Gene Summary

Gene:PSIP1; PC4 and SFRS1 interacting protein 1
Aliases: p52, p75, PAIP, DFS70, LEDGF, PSIP2
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:PC4 and SFRS1-interacting protein
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 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.

  • Acute Myeloid Leukaemia
  • Histone Methyltransferases
  • Messenger RNA
  • KMT2A
  • Cell Proliferation
  • Triple Negative Breast Cancer
  • Trans-Activators
  • Leukaemia
  • Protein Structure, Tertiary
  • Tumor Suppressor Proteins
  • Signal Transduction
  • Transcription Factors
  • Transcriptional Activation
  • Ovarian Cancer
  • Chromatin Assembly and Disassembly
  • Bladder Cancer
  • Nuclear Pore Complex Proteins
  • Histone-Lysine N-Methyltransferase
  • Mutation
  • Myeloid Progenitor Cells
  • Single Nucleotide Polymorphism
  • Signal Transducing Adaptor Proteins
  • HeLa Cells
  • Vascular Endothelial Growth Factor C
  • Chromatin
  • Multiple Endocrine Neoplasia Type 1
  • Cervical Cancer
  • Promoter Regions
  • Base Sequence
  • Leukemic Gene Expression Regulation
  • Angiogenesis
  • U937 Cells
  • Nuclear Proteins
  • Survival Rate
  • Proto-Oncogene Proteins
  • Oncogene Fusion Proteins
  • Cancer Gene Expression Regulation
  • Neoplastic Cell Transformation
  • Chromosome 9
  • X-linked Nuclear Protein
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: PSIP1 (cancer-related)

Chaszczewska-Markowska M, Kosacka M, Chryplewicz A, et al.
Anticancer Res. 2019; 39(6):3269-3272 [PubMed] Related Publications
BACKGROUND/AIM: Although genetic factors are presumed to account only for a part of the inter-individual variation in lung cancer susceptibility, the results are conflicting and there are no data available regarding the Polish population. We, therefore, performed a case-control study to investigate the association of seven selected single nucleotide polymorphisms (SNPs), in genes coding for excision repair cross-complimentary group 1 (ERCC1: rs11615, rs3212986, rs2298881), nuclear factor ĸB (NFKB2: rs7897947, rs12769316), bone morphogenetic protein 4 (BMP4: rs1957860), complement receptor 1 (CR1: rs7525160) and del/ins polymorphism in the family hypoxia inducible factor 2 gene (EGLN2: rs10680577), with non-small cell lung cancer (NSCLC) risk.
MATERIALS AND METHODS: Real-time PCR with melting curve analysis was used for genotyping of NSCLC patients and healthy individuals of Polish origin.
RESULTS: The ERCC1 rs11615 T allele and rs3212986 GG homozygosity were found to be associated with a higher risk of developing NSCLC. In addition, NFKB2 rs12769316 GG homozygosity was more frequently detected among male patients than controls, while no significant differences were found between the five polymorphisms.
CONCLUSION: ERCC1 polymorphisms may affect NSCLC risk in the Polish population, while the NFKB2 variant may be a possible marker of the disease in males.

Zajda K, Rak A, Ptak A, Gregoraszczuk EL
Compounds of PAH mixtures dependent interaction between multiple signaling pathways in granulosa tumour cells.
Toxicol Lett. 2019; 310:14-22 [PubMed] Related Publications
Mechanism of PAH mixtures, using granulosa tumour cells, was investigated. Cells were exposed to a mixture of all 16 priority PAHs (M1) or a mixture of five PAHs not classified as human carcinogens (M2). The effect of siAHR, siAHRR and siNFKB2 on the expression of CYP1A1, CYP1B1, GSTM1, ERα, AR and cell proliferation was described. M1 decreased AhR and CYP1A1, while increased AhRR and ARNT expression. M2 also decreased AhR and CYP1A1 but had no effect on AhRR expression. siAHRR reversed the inhibitory effect of M1 on AhR and CYP1A1,while inhibitory effect of M2 was still observed. siNFKB2 reversed inhibitory effect of both mixtures on AhR and CYP1A1 expression and stimulatory effect of M1 on AhRR expression. siAHR reversed stimulatory effect of both mixtures on ERα expression. Stimulatory effect of M1 on cell proliferation was not observed in siAHR, was still observed in siESR1 cells. M2 had no effect on cell proliferation, however stimulatory effect was appeared in siAHR and siESR1cells. In conclusion: M1 by activation of AhRR and NFkB p52, but M2 only by activation of NFκB attenuated AhR signalling and ligand-induced CYP1A1 expression. Interaction between AhR and ER following M1 and M2 exposure is primarily initiated through AhR.

Laus AC, de Paula FE, de Lima MA, et al.
EGF+61 A>G polymorphism is not associated with lung cancer risk in the Brazilian population.
Mol Biol Rep. 2019; 46(2):2417-2425 [PubMed] Related Publications
Epidermal growth factor (EGF) and its receptor (EGFR) play an important role in lung carcinogenesis. A functional single nucleotide polymorphism (SNP) in EGF promoter region (EGF+61 A>G-rs4444903) has been associated with cancer susceptibility. Yet, in lung cancer, the EGF+61 A>G role is unclear. The aim of this study was to evaluate the risk of lung cancer associated with EGF+61 A>G SNP in the Brazilian population. For that, 669 lung cancer patients and 1104 controls were analyzed. EGF+61 A>G genotype was assessed by PCR-RFLP and TaqMan genotyping assay. Both patients and controls were in Hardy-Weinberg equilibrium. As expected, uni- and multivariate analyses showed that tobacco consumption and age were significant risk factors for lung cancer. The genotype frequencies in lung cancer patients were 27.3% of AA, 47.4% of AG and 25.3% of GG, and for controls were 25.3% of AA, 51.6% of AG and 23.1% of GG. The allele frequencies were 51.1% of A and 48.9% of G for both cases and controls. No significant differences for the three genotypes (AA, AG and GG-codominant model) were observed between cases and controls. We then grouped AG and GG (recessive model) genotypes, as well as AA and AG (dominant model), and again, no significant differences were also found. This is the largest study to explore EGF+61 A>G polymorphism association with lung cancer risk and suggests that this SNP is not a risk factor for lung cancer in the Brazilian population.

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.

Das R, Coupar J, Clavijo PE, et al.
Lymphotoxin-β receptor-NIK signaling induces alternative RELB/NF-κB2 activation to promote metastatic gene expression and cell migration in head and neck cancer.
Mol Carcinog. 2019; 58(3):411-425 [PubMed] Related Publications
Head and neck squamous cell carcinomas (HNSCC) preferentially spread to regional cervical tissues and lymph nodes. Here, we hypothesized that lymphotoxin-β (LTβ), receptor LTβR, and NF-κB-inducing kinase (NIK), promote the aberrant activation of alternative NF-κB2/RELB pathway and genes, that enhance migration and invasion of HNSCC. Genomic and expression alterations of the alternative NF-kB pathway were examined in 279 HNSCC tumors from The Cancer Genome Atlas (TCGA) and a panel of HNSCC lines. LTβR is amplified or overexpressed in HNSCC of the larynx or oral cavity, while LTβ, NIK, and RELB are overexpressed in cancers arising within lymphoid oropharyngeal and tonsillar sites. Similarly, subsets of HNSCC lines displayed overexpression of LTβR, NIK, and RELB proteins. Recombinant LTβ, and siRNA depletion of endogenous LTβR and NIK, modulated expression of LTβR, NIK, and nuclear translocation of NF-κB2(p52)/RELB as well as functional NF-κB promoter reporter activity. Treatment with a NIK inhibitor (1,3[2H,4H]-Iso-Quinoline Dione) reduced the protein expression of NIK and NF-κB2(p52)/RELB, and blocked LTβ induced nuclear translocation of RELB. NIK and RELB siRNA knockdown or NIK inhibitor slowed HNSCC migration or invation in vitro. LTβ-induces expression of migration and metastasis related genes, including hepatocyte growth/scatter factor receptor MET. Knockdown of NIK or MET similarly inhibited the migration of HNSCC cell lines. This may help explain why HNSCC preferentially migrate to local lymph nodes, where LTβ is expressed. Our findings show that LTβ/LTβR promotes activation of the alternative NIK-NF-κB2/RELB pathway to enhance MET-mediated cell migration in HNSCC, which could be potential therapeutic targets in HNSCC.

Yang WH, Cheng CY, Chen MF, Wang TC
Cell Subpopulations Overexpressing p75NTR Have Tumor-initiating Properties in the C6 Glioma Cell Line.
Anticancer Res. 2018; 38(9):5183-5192 [PubMed] Related Publications
BACKGROUND/AIM: Glioma is the most common and lethal primary brain tumor. Even with the development of multidisciplinary treatment approaches, results are disappointing because of the unavoidable tumor recurrence, which may be caused by the existence of tumor-initiating cells. The p75 neurotrophin receptor (p75NTR), which belongs to the tumor necrosis factor receptor superfamily, is not only involved in various cellular functions but also related to tumor growth. This study is focused, on the possible role of p75NTR in glioma tumor initiation.
MATERIALS AND METHODS: C6 cells with high and low expression of p75NTR were sorted using flow cytometry. The neurosphere characteristics and properties of these two subpopulations were assessed and compared with those of parental cells. Radiation and chemotherapy sensitivity was also analyzed in these cell populations. Finally, in vivo tumorigenicity of cells was tested in a rat model.
RESULTS: Cells overexpressing p75NTR (C6p75+++ cells) demonstrated greater ability of neurosphere formation, colony proliferation, and certain stem cell marker overexpression than cells with low p75NTR expression (C6p75+) and parental cells. In addition, following irradiation or temozolomide treatment, more viable C6p75+++ cells remained, and they proliferated into more colonies. In vivo, C6p75+++ cell implantation in Sprague Dawley rats reduced the survival time.
CONCLUSION: Cells with p75NTR overexpression demonstrated certain unique characteristics of tumor-initiating cells, such as neurosphere formation, high colony proliferation, and resistance to radio- and chemotherapy. With regard to the heterogeneous composition of glioma cells, p75NTR can be used as an alternative marker to identify a glioma subpopulation with tumor-initiating properties.

Meyer HJ, Leifels L, Hamerla G, et al.
ADC-histogram analysis in head and neck squamous cell carcinoma. Associations with different histopathological features including expression of EGFR, VEGF, HIF-1α, Her 2 and p53. A preliminary study.
Magn Reson Imaging. 2018; 54:214-217 [PubMed] Related Publications
OBJECTIVE: Apparent diffusion coefficient (ADC) values derived from Diffusion-weighted images are able to reflect tumor microstructure, such as cellularity, extracellular matrix or proliferation potential. This present study sought to correlate prognostic relevant histopathologic parameters with ADC values derived from a whole lesion measurement in head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS: Thirty-four patients with histological proven primary HNSCC were prospectively acquired. Histogram analysis was derived from ADC maps. In all cases, expression of Hif1-alpha, VEGF, EGFR, p53, p16, Her 2 were analyzed.
RESULTS: In the overall patient sample, ADCmax correlated with p53 expression (p = -0.446, p = 0.009) and ADCmode correlated with Her2-expression (p = -0.354, p = 0.047). In the p16 positive group there were several correlations. P25, P90 and entropy correlated with Hif1-alpha (p = -0.423, p = 0.05, p = -0.494, p = 0.019, p = 0.479, p = 0.024, respectively). Kurtosis correlated with P53 expression (p = -0.466, p = 0.029). For p16 negative carcinomas the following associations could be identified. Mode correlated with VEGF-expression (p = -0.657, p = 0.039). ADCmax, P75, P90, and Std correlated with p53-expression (p = -0.827, p = 0.002, p = -0.736, p = 0.01, p = -0.836, p = 0.001 and p = -0.70, p = 0.016, respectively). There were no statistically significant differences of ADC histogram parameters between p16 positive and p16 negative carcinomas.
CONCLUSION: ADC histogram values can reflect different histopathological features in HNSCC. Associations between ADC histogram analysis parameters and histopathology depend on p16 status.

Tao Y, Liu Z, Hou Y, et al.
Alternative NF-κB signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3.
Oncogene. 2018; 37(44):5887-5900 [PubMed] Related Publications
Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-κB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-κB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-κB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27

House CD, Grajales V, Ozaki M, et al.
IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts.
BMC Cancer. 2018; 18(1):595 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC.
METHODS: Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition.
RESULTS: This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins.
CONCLUSIONS: This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.

Wang H, Liang L, Dong Q, et al.
Long noncoding RNA miR503HG, a prognostic indicator, inhibits tumor metastasis by regulating the HNRNPA2B1/NF-κB pathway in hepatocellular carcinoma.
Theranostics. 2018; 8(10):2814-2829 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have been associated with hepatocellular carcinoma (HCC), but the underlying molecular mechanisms of their specific association with hepatocarcinogenesis have not been fully explored.

Zhang Y, Tong L, Chen S, et al.
Analysis of NFKB2‑mediated regulation of mechanisms underlying the development of Hodgkin's lymphoma.
Mol Med Rep. 2018; 17(6):8129-8136 [PubMed] Free Access to Full Article Related Publications
Nuclear factor‑κB (NF‑κB) is widely involved in various lymphoid malignancies. However, its exact functional role and potential regulatory mechanisms in Hodgkin's lymphoma (HL) remains unclear. The present study aimed to investigate the regulatory mechanism of NF‑κB in HL by analysis of a gene expression profile that was obtained from HL cells with or without NF‑κB subunit 2 (NFKB2) knockdown. The GSE64234 dataset containing 6 HL cell line specimens transfected with small interfering (si)RNA against NFKB2 and 6 control specimens transfected with non‑targeting siRNA sequences was downloaded from the Gene Expression Omnibus database. Based on these data, differentially expressed genes (DEGs) were screened for following data preprocessing. Functional enrichment analysis was subsequently conducted among the identified upregulated and downregulated DEGs. Additionally, a protein‑protein interaction (PPI) network was constructed and module analyses were performed. Finally, microRNAs (miRNAs/miRs) targeting the identified DEGs were predicted for the construction of a miRNA‑target regulatory network. A total of 253 DEGs were identified, consisting of 109 upregulated and 144 downregulated DEGs. Pathway enrichment analysis revealed that B‑cell lymphoma 2‑like 1 (BCL2L1) was significantly enriched in the NF‑κB signaling pathway, and colony‑stimulating factor 2 (CSF2) and BCL2L1 were enriched in the Jak‑signal transducer and activator of transcription (STAT) signaling pathway. BCL2L1 and CSF2 were determined to be hub genes in the PPI network. A total of 6 miRNAs, including let‑7a‑5p, miR‑9‑5p, miR‑155‑5p, miR‑135a‑5p, miR‑17‑5p and miR‑375, were identified in the miRNA‑target regulatory network. The results of the present study indicated that NFKB2 may be involved in HL development through regulation of BCL2L1, CSF2, miR‑135a‑5p, miR‑155‑5p and miR‑9‑5p expression, as well as the modulation of Jak‑STAT and NF‑κB signaling pathways.

Bao X, Shi J, Xie F, et al.
Proteolytic Release of the p75
Cancer Res. 2018; 78(9):2262-2276 [PubMed] Related Publications
Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75

Zhang C, Chen B, Jiang K, et al.
Activation of TNF-α/NF-κB axis enhances CRL4B
Mol Oncol. 2018; 12(4):476-494 [PubMed] Free Access to Full Article Related Publications
Cullin 4B, a member of the Cullins, which serve as scaffolds to facilitate the assembly of E3 ligase complexes, is aberrantly expressed in many cancers, including osteosarcoma. Recently, we observed that CUL4B forms the CRL4B

Dzieran J, Rodriguez Garcia A, Westermark UK, et al.
Proc Natl Acad Sci U S A. 2018; 115(6):E1229-E1238 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma (NB) is a remarkably heterogenic childhood tumor of the sympathetic nervous system with clinical behavior ranging from spontaneous regression to poorly differentiated tumors and metastasis.

Mueller S, Engleitner T, Maresch R, et al.
Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.
Nature. 2018; 554(7690):62-68 [PubMed] Free Access to Full Article Related Publications
The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras

Chen J, Nagle AM, Wang YF, et al.
Controlled dimerization of insulin-like growth factor-1 and insulin receptors reveals shared and distinct activities of holo and hybrid receptors.
J Biol Chem. 2018; 293(10):3700-3709 [PubMed] Free Access to Full Article Related Publications
Breast cancer development and progression are influenced by insulin-like growth factor receptor 1 (IGF1R) and insulin receptor (InsR) signaling, which drive cancer phenotypes such as cell growth, proliferation, and migration. IGF1R and InsR form IGF1R/InsR hybrid receptors (HybRs) consisting of one molecule of IGF1R and one molecule of InsR. The specific signaling and functions of HybR are largely unknown, as HybR is activated by both IGF1 and insulin, and no cellular system expresses HybR in the absence of holo-IGF1R or holo-InsR. Here we studied the role of HybR by constructing inducible chimeric receptors and compared HybR signaling with that of holo-IGF1R and holo-InsR. We cloned chemically inducible chimeric IGF1R and InsR constructs consisting of the extracellular domains of the p75 nerve growth factor receptor fused to the intracellular β subunit of IGF1R or InsR and a dimerization domain. Dimerization with the drugs AP20187 or AP21967 allowed specific and independent activation of holo-IGF1R, holo-InsR, or HybR, resulting in activation of the PI3K pathway. Holo-IGF1R and HybR both promoted cell proliferation and glucose uptake, whereas holo-InsR only promoted glucose uptake, and only holo-IGF1R showed anti-apoptotic effects. We also found that the three receptors differentially regulated gene expression: holo-IGF1R and HybR up-regulated EGR3; holo-InsR specifically down-regulated JUN and BCL2L1; holo-InsR down-regulated but HybR up-regulated HK2; and HybR specifically up-regulated FHL2, ITGA6, and PCK2. Our findings suggest that, when expressed and activated in mammary epithelial cells, HybR acts in a manner similar to IGF1R and support further investigation of the role of HybR in breast cancer.

Blokken J, De Rijck J, Christ F, Debyser Z
Protein-protein and protein-chromatin interactions of LEDGF/p75 as novel drug targets.
Drug Discov Today Technol. 2017; 24:25-31 [PubMed] Related Publications
Lens epithelium-derived growth factor p75 (LEDGF/p75), a transcriptional co-activator, plays an important role in tethering protein complexes to the chromatin. Through this tethering function LEDGF/p75 is implicated in a diverse set of human diseases including HIV infection and mixed lineage leukemia, an aggressive form of cancer with poor prognosis. Here we provide an overview of recent progress in resolving protein-protein and protein-chromatin interaction mechanisms of LEDGF/p75. This review will focus on two well-characterized domains, the PWWP domain and the integrase binding domain (IBD). The PWWP domain interacts with methylated lysine 36 in histone H3, a marker of actively transcribed genes. The IBD interacts with the IBD binding motif, available in cellular binding partners of LEDGF/p75. Each domain forms an interesting new target for drug discovery.

Steinhilber D, Marschalek R
How to effectively treat acute leukemia patients bearing MLL-rearrangements ?
Biochem Pharmacol. 2018; 147:183-190 [PubMed] Related Publications
Chromosomal translocations - leading to the expression of fusion genes - are well-studied genetic abberrations associated with the development of leukemias. Most of them represent altered transcription factors that affect transcription or epigenetics, while others - like BCR-ABL - are enhancing signaling. BCR-ABL has become the prototype for rational drug design, and drugs like Imatinib and subsequently improved drugs have a great impact on cancer treatments. By contrast, MLL-translocations in acute leukemia patients are hard to treat, display a high relapse rate and the overall survival rate is still very poor. Therefore, new treatment modalities are urgently needed. Based on the molecular insights of the most frequent MLL rearrangements, BET-, DOT1L-, SET- and MEN1/LEDGF-inhibitors have been developed and first clinical studies were initiated. Not all results of these studies have are yet available, however, a first paper reports a failure in the DOT1L-inhibitor study although it was the most promising drug based on literature data. One possible explanation is that all of the above mentioned drugs also target the cognate wildtype proteins. Here, we want to strengthen the fact that efforts should be made to develop drugs or strategies to selectively inhibit only the fusion proteins. Some examples will be given that follow exactly this guideline, and proof-of-concept experiments have already demonstrated their feasibility and effectiveness. Some of the mentioned approaches were using drugs that are already on the market, indicating that there are existing opportunities for the future which should be implemented in future therapy strategies.

Xiao X, Li H, Jin H, et al.
Identification of 11(13)-dehydroivaxillin as a potent therapeutic agent against non-Hodgkin's lymphoma.
Cell Death Dis. 2017; 8(9):e3050 [PubMed] Free Access to Full Article Related Publications
Despite great advancements in the treatment of non-Hodgkin lymphoma (NHL), sensitivity of different subtypes to therapy varies. Targeting the aberrant activation NF-κB signaling pathways in lymphoid malignancies is a promising strategy. Here, we report that 11(13)-dehydroivaxillin (DHI), a natural compound isolated from the Carpesium genus, induces growth inhibition and apoptosis of NHL cells. Multiple signaling cascades are influenced by DHI in NHL cells. PI3K/AKT and ERK are activated or inhibited in a cell type dependent manner, whereas NF-κB signaling pathway was inhibited in all the NHL cells tested. Applying the cellular thermal shift assay, we further demonstrated that DHI directly interacts with IKKα/IKKβ in NHL cells. Interestingly, DHI treatment also reduced the IKKα/IKKβ protein level in NHL cells. Consistent with this finding, knockdown of IKKα/IKKβ inhibits cell proliferation and enhances DHI-induced proliferation inhibition. Overexpression of p65, p52 or RelB partially reverses DHI-induced cell growth inhibition. Furthermore, DHI treatment significantly inhibits the growth of NHL cell xenografts. In conclusion, we demonstrate that DHI exerts anti-NHL effect in vitro and in vivo, through a cumulative effect on NF-κB and other pathways. DHI may serve as a promising lead compound for the therapy of NHL.

Meldolesi J
Neurotrophin Trk Receptors: New Targets for Cancer Therapy.
Rev Physiol Biochem Pharmacol. 2018; 174:67-79 [PubMed] Related Publications
In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75

Sundaresan S, Meininger CA, Kang AJ, et al.
Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells.
Gastroenterology. 2017; 153(6):1555-1567.e15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia.
METHODS: Primary enteric glial cultures were generated from the VillinCre:Men1
RESULTS: Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas.
CONCLUSIONS: MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.

Okumura T, Yamaguchi T, Watanabe T, et al.
Flow Cytometric Detection of Circulating Tumor Cells Using a Candidate Stem Cell Marker, p75 Neurotrophin Receptor (p75NTR).
Methods Mol Biol. 2017; 1634:211-217 [PubMed] Related Publications
The most widely studied detection for circulating tumor cells (CTCs) in peripheral blood of cancer patients has been based on immunomagnetic enrichment using antibodies against epithelial cell adhesion molecule (EpCAM), which is overexpressed in epithelial cells. A neurotrophin receptor p75 (p75NTR) is expressed in a candidate stem cell fraction in esophageal squamous cell carcinoma (ESCC), which shows significantly higher colony formation, enhanced tumor formation in mice, along with strong expression of epithelial mesenchymal transition-related genes. Here, we describe a method to detect CTCs in ESCC based on the combined expression of EpCAM and p75NTR using flow cytometry, demonstrating the feasibility of expression analysis of multiple cell surface markers in viable cells.

Singh DK, Gholamalamdari O, Jadaliha M, et al.
PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes.
Carcinogenesis. 2017; 38(10):966-975 [PubMed] Free Access to Full Article Related Publications
Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in BC initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in BC progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses revealed that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.

Okumura T, Yamaguchi T, Watanabe T, et al.
Clinical Relevance of a Candidate Stem Cell Marker, p75 Neurotrophin Receptor (p75NTR) Expression in Circulating Tumor Cells.
Adv Exp Med Biol. 2017; 994:247-254 [PubMed] Related Publications
Despite advances in its diagnosis and multimodal therapies, the prognosis of esophageal squamous cell carcinoma (ESCC) patients remains poor, because of high incidences of metastasis . Recent reports suggested that circulating tumor stem cells (CTSCs), rather than circulating tumor cells (CTCs), were more accurate diagnostic marker for metastasis, because tumor stem cells or cancer stem cells (CSCs) are more responsible for metastasis through processes such as epithelial mesenchymal transition (EMT) and tumor initiation. A neurotrophin receptor p75 (p75NTR) is expressed in a candidate CSC s in ESCC, which possess enhanced tumorigenicity along with strong expression of EMT-related genes. Our recent report using two-color flow cytometry demonstrated that CTC counts based on a combined expression of epithelial cell adhesion molecule (EpCAM) and p75NTR was significantly higher in peripheral blood samples of ESCC patients than healthy controls. In addition, EpCAM + p75NTR+, but not EpCAM + p75NTR- CTC counts, correlated with clinically diagnosed distant metastasis and pathological venous invasion in surgically resected primary ESCC tumors. Malignant cytology of the isolated EpCAM + p75NTR+ cells was microscopically confirmed as well. These results demonstrated that EpCAM + p75NTR+ CTC count was a more accurate diagnostic marker than EpCAM+ CTC count, suggesting the highly metastatic potential of CTCs with p75NTR expression.Investigation using the isolated EpCAM + p75NTR+ CTCs to assess their stem cell properties may shed light on their roles in tumor metastasis in ESCC.Further investigations based on large-scale prospective studies with long term follow up may provide us with evidences for its clinical use.

Kojima H, Okumura T, Yamaguchi T, et al.
Enhanced cancer stem cell properties of a mitotically quiescent subpopulation of p75NTR-positive cells in esophageal squamous cell carcinoma.
Int J Oncol. 2017; 51(1):49-62 [PubMed] Free Access to Full Article Related Publications
Mitotically quiescent cancer stem cells (CSCs) possess higher malignant potential than other CSCs, indicating their higher contribution to therapeutic resistance than that of other CSCs. In esophageal squamous cell carcinoma (ESCC), p75 neurotrophin receptor (p75NTR) is expressed in a candidate CSC population showing high tumorigenicity and chemoresistance. In the present study, we isolated and characterized quiescent CSCs population in ESCC based on p75NTR expression and cell cycle status. Expression of p75NTR and Ki-67 in ESCC cell lines (KYSE cells) and surgically resected ESCC specimens was detected by performing immunocytochemical analysis. p75NTR-positive KYSE cells were fractionated into quiescent and proliferating cells by performing flow cytometry with a fluorescent DNA-staining dye to determine their CSC phenotype. Immunocytochemical analysis showed that 21.8 and 36.5% of the p75NTR-positive cells were Ki-67-negative (G0), which accounted for 11.4 and 15.7% of cells in KYSE-30 and KYSE-140 cell lines, respectively. Flow cytometric cell sorting showed that p75NTR-positive cells in the G0-G1 phase (p75NTR-positive/G0-1 cells) but not in the S-G2-M phase (p75NTR-positive/S-G2-M cells) showed strong expression of stem cell-related genes Nanog, BMI-1, and p63; high colony formation ability; high tumorigenicity in a mouse xenograft model; and strong chemoresistance against cisplatin because of the expression of drug resistance genes ABCG2 and ERCC1. Label-retention assay showed that 3.4% p75NTR-positive cells retained fluorescent cell-tracing dye, but p75NTR-negative cells did not. Immunohistochemical analysis of ESCC specimens showed p75NTR expression in 39 of 95 (41.1%) patients, with a median of 13.2% (range, 3.0-80.1%) p75NTR-positive/Ki-67-negative cells, which were found to be associated with poorly differentiated histology. Our results suggest that p75NTR-positive/G0-1 cells represent quiescent CSCs in ESCC and indicate that these cells can be used as targets to investigate molecular processes regulating CSC phenotype and to develop novel therapeutic strategies.

Foro Arnalot P, Pera O, Rodriguez N, et al.
Influence of incidental radiation dose in the subventricular zone on survival in patients with glioblastoma multiforme treated with surgery, radiotherapy, and temozolomide.
Clin Transl Oncol. 2017; 19(10):1225-1231 [PubMed] Related Publications
PURPOSE: To determine if there is an association between the incidental radiation dose to the subventricular zone and survival in patients with glioblastoma multiforme treated with surgery, radiotherapy and temozolomide.
METHODS AND MATERIALS: Sixty-five patients, treated between 2006 and 2015, were included in this retrospective study. The doses (75th percentile; p75) administered to the ipsilateral, contralateral and bilateral subventricular zone were compared to overall survival and progression-free survival using Cox proportional hazards models. Covariates included: age, sex, surgery, tumor location, and concomitant and adjuvant temozolomide.
RESULTS: Median progression-free survival and overall survival were 11.5 ± 9.96 and 18.8 ± 18.5 months, respectively. The p75 doses to the ipsilateral, contralateral and bilateral subventrivular zone were, respectively, 57.30, 48.8, and 52.7 Gy. Patients who received a dose ≥48.8 Gy in the contralateral subventricular zone had better progression-free survival than those who received lower doses (HR 0.46; 95% CI 0.23-0.91 P = 0.028). This association was not found for overall survival (HR 0.60; 95% CI 0.30-1.22 P = 0.16). Administration of adjuvant temozolomide was significantly associated with improved progression-free survival (HR 0.19; 95% CI 0.09-0.41 P < 0.0001) and overall survival (HR 0.11; 95% CI 0.05-0.24 P = 0.001). In the subgroup of 46 patients whose O6-methylguanine-DNA methyltransferase gene promoter status was known, the methylation had no effect on either progression-free survival (P = 0.491) or overall survival (P = 0.203).
CONCLUSION: High-dose radiation in the contralateral subventricular zone was associated with a significant improvement in progression-free survival but not overall survival in patients treated for glioblastoma multiforme.

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.

Burnett JP, Lim G, Li Y, et al.
Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells.
Cancer Lett. 2017; 394:52-64 [PubMed] Related Publications
Triple negative breast cancer (TNBC) typically exhibits rapid progression, high mortality and faster relapse rates relative to other breast cancer subtypes. In this report we examine the combination of taxanes (paclitaxel or docetaxel) with a breast cancer stem cell (CSC)-targeting agent sulforaphane for use against TNBC. We demonstrate that paclitaxel or docetaxel treatment induces IL-6 secretion and results in expansion of CSCs in TNBC cell lines. Conversely, sulforaphane is capable of preferentially eliminating CSCs, by inhibiting NF-κB p65 subunit translocation, downregulating p52 and consequent downstream transcriptional activity. Sulforaphane also reverses taxane-induced aldehyde dehydrogenase-positive (ALDH+) cell enrichment, and dramatically reduces the size and number of primary and secondary mammospheres formed. In vivo in an advanced treatment orthotopic mouse xenograft model together with extreme limiting dilution analysis (ELDA), the combination of docetaxel and sulforaphane exhibits a greater reduction in primary tumor volume and significantly reduces secondary tumor formation relative to either treatment alone. These results suggest that treatment of TNBCs with cytotoxic chemotherapy would be greatly benefited by the addition of sulforaphane to prevent expansion of and eliminate breast CSCs.

Tajbakhsh A, Mokhtari-Zaer A, Rezaee M, et al.
Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives.
J Cell Biochem. 2017; 118(9):2502-2515 [PubMed] Related Publications
Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to stimulate breast cancer cell growth and metastasis via tyrosine kinase receptors TrkA, TrkB, and the p75

Aghdaei FH, Soltani BM, Dokanehiifard S, et al.
Overexpression of hsa-miR-939 follows by NGFR down-regulation and apoptosis reduction.
J Biosci. 2017; 42(1):23-30 [PubMed] Related Publications
Neurotrophin receptors play a crucial role in neuronal survival, differentiation and regeneration. Nerve growth factor receptor (NGFR) or P75

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