Schneider MA, Christopoulos P, Muley T, et al.
AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients.
Int J Oncol. 2017; 50(2):365-372 [PubMed] Free Access to Full Article Related Publications
The growth of a tumor depends to a certain extent on an increase in mitotic events. Key steps during mitosis are the regulated assembly of the spindle apparatus and the separation of the sister chromatids. The microtubule-associated protein Aurora kinase A phosphorylates DLGAP5 in order to correctly segregate the chromatids. Its activity and recruitment to the spindle apparatus is regulated by TPX2. KIF11 and CKAP5 control the correct arrangement of the microtubules and prevent their degradation. In the present study, we investigated the role of these five molecules in non-small cell lung cancer (NSCLC). We analyzed the expression of the five genes in a large cohort of NSCLC patients (n=362) by quantitative real-time PCR. Each of the genes was highly overexpressed in the tumor tissues compared to corresponding normal lung tissue. The correlation of the expression of the individual genes depended on the histology. An increased expression of AURKA, DLGAP5, TPX2, KIF11 and CKAP5 was associated with poor overall survival (P=0.001-0.065). AURKA was a significant prognostic marker using multivariate analyses (P=0.006). Immunofluorescence studies demonstrated that the five mitosis-associated proteins co-localized with the spindle apparatus during cell division. Taken together, our data demonstrate that the expression of the mitosis-associated genes AURKA, DLGAP5, TPX2, KIF11 and CKAP5 is associated with the prognosis of NSCLC patients.

Gutierrez-Beltran E, Denisenko TV, Zhivotovsky B, Bozhkov PV
Tudor staphylococcal nuclease: biochemistry and functions.
Cell Death Differ. 2016; 23(11):1739-1748 [PubMed] Free Access to Full Article Related Publications
Tudor staphylococcal nuclease (TSN, also known as Tudor-SN, SND1 or p100) is an evolutionarily conserved protein with invariant domain composition, represented by tandem repeat of staphylococcal nuclease domains and a tudor domain. Conservation along significant evolutionary distance, from protozoa to plants and animals, suggests important physiological functions for TSN. It is known that TSN is critically involved in virtually all pathways of gene expression, ranging from transcription to RNA silencing. Owing to its high protein-protein binding affinity coexistent with enzymatic activity, TSN can exert its biochemical function by acting as both a scaffolding molecule of large multiprotein complexes and/or as a nuclease. TSN is indispensible for normal development and stress resistance, whereas its increased expression is closely associated with various types of cancer. Thus, TSN is an attractive target for anti-cancer therapy and a potent tumor marker. Considering ever increasing interest to further understand a multitude of TSN-mediated processes and a mechanistic role of TSN in these processes, here we took an attempt to summarize and update the available information about this intriguing multifunctional protein.

Dewert N, Amschler K, Lorenz V, Schön MP
The IKKα-dependent non-canonical pathway of NF-κB activation is constitutively active and modulates progression-related functions in a subset of human melanomas.
Arch Dermatol Res. 2016; 308(10):733-742 [PubMed] Related Publications
Owing to activation of several resistance-mediating pathways including NF-κB signaling, metastasized melanoma is almost universally resistant against chemotherapy. Given that blocking of NF-κB either by proteasome-, pan-IKK- or selective IKKβ-inhibitors may increase the susceptibility of melanoma cells to chemotherapy, we have assessed the role of the second kinase within the IKK complex, IKKα. While expression of IKKα and overall activation of NF-κB were heterogeneous, the IKKα-specific p100/p52 processing was detected in a small subset of melanomas (1/9 primary and 1/12 metastatic melanomas) as well as in 1/8 melanoma cell lines. Down-modulation of IKKα by siRNA resulted in diminution of doxorubicin-induced NF-κB activation, constitutive and TNFα-stimulated expression of CXCL8 and ICAM-1, and cell migration. In contrast, overexpression of IKKα in melanoma cells did not significantly affect progression-related functions. Thus, IKKα may be a worthwhile target only in selected individualized therapies but not in general melanoma therapy.

Roy P, Mukherjee T, Chatterjee B, et al.
Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway.
Oncogene. 2017; 36(10):1417-1429 [PubMed] Free Access to Full Article Related Publications
Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.

Treekitkarnmongkol W, Katayama H, Kai K, et al.
Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer.
Carcinogenesis. 2016; 37(12):1180-1189 [PubMed] Free Access to Full Article Related Publications
Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.

Liang B, Zheng W, Fang L, et al.
Overexpressed targeting protein for Xklp2 (TPX2) serves as a promising prognostic marker and therapeutic target for gastric cancer.
Cancer Biol Ther. 2016; 17(8):824-32 [PubMed] Free Access to Full Article Related Publications
The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a putative oncogene in different human cancers. This study assessed TPX2 expression in gastric cancer tissue samples and then determined the effects of TPX2 knockdown on the regulation of gastric cancer cell malignant behaviors in vitro. Tissue samples from 115 gastric cancer patients were analyzed for TPX2 expression. The effects of TPX2 siRNA on gastric cancer cells were assessed in vitro, including cell viability, cell cycle distribution, apoptosis, migration, and invasion. The data showed that TPX2 was overexpressed in gastric cancer tissues compared to that in the adjacent normal epithelia. Moreover, TPX2 overexpression was associated with a poor overall survival and was an independent prognostic predictor of gastric cancer. In addition, the in vitro study further confirmed the ex vivo data, i.e., knockdown of TPX2 expression reduced gastric cancer cell viability but induced apoptosis and arrested cells at the G2/M phase of the cell cycle. Knockdown of TPX2 expression also inhibited the tumor cell migration and invasion capacity in vitro. At the gene level, knockdown of TPX2 expression upregulated the levels of cyclin B1, cdk4, p53, Bax, caspase-3, and E-cadherin, but downregulated the levels of cyclin D1, cdk2, N-cadherin, slug, matrix metalloprotease (MMP)-2, and MMP-9, suggesting that knockdown of TPX2 expression suppressed tumor cell epithelial-mesenchymal transition (EMT). This study demonstrated that detection of TPX2 overexpression could serve as a prognostic marker and therapeutic target for gastric cancer.

Heilmann T, Dittmann L, van Mackelenbergh M, et al.
Head-to-head comparison of the impact of Aurora A, Aurora B, Repp86, CDK1, CDK2 and Ki67 expression in two of the most relevant gynaecological tumor entities.
Arch Gynecol Obstet. 2016; 294(4):813-23 [PubMed] Related Publications
PURPOSE: The dysregulation of cell cycle kinases plays a crucial role in carcinogenesis and the expression of various kinases has been attributed to aggressive tumor growth and an unfavourable prognosis in oncological patients. We, therefore, aimed to evaluate the expression of Ki67 among five additional cell cycle kinases in a collective of mammary and ovarian tumor specimens and to find a correlation with clinicopathological parameters.
METHODS: 76 mammary and 93 ovarian benign and malignant tumor samples were immunohistochemically stained and evaluated for the expression of Aurora A and B, Repp86, CDK1 and 2 (only breast specimens) and Ki67. The expression patterns of these cell cycle kinases were matched with retrospectively collected clinicopathological parameters.
RESULTS: All examined cell cycle kinases accurately discriminated benign from malignant breast and ovarian tissues. In breast cancer, Aurora A and B-, Repp86-, CDK2- and Ki67-expression was inversely associated with ER expression. No correlation with the HER2-status was found in our collective. Importantly, we found a significant correlation between the expression of Aurora A and CDK1 and axillary lymph node metastasis in breast cancer. Furthermore, a shortened disease free survival (DFS) upon expression of Aurora B and CDK2 was shown in breast cancer patients. None of the cell cycle kinases was associated with predictive or prognostic factors in epithelial ovarian cancer.
CONCLUSION: The prognostic value of the expression of Ki67 is overtrumped by alternative cell cycle kinases when it comes to prediction of axillary tumor spread and a shortened DFS, which might allow a further risk stratification in breast cancer patients.

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