Research IndicatorsGraph generated 20 August 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 20 August, 2015 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: TPX2 (cancer-related)
Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that the expression level of TPX2 was obviously higher in hepatocellular carcinoma (HCC) tissues than in matched nontumor tissues. Elevated expressions of TPX2 mRNA were observed in all HCC cell lines (HepG2, Hep3B, SMMC-7721, Bel-7402 and Huh7) as compared with that in a non-transformed hepatic cell line (LO2). Clinical analysis indicated that the positive expression of TPX2 was significantly correlated with venous infiltration, high Edmondson-Steiner grading and advanced TNM tumor stage in HCC. Furthermore, TPX2 was a novel prognostic marker for predicting 5-year overall survival (OS) and disease-free survival (DFS) of HCC patients. In vitro studies found that TPX2 knockdown significantly inhibited cell proliferation and viability in both Hep3B and HepG2 cells. Moreover, TPX2 knockdown obviously slowed down tumor growth in a nude mouse xenograft model. Otherwise, TPX2 knockdown prominently suppressed HCC cell invasion and migration. In conclusion, these results indicate that TPX2 may serve as a prognostic marker and promotes tumorigenesis and metastasis of HCC.
There are two major pathways leading to induction of NF-κB subunits. The classical (or canonical) pathway typically leads to the induction of RelA or c-Rel containing complexes, and involves the degradation of IκBα in a manner dependent on IκB kinase (IKK) β and the IKK regulatory subunit NEMO. The alternative (or non-canonical) pathway, involves the inducible processing of p100 to p52, leading to the induction of NF-κB2(p52)/RelB containing complexes, and is dependent on IKKα and NF-κB inducing kinase (NIK). Here we demonstrate that in primary human fibroblasts, the alternative NF-κB pathway subunits NF-κB2 and RelB have multiple, but distinct, effects on the expression of key regulators of the cell cycle, reactive oxygen species (ROS) generation and protein stability. Specifically, following siRNA knockdown, quantitative PCR, western blot analyses and chromatin immunoprecipitation (ChIP) show that NF-κB2 regulates the expression of CDK4 and CDK6, while RelB, through the regulation of genes such as PSMA5 and ANAPC1, regulates the stability of p21WAF1 and the tumour suppressor p53. These combine to regulate the activity of the retinoblastoma protein, Rb, leading to induction of polycomb protein EZH2 expression. Moreover, our ChIP analysis demonstrates that EZH2 is also a direct NF-κB target gene. Microarray analysis revealed that in fibroblasts, EZH2 antagonizes a subset of p53 target genes previously associated with the senescent cell phenotype, including DEK and RacGAP1. We show that this pathway provides the major route of crosstalk between the alternative NF-κB pathway and p53, a consequence of which is to suppress cell senescence. Importantly, we find that activation of NF-κB also induces EZH2 expression in CD40L stimulated cells from Chronic Lymphocytic Leukemia patients. We therefore propose that this pathway provides a mechanism through which microenvironment induced NF-κB can inhibit tumor suppressor function and promote tumorigenesis.
Liu HC, Zhang GH, Liu YH, et al.TPX2 siRNA regulates growth and invasion of esophageal cancer cells.
Biomed Pharmacother. 2014; 68(7):833-9 [PubMed
] Related Publications
PURPOSE: Observe how specific small RNA interference (siRNA) aimed at TPX2 gene suppresses TPX2 gene expression in esophageal cancer EC9706 cells and the effect on esophageal cancer cell growth and invasion ability.
METHODS: Transfect TPX2 siRNA into EC9706 cells via lipofectamin 2000. The experiments were divided into three groups, a negative control, a blank control and an siRNA interference group (24h, 48h, 72h, 96h). We examined RNA and protein level alteration of the TPX2 gene after TPX2 siRNA transfection by RT-PCR and Western blot analysis. Detection of how TPX2 siRNA influences EC9706 cell proliferation was done by MTT, cell apoptosis monitored through Tunel assay, in vitro invasion ability via Boyden chamber and cell cycle change by flow cytometry.
RESULTS: After effective siRNA transfection, TPX2 mRNA and protein expression level in siRNA interference group were (0.31±0.08, 0.39±0.12),72h after transfection, significantly lower than blank control group (1.00±0.01) and negative control group (0.98±0.11), (F=71.182, t1=8.17, t2=7.90, P<0.05); MTT results demonstrated that cell growth and proliferation were inhibited and the inhibition rate was up to 35.4% (P<0.05) compared with the control group. TUNEL results indicated that cell apoptosis index in siRNA interference group was 18.28±0.35, higher than that in blank control group (4.07±0.26)and negative control group (4.13±0.22), (F=244.5, t1=60.61, t2=53.32, P<0.01). Boyden chamber results showed that the transmembrane cell number was 45.30±8.08 in siRNA interference group, less than blank control group (121.90±7.83), (F=122.46, t1=11.81, t2=10.47, P<0.01); besides, in siRNA interference group cell invasion inhibition rate was 71.42±9.12, higher than negative control group (5.65±3.55), (t=14.256, P<0.01). Flow cytometry results illustrated that more EC9706 cells went into apoptosis and cell cycle arrested in S phase. Similar results were obtained by in vivo transplantation, as TPX2 siRNA transfection significantly reduced tumor growth of the xenograft in nude mice.
CONCLUSION: siRNA could effectively inhibit the invasion and metastasis of EC9706 cells, promote the apoptosis of tumor cells and may become a new approach for treatment of esophageal carcinoma.
Yu J, Wang Y, Yan F, et al.Noncanonical NF-κB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer.
J Immunol. 2014; 193(5):2574-86 [PubMed
] Related Publications
Immunotherapy for cancer treatment is achieved through the activation of competent immune effector cells and the inhibition of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). Although MDSCs have been shown to contribute to breast cancer development, the mechanism underlying MDSC-mediated immunosuppression is unclear. We have identified a poorly differentiated MDSC subset in breast cancer-suppressing T cell function through STAT3-dependent IDO upregulation. In this study we investigated the mechanisms underlying aberrant expression of IDO in MDSCs. MDSCs were induced by coculturing human CD33(+) myeloid progenitors with MDA-MB-231 breast cancer cells. Increased STAT3 activation in MDSCs was correlated with activation of the noncanonical NF-κB pathway, including increased NF-κB-inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-κB kinase α and p100, and RelB-p52 nuclear translocation. Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knockdown of NIK in MDSCs suppressed IDO expression but not STAT3 activation. RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs. IL-6 was found to stimulate STAT3-dependent, NF-κB-mediated IDO upregulation in MDSCs. Furthermore, significant positive correlation between the numbers of pSTAT3(+) MDSCs, IDO(+) MDSCs, and NIK(+) MDSCs was observed in human breast cancers. These results demonstrate a STAT3/NF-κB/IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer.
Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER(+)) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER(+) breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.
Jiang P, Shen K, Wang X, et al.TPX2 regulates tumor growth in human cervical carcinoma cells.
Mol Med Rep. 2014; 9(6):2347-51 [PubMed
] Related Publications
The targeting protein for the Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, has been utilized as a tool to evaluate, more precisely, the proliferative behavior of tumor cells. The abnormal expression of TPX2 in a variety of malignant tumor types has been reported, however less is known about its role in cervical cancer. In the present study, the association between TPX2 expression and the biological behavior of cervical cancer, was investigated. Immunohistochemistry and RT-PCR were used to detect the expression of TPX2 in cervical cancer tissues. The inhibitory effect of TPX2-siRNA on the growth of SiHa human cervical carcinoma cells was studied in vitro. TPX2 expression was identified as significantly higher in cervical carcinoma compared with the control, normal cervical tissues. TPX2 siRNA transfected into SiHa cells induced apoptosis and inhibited cell proliferation and invasion. Similar results were obtained by in vivo transplantation, as TPX2 siRNA transfection significantly reduced tumor growth of the xenograft in nude mice. The results demonstrated that TPX2 is important in the regulation of tumor growth in cervical cancer and therefore may be a potential therapeutic target as a novel treatment strategy.
Shigeishi H, Higashikawa K, Takechi MRole of receptor for hyaluronan-mediated motility (RHAMM) in human head and neck cancers.
J Cancer Res Clin Oncol. 2014; 140(10):1629-40 [PubMed
] Related Publications
The receptor for hyaluronan (HA)-mediated motility (RHAMM) is a HA-binding protein located in the cytoskeleton and centrosome. RHAMM has multiple functions that manifest with different cellular localizations, for example, modulation of growth factor receptor, regulation of cell signaling pathways, and mitotic spindle assembly. In addition, its increased expression has major roles in tumorigenesis and can induce genomic instability and cancer progression. In head and neck cancers, increased expression of RHAMM is associated with high proliferation of cancer cells and decreased survival. CD44, a cell-adhesion molecule and HA receptor, can modulate intracellular signaling by forming complexes with RHAMM to promote invasion and metastasis of cancer cells. In this review, we provide an overview of the biological functions of RHAMM in non-neoplastic cells and cancer cells, as well as its association with CD44, and also introduce studies that particularly implicate RHAMM in the pathogenesis of head and neck cancers.
GLIPR1 is a p53 target gene known to be downregulated in prostate cancer, and increased endogenous GLIPR1 expression has been associated with increased production of reactive oxygen species, increased apoptosis, decreased c-Myc protein levels and increased cell cycle arrest. Recently, we found that upregulation of GLIPR1 in prostate cancer cells increases mitotic catastrophe through interaction with heat shock cognate protein 70 (Hsc70) and downregulation of Aurora kinase A and TPX2. In this study, we evaluated the mechanisms of recombinant GLIPR1 protein (glioma pathogenesis-related protein 1-transmembrane domain deleted [GLIPR1-ΔTM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-ΔTM administration in a prostate cancer xenograft mouse model. GLIPR1-ΔTM was selectively internalized by prostate cancer cells, leading to increased apoptosis through reactive oxygen species production and to decreased c-Myc protein levels. Interestingly, GLIPR1-ΔTM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-ΔTM significantly inhibited VCaP xenograft growth. GLIPR1-ΔTM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-ΔTM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-ΔTM significantly inhibits growth of VCaP xenografts without substantial toxicity.
Neumayer G, Belzil C, Gruss OJ, Nguyen MDTPX2: of spindle assembly, DNA damage response, and cancer.
Cell Mol Life Sci. 2014; 71(16):3027-47 [PubMed
] Related Publications
For more than 15 years, TPX2 has been studied as a factor critical for mitosis and spindle assembly. These functions of TPX2 are attributed to its Ran-regulated microtubule-associated protein properties and to its control of the Aurora A kinase. Overexpressed in cancers, TPX2 is being established as marker for the diagnosis and prognosis of malignancies. During interphase, TPX2 resides preferentially in the nucleus where its function had remained elusive until recently. The latest finding that TPX2 plays a role in amplification of the DNA damage response, combined with the characterization of TPX2 knockout mice, open new perspectives to understand the biology of this protein. This review provides an historic overview of the discovery of TPX2 and summarizes its cytoskeletal and signaling roles with relevance to cancer therapies. Finally, the review aims to reconcile discrepancies between the experimental and pathological effects of TPX2 overexpression and advances new roles for compartmentalized TPX2.
Yang X, Liu G, Xiao H, et al.TPX2 overexpression in medullary thyroid carcinoma mediates TT cell proliferation.
Pathol Oncol Res. 2014; 20(3):641-8 [PubMed
] Related Publications
TPX2 (targeting protein for xenopus kinesin-like protein 2), a microtubule-associated protein, plays an important role in the formation of the mitotic spindle. Abnormal expression of TPX2 in various types of malignant tumors has been reported, but less is known for medullary thyroid cancer (MTC). We investigated the expression of TPX2 in human MTC tissues and its potential use as a therapeutic target. Immunohistochemical analysis of TPX2 expression was performed for 32 cases of MTC and 8 cases of normal thyroid. TPX2 expression was found to be significantly higher in MTC compared to normal thyroid tissues (P < 0.05), and to be associated with tumor size, lymph node metastasis, and advanced disease stage. The cellular effects of TPX2 knockdown, including cell proliferation, apoptosis, cell cycle diffusions, and mitotic gene expression were investigated using small interfering RNA (siRNA). TPX2-siRNA caused G1 and G2-phase cell cycle arrest, inhibited cell proliferation, and induced apoptosis. TPX2-siRNA also downregulated Aurora-A and cyclinB1 protein expression in MTC cells and enhanced the expression of p53 protein (P < 0.05). These results suggest that TPX2 may be of potential use as a new marker for MTC prognosis and therapy.
BACKGROUND: We have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer.
METHODS: TPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo.
RESULTS: TPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity.
CONCLUSIONS: These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease.
Bao ZS, Li MY, Wang JY, et al.Prognostic value of a nine-gene signature in glioma patients based on mRNA expression profiling.
CNS Neurosci Ther. 2014; 20(2):112-8 [PubMed
] Related Publications
INTRODUCTION: Gliomas are the most common primary brain tumors in adults and a significant cause of cancer-related mortality. A 9-gene signature was identified as a novel prognostic model reflecting survival situation obviously in gliomas.
AIMS: To identify an mRNA expression signature to improve outcome prediction for patients with different glioma grades.
RESULTS: We used whole-genome mRNA expression microarray data of 220 glioma samples of all grades from the Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn) as a discovery set and data from Rembrandt and GSE16011 for validation sets. Data from every single grade were analyzed by the Kaplan-Meier method with a two-sided log-rank test. Univariate Cox regression and linear risk score formula were applied to derive a gene signature with better prognostic performance. We found that patients who had high risk score according to the signature had poor overall survival compared with patients who had low risk score. Highly expressed genes in the high-risk group were analyzed by gene ontology (GO) and gene set variation analysis (GSVA). As a result, the reason for the divisibility of gliomas was likely due to cell life processes and adhesion.
CONCLUSION: This 9-gene-signature prediction model provided a more accurate predictor of prognosis that denoted patients with high risk score have poor outcome. Moreover, these risk models based on defined molecular profiles showed the considerable prospect in personalized cancer management.
Chanut A, Duguet F, Marfak A, et al.RelA and RelB cross-talk and function in Epstein-Barr virus transformed B cells.
Leukemia. 2014; 28(4):871-9 [PubMed
] Related Publications
In this study, we determined the respective roles of RelA and RelB NF-κB subunits in Epstein-Barr virus (EBV)-transformed B cells. Using different EBV-immortalized B-cell models, we showed that only RelA activation increased both survival and cell growth. RelB activity was induced secondarily to RelA activation and repressed RelA DNA binding by trapping the p50 subunit. Reciprocally, RelA activation repressed RelB activity by increasing expression of its inhibitor p100. To search for such reciprocal inhibition at the transcriptional level, we studied gene expression profiles of our RelA and RelB regulatable cellular models. Ten RelA-induced genes and one RelB-regulated gene, ARNTL2, were repressed by RelB and RelA, respectively. Apart from this gene, RelB signature was included in that of RelA Functional groups of RelA-regulated genes were for control of energy metabolism, genetic instability, protection against apoptosis, cell cycle and immune response. Additional functions coregulated by RelA and/or RelB were autophagy and plasma cell differentiation. Altogether, these results demonstrate a cross-inhibition between RelA and RelB and suggest that, in fine, RelB was subordinated to RelA. In the view of future drug development, RelA appeared to be pivotal in both classical and alternative activation pathways, at least in EBV-transformed B cells.
Hsu PK, Chen HY, Yeh YC, et al.TPX2 expression is associated with cell proliferation and patient outcome in esophageal squamous cell carcinoma.
J Gastroenterol. 2014; 49(8):1231-40 [PubMed
] Related Publications
BACKGROUND: The molecular and genetic changes underlying esophageal squamous cell carcinoma (ESCC) tumor formation and rapid progression are poorly understood. Using high-throughput data analysis, we examined molecular changes involved in ESCC pathogenesis and investigated their clinical relevance.
METHODS: Five independent microarray datasets were examined for differentially expressed genes and pathways. For validation, mRNA expression in tumor and matched normal tissues from 16 ESCC cases was examined by cDNA microarray, and protein expression in 97 ESCC specimens was investigated using immunohistochemical stains. The association between clinicopathological parameters and the expression of Aurora kinase A (Aurora-A) and TPX2 was analyzed. The impact of TPX2 expression was also assessed in ESCC cancer cells.
RESULTS: AURKA and TPX2, members of the "Role of Ran in mitotic spindle regulation" pathway, were selected for further investigation. Verification by cDNA microarray showed that both genes were overexpressed in tumor tissues, and immunohistochemical staining showed Aurora-A and TPX2 expression in 88.4 and 90.6 % of ESCC specimens, respectively. High TPX2 expression was a significant prognosticator for overall and disease-free survival in univariate analysis and remained an independent prognostic factor in multivariate analysis (HR 1.802, p = 0.037). TPX2 knockdown clones showed inhibited cellular proliferation in growth curve studies and formed fewer colonies in the clonogenic assay.
CONCLUSIONS: Using bioinformatics resources, which were validated by microarray analysis and immunohistochemistry stains, and manipulation of TPX2 expression in ESCC cell lines, we demonstrated that TPX2 expression is associated with cell proliferation and poor prognosis among patients with resected ESCC.
Yan L, Li S, Xu C, et al.Target protein for Xklp2 (TPX2), a microtubule-related protein, contributes to malignant phenotype in bladder carcinoma.
Tumour Biol. 2013; 34(6):4089-100 [PubMed
] Related Publications
Increasing evidence demonstrated that TPX2 was highly expressed and tightly associated with human tumor development and progression. However, its precise role in bladder carcinoma remains to be delineated. In the present study, we revealed the high expression of TPX2 at both mRNA and protein levels in bladder carcinoma tissues and cells, and TPX2 levels in pN1-3 and pT2-4 status were significantly higher than those in pN0 and pTa-T1 status, respectively. Additionally, high TPX2 level was strongly associated with pT status (P = 0.001), higher histological grade (P = 0.001), lymph node metastasis (P = 0.022), and shorter survival time (P = 0.0279). Further investigation showed that TPX2 level in T24 cells was markedly higher than those in 5637, J82 and RT4 cells, in which RT4, a well-differentiated cell line derived from bladder carcinoma with low-grade non-invasive T0, displayed the lowest TPX2 mRNA and protein levels. Besides, TPX2 overexpression promoted proliferation and tumorigenicity, shortened cell cycle in G0/G1 phase, and suppressed cell apoptosis in T24 cells; conversely, TPX2 depletion exhibited opposite effects. Furthermore, TPX2 overexpression evoked the elevation of cyclin D1 and cdk2 levels as well as reduction of p21 level and caspase-3 activity, whereas reversed effects were observed in TPX2-depleted T24 cells. Taken altogether, TPX2 may play a central role in the development and progression of bladder carcinoma, and thus inhibition of TPX2 level may be a novel strategy for therapy of the patients with bladder carcinoma.
Liu HC, Zhang Y, Wang XL, et al.Upregulation of the TPX2 gene is associated with enhanced tumor malignance of esophageal squamous cell carcinoma.
Biomed Pharmacother. 2013; 67(8):751-5 [PubMed
] Related Publications
PURPOSE: To explore the expression of TPX2 and its significance in esophageal squamous cell carcinoma (ESCC) tissue and approach relationship between the TPX2 and clinicopathological characteristic of esophageal squamous cell carcinoma.
METHOD: RT-PCR and immunohistochemical staining were used to compare the expression of TPX2 in 62 esophageal squamous cell carcinoma, 31 atypical hyperplasia and 62 normal esophageal mucosa.
RESULTS: In ESCC, atypical hyperplasia and in normal mucous membrane tissues, the positive rate of TPX2 protein expression was 85.5% (53/62), 51.6% (16/31) and 4.8% (3/62); the positive rate of TPX2 mRNA expression was 65.5% (40/62), 35.5 (11/31) and 4.83% (3/62). The expression of TPX2 protein and mRNA were correlated with invasive depth and lymphatic metastasis of ESCC (P<0.01).
CONCLUSIONS: Overexpression of TPX2 may be risk factor of lymph node in esophageal carcinoma, and maybe a potential biomarker for early diagnosis and prognosis of esophageal squamous cell carcinoma.
Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.
Choudhary S, Kalita M, Fang L, et al.Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation.
J Biol Chem. 2013; 288(20):14612-23 [PubMed
] Free Access to Full Article Related Publications
The NF-κB transcription factor mediates the inflammatory response through distinct (canonical and non-canonical) signaling pathways. The mechanisms controlling utilization of either of these pathways are largely unknown. Here we observe that TNF stimulation induces delayed NF-κB2/p100 processing and investigate the coupling mechanism. TNF stimulation induces TNF-associated factor-1 (TRAF-1) that directly binds NF-κB-inducing kinase (NIK) and stabilizes it from degradation by disrupting its interaction with TRAF2·cIAP2 ubiquitin ligase complex. We show that TRAF1 depletion prevents TNF-induced NIK stabilization and reduces p52 production. To further examine the interactions of TRAF1 and NIK with NF-κB2/p100 processing, we mathematically modeled TRAF1·NIK as a coupling signaling complex and validated computational inference by siRNA knockdown to show non-canonical pathway activation is dependent not only on TRAF1 induction but also NIK stabilization by forming TRAF1·NIK complex. Thus, these integrated computational-experimental studies of TNF-induced TRAF1 expression identified TRAF1·NIK as a central complex linking canonical and non-canonical pathways by disrupting the TRAF2-cIAP2 ubiquitin ligase complex. This feed-forward kinase pathway is essential for the activation of non-canonical pathway.
Tchoghandjian A, Jennewein C, Eckhardt I, et al.Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells.
Cell Death Dis. 2013; 4:e564 [PubMed
] Free Access to Full Article Related Publications
As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-κB (NF-κB) signaling and a tumor necrosis factor-α (TNFα)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth in vivo underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-κB DNA binding and enhanced NF-κB transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-κB DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-κB pathway. BV6-stimulated NF-κB activation leads to elevated mRNA levels of TNFα and additional NF-κB target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-κB signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-κB target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNFα autocrine/paracrine loop by the TNFα-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-κB signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics.
Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells.
PURPOSE: Quantifying chromosomal instability (CIN) has both prognostic and predictive clinical utility in breast cancer. In order to establish a robust and clinically applicable gene expression-based measure of CIN, we assessed the ability of four qPCR quantified genes selected from the 70-gene Chromosomal Instability (CIN70) expression signature to stratify outcome in patients with grade 2 breast cancer.
METHODS: AURKA, FOXM1, TOP2A and TPX2 (CIN4), were selected from the CIN70 signature due to their high level of correlation with histological grade and mean CIN70 signature expression in silico. We assessed the ability of CIN4 to stratify outcome in an independent cohort of patients diagnosed between 1999 and 2002. 185 formalin-fixed, paraffin-embedded (FFPE) samples were included in the qPCR measurement of CIN4 expression. In parallel, ploidy status of tumors was assessed by flow cytometry. We investigated whether the categorical CIN4 score derived from the CIN4 signature was correlated with recurrence-free survival (RFS) and ploidy status in this cohort.
RESULTS: We observed a significant association of tumor proliferation, defined by Ki67 and mitotic index (MI), with both CIN4 expression and aneuploidy. The CIN4 score stratified grade 2 carcinomas into good and poor prognostic cohorts (mean RFS: 83.8±4.9 and 69.4±8.2 months, respectively, p = 0.016) and its predictive power was confirmed by multivariate analysis outperforming MI and Ki67 expression.
CONCLUSIONS: The first clinically applicable qPCR derived measure of tumor aneuploidy from FFPE tissue, stratifies grade 2 tumors into good and poor prognosis groups.
Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, et al.Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer.
Clin Cancer Res. 2013; 19(8):1994-2003 [PubMed
] Related Publications
PURPOSE: Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited.
EXPERIMENTAL DESIGN: We combined the data from genome-wide siRNA screens on tumor cell lethality in a lung and a head and neck cancer cell line.
RESULTS: We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2-M phase transition, underlining the importance of this cell-cycle checkpoint for tumor cell survival. Five genes from this cluster (CKAP5, KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown of KIF11 (kinesin family member 11) were reproduced by inhibition of KIF11 using the small-molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment.
CONCLUSION: This study identified a wide array of druggable genes for both lung and head and neck cancer. In particular, multiple genes involved in the G2-M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets.
Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.
In this study we report that expression of glioma pathogenesis-related protein 1 (GLIPR1) regulated numerous apoptotic, cell cycle, and spindle/centrosome assembly-related genes, including AURKA and TPX2, and induced apoptosis and/or mitotic catastrophe (MC) in prostate cancer (PCa) cells, including p53-mutated/deleted, androgen-insensitive metastatic PCa cells. Mechanistically, GLIPR1 interacts with heat shock cognate protein 70 (Hsc70); this interaction is associated with SP1 and c-Myb destabilization and suppression of SP1- and c-Myb-mediated AURKA and TPX2 transcription. Inhibition of AURKA and TPX2 using siRNA mimicked enforced GLIPR1 expression in the induction of apoptosis and MC. Recombinant GLIPR1-ΔTM protein inhibited AURKA and TPX2 expression, induced apoptosis and MC, and suppressed orthotopic xenograft tumor growth. Our results define a novel GLIPR1-regulated signaling pathway that controls apoptosis and/or mitotic catastrophe in PCa cells and establishes the potential of this pathway for targeted therapies.
Mohan P, Castellsague J, Jiang J, et al.Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition.
Oncotarget. 2013; 4(1):80-93 [PubMed
] Free Access to Full Article Related Publications
Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM.
BACKGROUND: The oncogenesis of ovarian cancer is poorly understood. The aim of this study was to identify mRNAs differentially expressed between moderately and poorly differentiated (MD/PD) serous ovarian carcinomas (SC), serous ovarian borderline tumours (SBOT) and superficial scrapings from normal ovaries (SNO), and to correlate these mRNAs with clinical parameters including survival.
METHODS: Differences in mRNA expression between MD/PD SC, SBOT and SNO were analyzed by global gene expression profiling (n = 23), validated by RT-qPCR (n = 41) and correlated with clinical parameters.
RESULTS: Thirty mRNAs differentially expressed between MD/PD SC, SBOT and SNO were selected from the global gene expression analyses, and 21 were verified (p<0.01) by RT-qPCR. Of these, 13 mRNAs were differentially expressed in MD/PD SC compared with SNO (p<0.01) and were correlated with clinical parameters. ZNF385B was downregulated (FC = -130.5, p = 1.2×10(-7)) and correlated with overall survival (p = 0.03). VEGFA was upregulated (FC = 6.1, p = 6.0×10(-6)) and correlated with progression-free survival (p = 0.037). Increased levels of TPX2 and FOXM1 mRNAs (FC = 28.5, p = 2.7×10(-10) and FC = 46.2, p = 5.6×10(-4), respectively) correlated with normalization of CA125 (p = 0.03 and p = 0.044, respectively). Furthermore, we present a molecular pathway for MD/PD SC, including VEGFA, FOXM1, TPX2, BIRC5 and TOP2A, all significantly upregulated and directly interacting with TP53.
CONCLUSIONS: We have identified 21 mRNAs differentially expressed (p<0.01) between MD/PD SC, SBOT and SNO. Thirteen were differentially expressed in MD/PD SC, including ZNF385B and VEGFA correlating with survival, and FOXM1 and TPX2 with normalization of CA125. We also present a molecular pathway for MD/PD SC.
The TNF-receptor superfamily member CD30 is expressed on normal and malignant lymphocytes, including anaplastic large cell lymphoma (ALCL) cells. CD30 transmits multiple effects, including activation of NF-κB signaling, cell proliferation, growth arrest and apoptosis. How CD30 generates these pleiotropic effects is currently unknown. Herein we describe ALCL cells expressing truncated forms of the CD30 intracellular domain that allowed us to identify the key regions responsible for transmitting its biological effects in lymphocytes. The first region (CD30(519-537)) activated both the alternative and canonical NF-κB pathways as detected by p100 and IκBα degradation, IKKβ-dependent transcription of both IκBα and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and induction of cell cycle arrest. In contrast, the second region of CD30 (CD30(538-595)) induced some aspects of canonical NF-κB activation, including transcription of IκBα, but failed to activate the alternative NF-κB pathway or drive p21(WAF1/CIP1)-mediated cell-cycle arrest. Direct comparison of canonical NF-κB activation by the two motifs revealed 4-fold greater p65 nuclear translocation following CD30(519-537) engagement. These data reveal that independent regions of the CD30 cytoplasmic tail regulate the magnitude and type of NF-κB activation and additionally identify a short motif necessary for CD30-driven growth arrest signals in ALCL cells.
Yan GR, Zou FY, Dang BL, et al.Genistein-induced mitotic arrest of gastric cancer cells by downregulating KIF20A, a proteomics study.
Proteomics. 2012; 12(14):2391-9 [PubMed
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Genistein exerts its anticarcinogenic effects by inducing G2/M arrest and apoptosis of cancer cells. However, the precise molecular mechanism of action of genistein has not been completely elucidated. In this study, we used quantitative proteomics to identify the genistein-induced protein alterations in gastric cancer cells and investigate the molecular mechanism responsible for the anti-cancer actions of genistein. Total 86 proteins were identified to be regulated by genistein, most of which were clustered into the regulation of cell division and G2/M transition, consistent with the anti-cancer effect of genistein. Many proteins including kinesin family proteins, TPX2, CDCA8, and CIT were identified for the first time to be regulated by genistein. Interestingly, five kinesin family proteins including KIF11, KIF20A, KIF22, KIF23, and CENPF were found to be simultaneously downregulated by genistein. Significantly decreased KIF20A was selected for further functional studies. The silencing of KIF20A inhibited cell viability and induced G2/M arrest, similar to the effects of genistein treatment in gastric cancer. And the silencing of KIF20A also increased cancer cell sensitivity to genistein inhibition, whereas overexpression of KIF20A markedly attenuated genistein-induced cell viability inhibition and G2/M arrest. These observations suggested that KIF20A played an important role in anti-cancer actions of genistein, and thus may be a potential molecular target for drug intervention of gastric cancer.
Jacque E, Billot K, Authier H, et al.RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation.
Oncogene. 2013; 32(21):2661-9 [PubMed
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The alternative nuclear factor-kappaB (NF-κB) -activation pathway proceeds via inducible p100 processing, leading to the activation of RelB-containing dimers. This pathway is aberrantly activated in several types of tumors; however, a direct role for RelB in the control of cell proliferation is still largely unexplored. Here, we demonstrate that RelB provides cell proliferation-inhibitory signals in murine fibroblasts. In agreement with these results, RelB ectopic expression inhibits xenograft tumor growth in vivo, whereas RelB knockdown enhances it. Significantly, we show that RelB inhibits cell proliferation and tumor growth in a p53-dependent manner. Mechanistic studies indicate that RelB regulates the transcription of the p53 tumor-suppressor gene through direct recruitment to the p53 promoter, thus increasing both p53 protein levels and expression of p53 target genes such as p21. Our findings define a novel link between NF-κB and growth-inhibitory pathways involving the RelB-dependent transcriptional upregulation of p53. Furthermore, they suggest that inhibition of RelB in some tumor types that retain wild-type p53 may diminish rather than improve therapeutic responses.
Prostate cancer is a heterogeneous group of diseases and there is a need for more efficient and targeted methods of treatment. In this study, the potential of gene expression data and RNA interference technique were combined to advance future personalized prostate cancer therapeutics. To distinguish the most promising in vivo prevalidated prostate cancer drug targets, a bioinformatic analysis was carried out using genome-wide gene expression data from 9873 human tissue samples. In total, 295 genes were selected for further functional studies in cultured prostate cancer cells due to their high mRNA expression in prostate, prostate cancer or in metastatic prostate cancer samples. Second, RNAi based cell viability assay was performed in VCaP and LNCaP prostate cancer cells. Based on the siRNA results, gene expression patterns in human tissues and novelty, endoplasmic reticulum function associated targets AIM1, ERGIC1 and TMED3, as well as mitosis regulating TPX2 were selected for further validation. AIM1, ERGIC1, and TPX2 were shown to be highly expressed especially in prostate cancer tissues, and high mRNA expression of ERGIC1 and TMED3 associated with AR and ERG oncogene expression. ERGIC1 silencing specifically regulated the proliferation of ERG oncogene positive prostate cancer cells and inhibited ERG mRNA expression in these cells, indicating that it is a potent drug target in ERG positive subgroup of prostate cancers. TPX2 expression associated with PSA failure and TPX2 silencing reduced PSA expression, indicating that TPX2 regulates androgen receptor mediated signaling. In conclusion, the combinatorial usage of microarray and RNAi techniques yielded in a large number of potential novel biomarkers and therapeutic targets, for future development of targeted and personalized approaches for prostate cancer management.