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PEBP1; phosphatidylethanolamine binding protein 1 (12q24.23)

Gene Summary

Gene:PEBP1; phosphatidylethanolamine binding protein 1
Aliases: PBP, HCNP, PEBP, RKIP, HCNPpp, PEBP-1, HEL-210, HEL-S-34
Location:12q24.23
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:phosphatidylethanolamine-binding protein 1
HPRD
Source:NCBI
Updated:11 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (39)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 11 December 2014 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.

  • Neoplasm Metastasis
  • Breast Cancer
  • Young Adult
  • ROC Curve
  • Down-Regulation
  • RNA Interference
  • Immunohistochemistry
  • Phosphorylation
  • Neoplasm Invasiveness
  • Cell Proliferation
  • Protein Binding
  • von Willebrand Factor
  • Cancer Gene Expression Regulation
  • Melanoma
  • Tumor Suppressor Proteins
  • Antineoplastic Agents
  • Western Blotting
  • Messenger RNA
  • Disease Progression
  • Prostate Cancer
  • Gene Expression
  • Mutation
  • Transfection
  • Adenocarcinoma
  • Chromosomes, Human, Pair None
  • raf Kinases
  • Promoter Regions
  • Phosphatidylethanolamine Binding Protein
  • RTPCR
  • ras Proteins
  • MicroRNAs
  • Colorectal Cancer
  • Tumor Markers
  • Signal Transduction
  • NF-kappa B
  • Treatment Failure
  • Staging
  • Triple Negative Breast Cancer
  • Receptor, erbB-2
  • BRAF
Tag cloud generated 11 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (5)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Prostate CancerPEBP1 and Prostate Cancer View Publications4
Breast CancerPEBP1 and Breast Cancer View Publications11
Colorectal CancerPEBP1 and Colorectal Cancer View Publications7
MelanomaPEBP1 and Melanoma View Publications5
-PEBP1 and Triple Negative Breast Cancer View Publications1

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

Related Links

Latest Publications: PEBP1 (cancer-related)

Zaravinos A, Kanellou P, Lambrou GI, Spandidos DA
Gene set enrichment analysis of the NF-κB/Snail/YY1/RKIP circuitry in multiple myeloma.
Tumour Biol. 2014; 35(5):4987-5005 [PubMed] Related Publications
The presence of a dysregulated NF-κB/Snail/YY1/RKIP loop was recently established in metastatic prostate cancer cells and non-Hodgkin's lymphoma; however, its involvement in multiple myeloma (MM) has yet to be investigated. Aim of the study was to investigate the role of the NF-κB/Snail/YY1/RKIP circuitry in MM and how each gene is correlated with the remaining genes of the loop. Using gene set enrichment analysis and gene neighbours analysis in data received from four datasets included in the Multiple Myeloma Genomics Portal of the Multiple Myeloma Research Consortium, we identified various enriched gene sets associated with each member of the NF-κB/Snail/YY1/RKIP circuitry. In each dataset, the 20 most co-expressed genes with the circuitry genes were isolated subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment. Among many, we highlighted on FNDC3B, TPD52, BBX, MBNL1 and MFAP2. Many co-expressed genes participated in the regulation of metabolic processes and nucleic acid binding, or were transcription factor binding genes and genes with metallopeptidase activity. The transcription factors FOXO4, GATA binding factor, Sp1 and AP4 most likely affect the expression of the NF-κB/Snail/YY1/RKIP circuitry genes. Computational analysis of various GEO datasets revealed elevated YY1 and RKIP levels in MM vs. the normal plasma cells, as well as elevated RKIP levels in MM vs. normal B lymphocytes. The present study highlights the relationships of the NF-κB/Snail/YY1/RKIP circuitry genes with specific cancer-related gene sets in multiple myeloma.

Related: Myeloma Myeloma - Molecular Biology BRD4 gene


Wang Q, Wu X, Wu T, et al.
Clinical significance of RKIP mRNA expression in non-small cell lung cancer.
Tumour Biol. 2014; 35(5):4377-80 [PubMed] Related Publications
Raf-1 kinase inhibitor protein (RKIP) expression was associated with the onset, development, invasion, and metastasis of numerous tumor types including prostate cancer, melanoma, colorectal cancer, liver cancer, and breast cancer. However, RKIP mRNA expression and the clinical significance in non-small cell lung cancers (NSCLC) remain unresolved. Real-time PCR was performed to detect the expression of RKIP mRNA in 126 pairs of lung tumor tissues (TT) and surrounding normal tissues (sNT). Correlations between RKIP mRNA expression and clinicopathological features were evaluated by statistical analysis. In the 126 patients examined, RKIP mRNA expression was significantly lower in lung TT than the sNT (p < 0.05). Our results indicated that downregulation of RKIP mRNA expression was associated with a poorer N-stage (p = 0.019) and poorer pathological TNM stage (p = 0.015). However, no significant association was observed between the expression status of RKIP mRNA and clinicopathologic factors, such as gender, age, histological type, and the size of the tumor (p > 0.05). The level of RKIP mRNA expression was found to be significantly downregulated in NSCLC, and the lower mRNA levels correlated with poorer differentiation, advanced pathologic TNM stage in patients with NSCLC.

Related: Non-Small Cell Lung Cancer Lung Cancer


Lee J, Lee J, Farquhar KS, et al.
Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions.
Proc Natl Acad Sci U S A. 2014; 111(3):E364-73 [PubMed] Free Access to Full Article Related Publications
The sources and consequences of nongenetic variability in metastatic progression are largely unknown. To address these questions, we characterized a transcriptional regulatory network for the metastasis suppressor Raf kinase inhibitory protein (RKIP). We previously showed that the transcription factor BACH1 is negatively regulated by RKIP and promotes breast cancer metastasis. Here we demonstrate that BACH1 acts in a double-negative (overall positive) feedback loop to inhibit RKIP transcription in breast cancer cells. BACH1 also negatively regulates its own transcription. Analysis of the BACH1 network reveals the existence of an inverse relationship between BACH1 and RKIP involving both monostable and bistable transitions that can potentially give rise to nongenetic variability. Single-cell analysis confirmed monostable and bistable-like behavior. Treatment with histone deacetylase inhibitors or depletion of the polycomb repressor enhancer of zeste homolog 2 altered relative RKIP and BACH1 levels in a manner consistent with a prometastatic state. Together, our results suggest that the mutually repressive relationship between metastatic regulators such as RKIP and BACH1 can play a key role in determining metastatic progression in cancer.

Related: Breast Cancer


Chen Z, Cheng Q, Ma Z, et al.
Overexpression of RKIP inhibits cell invasion in glioma cell lines through upregulation of miR-98.
Biomed Res Int. 2013; 2013:695179 [PubMed] Free Access to Full Article Related Publications
Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor in cancer cells. MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on antimetastasis strategy. In this study, we found that the expression of RKIP and miR-98 in glioma tissues were significantly lower than that in normal brain tissues. Overexpression of RKIP upregulated miR-98 expression and inhibited glioma cell invasion and miR-98 target gene HMGA2 but had no effect in glioma cell proliferation. Moreover, forced expression of miR-98 accelerated the inhibition of glioma cell invasion and the expression of HMGA2 also had no effect in glioma cell proliferation. Our findings newly described RKIP/miR-98 to HMGA2 link and provided a potential mechanism for glioma cell invasion. RKIP and miR-98 may illustrate the potential therapeutic utility of signaling pathway signatures.

Related: HMGA2 gene Signal Transduction


Zhang B, Wang O, Qin J, et al.
cis-Acting elements and trans-acting factors in the transcriptional regulation of raf kinase inhibitory protein expression.
PLoS One. 2013; 8(12):e83097 [PubMed] Free Access to Full Article Related Publications
The Raf kinase inhibitory protein (RKIP) is down-regulated in multiple types of human cancers. Decreased RKIP transcription activity may be one of the major mechanisms responsible for the downregulation of RKIP expression in human diseases. To test this hypothesis, we need to gain basic knowledge of the transcriptional regulation of RKIP. To achieve this objective, we made a systematic effort to identify cis-acting elements and trans-acting factors that control RKIP promoter activity. We found that full RKIP promoter activity requires the region -56 to +261 relative to the transcription start site. Within the full promoter region, there are two motifs rich in G/C that responded to transcription factor Sp1, one cAMP-responsive element that responded to the transcription factor CREB, and one docking site for the histone acetylase p300. In human melanoma A375 cells and human cervical cancer HeLa cells, mutation or deletion of each of these cis-acting elements decreased promoter activity. In A375 cells, knockdown of the corresponding transcription factors Sp1, CREB, or p300 decreased RKIP promoter activity, whereas overexpression of CREB and p300 increased RKIP promoter activity. The results obtained with HeLa cells also supported the idea that Sp1 and CREB play positive roles in the regulation of RKIP transcription. These findings suggest that regulators of the expression or activity of Sp1, CREB, and p300 are involved in regulating RKIP transcription.

Related: Melanoma CREB1 gene


Lee U, Frankenberger C, Yun J, et al.
A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients.
PLoS One. 2013; 8(12):e82125 [PubMed] Free Access to Full Article Related Publications
Although triple negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, they currently lack targeted therapies. Because this classification still includes a heterogeneous collection of tumors, new tools to classify TNBCs are urgently required in order to improve our prognostic capability for high risk patients and predict response to therapy. We previously defined a gene expression signature, RKIP Pathway Metastasis Signature (RPMS), based upon a metastasis-suppressive signaling pathway initiated by Raf Kinase Inhibitory Protein (RKIP). We have now generated a new BACH1 Pathway Metastasis gene signature (BPMS) that utilizes targets of the metastasis regulator BACH1. Specifically, we substituted experimentally validated target genes to generate a new BACH1 metagene, developed an approach to optimize patient tumor stratification, and reduced the number of signature genes to 30. The BPMS significantly and selectively stratified metastasis-free survival in basal-like and, in particular, TNBC patients. In addition, the BPMS further stratified patients identified as having a good or poor prognosis by other signatures including the Mammaprint® and Oncotype® clinical tests. The BPMS is thus complementary to existing signatures and is a prognostic tool for high risk ER-HER2- patients. We also demonstrate the potential clinical applicability of the BPMS as a single sample predictor. Together, these results reveal the potential of this pathway-based BPMS gene signature to identify high risk TNBC patients that can respond effectively to targeted therapy, and highlight BPMS genes as novel drug targets for therapeutic development.

Related: Signal Transduction


Li H, Huang F, Fan L, et al.
Phosphatidylethanolamine-binding protein 4 is associated with breast cancer metastasis through Src-mediated Akt tyrosine phosphorylation.
Oncogene. 2014; 33(37):4589-98 [PubMed] Related Publications
Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.

Related: Breast Cancer MMP9: matrix metallopeptidase 9 AKT1


Gu H, Zhan X, Zhang G, et al.
Mapping the interactome of overexpressed RAF kinase inhibitor protein in a gastric cancer cell line.
BMC Cancer. 2013; 13:536 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric cancer (GC) is a threat to human health with increasing incidence and mortality worldwide. Down-regulation or absence of RAF kinase inhibitor protein (RKIP) was associated with the occurrence, differentiation, invasion, and metastasis of GC. This study aims to investigate the molecular mechanisms and biological functions of RKIP in the GC biology.
METHODS: The fusion expression plasmid pcDNA3.1-RKIP-3xFLAG was transfected into SGC7901 cells, the RKIP fusion proteins were purified with anti-flag M2 magnetic beads, and the RKIP-interacting proteins were identified with tandem mass spectrometry (MS/MS), and were analyzed with bioinformatics tools. Western blot and co-immunoprecipitation were used to confirm the interaction complex.
RESULTS: A total of 72 RKIP-interacting proteins were identified by MS/MS. Those proteins play roles in enzyme metabolism, molecular chaperoning, biological oxidation, cytoskeleton organization, signal transduction, and enzymolysis. Three RKIP-interaction protein network diagrams were constructed with Michigan Molecular Interactions, functional linage network, and Predictome analysis to address the molecular pathways of the functional activity of RKIP. The MS/MS-characterized components of the existing interaction complex (RKIP, HSP90, 14-3-3ε, and keratin 8) were confirmed by Western blot analysis and co-immunoprecipitation.
CONCLUSION: This study is the first discovery of the interaction of RKIP with HSP90, 14-3-3, and keratin. The present data would provide insight into the molecular mechanisms of how RKIP inhibits the occurrence and development of GC.

Related: Stomach Cancer Gastric Cancer


Al-Mulla F, Marafie M, Zea Tan T, Paul Thiery J
Raf kinase inhibitory protein role in the molecular subtyping of breast cancer.
J Cell Biochem. 2014; 115(3):488-97 [PubMed] Related Publications
In this study, we examined the association between the RKIP expression and the molecular subtypes of breast cancer. Microarray gene expression data of 2,333 human breast cancer from 26 different cohorts performed on Affymetrix U133A or U133Plus2 platforms were downloaded from Array Express and Gene Expression Omnibus and the molecular subtype of breast cancer for the samples was determined by single sample Gene Set Enrichment Analysis. Differences in recurrence-free survival (RFS) were tested using the Log-rank test in univariate analysis and displayed using Kaplan-Meier curves. Cox proportional-hazards model was used to calculate the hazard ratio using univariate and multivariate analysis. Loss or reduced RKIP expression was associated with reduced RFS in breast cancer using univariate and multivariate analyses, which was independent of lymph node (LN) metastasis status. Basal-like, Claudin-low, and Her-2-enriched tumors had significantly lower RKIP levels compared to other subclasses (P < 0.0001). Conversely, the Luminal subclass exhibited the highest expression levels of RKIP (P < 0.0001 for Luminal A and P = 0.0005 for Luminal B subtype), while in normal-like breast cancer subtype, RKIP expression was not informative. RKIP expression was prognostic in ER+ and ER- subgroups. RKIP expression had no significant prognostic power within Basal-like, Claudine-low, Luminal B, or Her-2-enriched breast cancer subtypes. However, its expression pinpointed excellent from intermediate-poor Luminal A survivors, in both ER+ (P = 0.035) and ER- (P = 0.012) subgroups, especially in LN negative breast cancers. In conclusion, RKIP expression adds significant value to the molecular subclassification of breast cancer especially for the Luminal A subtype.

Related: Breast Cancer


Park WS, Chung KW, Young MS, et al.
Differential protein expression of lymph node metastases of papillary thyroid carcinoma harboring the BRAF mutation.
Anticancer Res. 2013; 33(10):4357-64 [PubMed] Related Publications
BACKGROUND: The prognostic role of the T1799A BRAF mutation is controversial. We investigated the protein expression in papillary thyroid carcinoma (PTCs) samples harboring the specific mutation using proteomic tools.
MATERIALS AND METHODS: We performed two-dimensional gel electrophoresis to identify differential protein expression regarding lymph node metastasis (LNM). Proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Immunohistochemical staining was performed for 38 PTCs harboring the mutation. We validated the association between these proteins and clinicopathological factors in a test set of 121 PTCs.
RESULTS: The expression of vimentin was increased in PTCs with LNM, but the one for HSP60, SOD2 and PEBP1 was increased in samples without LNM. HSP60 protein was up-regulated in PTCs without LNM (84.2% vs. 36.8%. p=0.003) and in PTCs without LNM harboring the mutation (58% vs. 41.8%. p=0.003) in the test set as shown by immunohistochemical staining.
CONCLUSION: HSP60 protein expression may inhibit LNM in PTCs harboring the BRAF mutation and may be a useful prognostic marker.

Related: BRAF gene Thyroid Cancer


Cross-Knorr S, Lu S, Perez K, et al.
RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients.
BMC Cancer. 2013; 13:463 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients.
METHODS: HCT-116 colon cancer cells were treated with CPT, OXP, and IL-6 separately or in combination in a time and dose-dependent manner and examined for phosphorylated and non-phosphorylated RKIP and STAT3 via Western blot analysis. STAT3 transcriptional activity was measured via a luciferase reporter assay in HCT116 cells treated with CPT, IL-6 or transfected with JAK 1, 2 separately or in combination. We extended these observations and determined STAT3 and RKIP/ pRKIP in tumor microarrays (TMA) in stage II colon cancer patients.
RESULTS: We demonstrate IL-6-mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro in human colon cancer cells. OXP and CPT block IL-6 mediated STAT3 activation and RKIP phosphorylation via the inhibition of the interaction of STAT3 with gp130. We determined that STAT3 and nuclear pRKIP are significantly associated with poor patient prognosis in stage II colon cancer patients.
CONCLUSIONS: In the analysis of tumor samples from stage II colon cancer patients and the human colon carcinoma cell line HCT116, pRKIP and STAT3, 2 proteins potentially involved in the resistance to conventional treatments were detected. The phosphorylation of pRKIP and STAT3 are induced by the cytokine IL-6 and suppressed by the chemotherapeutic drugs CPT and OXP. Therefore, these results suggest that STAT3 and pRKIP may serve as prognostic biomarkers in stage II colon cancer patients and may improve chemotherapy.

Related: Signal Transduction Oxaliplatin


Chen TC, Hsu YL, Tsai YC, et al.
Gemifloxacin inhibits migration and invasion and induces mesenchymal-epithelial transition in human breast adenocarcinoma cells.
J Mol Med (Berl). 2014; 92(1):53-64 [PubMed] Related Publications
UNLABELLED: Gemifloxacin (GMF) is a fluoroquinolone antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV. The aim of this study was to investigate the anti-metastatic activities of GMF and its possible mechanisms of action, with a special focus on the induction of mesenchymal-epithelial transition (MET). The human breast adenocarcinoma cell lines MDA-MB-231 and MDA-MB-453 were used to assess the anti-metastatic activity of GMF on cell migration and invasion and in scratch wound-healing assays. The effects of GMF on the MET and its regulatory nuclear factor κB (NF-κB)/Snail pathway were assessed. The in vivo anti-metastatic effect of GMF was also evaluated in an animal model. This study demonstrated that GMF inhibited the migration and invasion of MDA-MB-231 and MDA-MB-453 cells and induced the MET. GMF suppressed the activation of NF-κB, as well as the cell migration and invasion induced by tumor necrosis factor α (TNF-α). GMF was shown to inhibit the phosphorylation of the inhibitor of κB (IκB) and the translocation of NF-κB/Snail in both cancer cell lines. This study showed that the Raf kinase inhibitor protein (RKIP), an inhibitor of IκB kinase, is upregulated after GMF treatment. Inhibition of RKIP by small hairpin RNA transfection significantly decreased the inhibitory effect of GMF on the NF-κB/Snail pathway and also inhibited cell migration and invasion. Overexpression of Snail suppressed GMF-mediated metastasis inhibition and E-cadherin upregulation. An animal model revealed that GMF effectively inhibits lipopolysaccharide-mediated metastasis in mice. This study has demonstrated that GMF might be a novel anticancer agent for the prevention and treatment of metastasis in breast cancer.
KEY MESSAGES: GMF inhibits the migration and invasion of human breast adenocarcinoma cells. GMF induces MET by reducing NF-κB and Snail activation and by increasing RKIP levels. GMF has potential clinical implication as an anti-metastatic agent for breast cancer.

Related: Breast Cancer Signal Transduction TNF


Sun M, Gomes S, Chen P, et al.
RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2.
Oncogene. 2014; 33(27):3528-37 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
Elucidating targets of physiological tumor metastasis suppressors can highlight key signaling pathways leading to invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP/PEBP1), we utilized an integrated approach based upon statistical analysis of tumor gene expression data combined with experimental validation. Previous studies from our laboratory identified the architectural transcription factor and oncogene, high mobility group AT-hook 2 (HMGA2), as a target of inhibition by RKIP. Here we identify two signaling pathways that promote HMGA2-driven metastasis. Using both human breast tumor cells and an MMTV-Wnt mouse breast tumor model, we show that RKIP induces and HMGA2 inhibits expression of miR-200b; miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2), which is aberrantly expressed in breast cancer, via downregulation of HMGA2; but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. RKIP, LOX and SDC2 are coordinately regulated and collectively encompass a prognostic signature for metastasis-free survival in ER-negative breast cancer patients. Taken together, our findings reveal two novel signaling pathways targeted by the metastasis suppressor RKIP that regulate remodeling of the extracellular matrix and tumor survival.

Related: Breast Cancer HMGA2 gene Signal Transduction


Misra P, Viswakarma N, Reddy JK
Peroxisome proliferator-activated receptor-α signaling in hepatocarcinogenesis.
Subcell Biochem. 2013; 69:77-99 [PubMed] Related Publications
Peroxisomes are subcellular organelles that are found in the cytoplasm of most animal cells. They perform diverse metabolic functions, including H2O2-derived respiration, β-oxidation of fatty acids, and cholesterol metabolism. Peroxisome proliferators are a large class of structurally dissimilar industrial and pharmaceutical chemicals that were originally identified as inducers of both the size and the number of peroxisomes in rat and mouse livers or hepatocytes in vitro. Exposure to peroxisome proliferators leads to a stereotypical orchestration of adaptations consisting of hepatocellular hypertrophy and hyperplasia, and transcriptional induction of fatty acid metabolizing enzymes regulated in parallel with peroxisome proliferation. Chronic exposure to peroxisome proliferators causes liver tumors in both male and female mice and rats. Evidence indicates a pivotal role for a subset of nuclear receptor superfamily members, called peroxisome proliferator-activated receptors (PPARs), in mediating energy metabolism. Upon activation, PPARs regulate the expression of genes involved in lipid metabolism and peroxisome proliferation, as well as genes involved in cell growth. In this review, we describe the molecular mode of action of PPAR transcription factors, including ligand binding, interaction with specific DNA response elements, transcriptional activation, and cross talk with other signaling pathways. We discuss the evidence that suggests that PPARα and transcriptional coactivator Med1/PBP, a key subunit of the Mediator complex play a central role in mediating hepatic steatosis to hepatocarcinogenesis. Disproportionate increases in H2O2-generating enzymes generates excess reactive oxygen species resulting in sustained oxidative stress and progressive endoplasmic reticulum (ER) stress with activation of unfolded protein response signaling. Thus, these major contributors coupled with hepatocellular proliferation are the key players of peroxisome proliferators-induced hepatocarcinogenesis.

Related: Liver Cancer Signal Transduction


Lee SJ, Lee SH, Yoon MH, Park BJ
A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation.
Neoplasia. 2013; 15(7):727-37 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
p53, a strong tumor suppressor protein, is known to be involved in cellular senescence, particularly premature cellular senescence. Oncogenic stresses, such as Ras activation, can initiate p53-mediated senescence, whereas activation of the Ras-mitogen-activated protein kinase (MAPK) pathway can promote cell proliferation. These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling. To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis. Through several molecular biologic analyses, we found that RKIP, an inhibitor of Raf kinase, is responsible for p53-mediated ERK suppression and senescence. Overexpression of RKIP can induce cellular senescence in several types of cell lines, including p53-deficient cells, whereas the elimination of RKIP by siRNA or forced expression of ERK blocks p53-mediated cellular senescence. These results suggested that RKIP is an essential protein for cellular senescence. Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence. These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression.

Related: Doxorubicin Etoposide Cancer Prevention and Risk Reduction Signal Transduction TP53


Wang X, Sun Y, Wong J, Conklin DS
PPARγ maintains ERBB2-positive breast cancer stem cells.
Oncogene. 2013; 32(49):5512-21 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers and is associated with aggressive disease and poor outcomes. Our recent findings have shown that NR1D1 and the peroxisome proliferator-activated receptor-γ (PPARγ)-binding protein (PBP) act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. NR1D1 and PBP are functionally related to PPARγ, a well-established positive regulator of adipogenesis and lipid storage. Here, we report that inhibition of the PPARγ pathway reduces the aldehyde dehydrogenase (ALDH)-positive population in ERBB2-positive breast cancer cells. Results from in vitro tumorsphere formation assays demonstrate that the PPARγ antagonists GW9662 and T0070907 decrease tumorsphere formation in ERBB2-positive cells, but not other breast cells. We show that the mechanism by which GW9662 treatment causes a reduction in ALDH-positive population cells is partially due to ROS, as it can be rescued by treatment with N-acetyl-cysteine. Furthermore, global gene expression analyses show that GW9662 treatment suppresses the expression of several lipogenic genes, including ACLY, MIG12, FASN and NR1D1, and the stem-cell related genes KLF4 and ALDH in BT474 cells. Antagonist treatment also decreases the level of acetylation in histone 3 and histone 4 in BT474 cells, compared with MCF7 cells. In vivo, GW9662 pre-treatment inhibits the tumor-seeding ability of BT474 cells. Together, these results show that the PPARγ pathway is critical for the cancer stem cell properties of ERBB2-positive breast cancer cells.

Related: Breast Cancer PPARG gene


Zhao D, Ma J, Shi J, et al.
Raf kinase inhibitor protein inhibits esophageal cancer cell invasion through downregulation of matrix metalloproteinase expression.
Oncol Rep. 2013; 30(1):304-12 [PubMed] Related Publications
Esophageal cancer is the eighth most common malignant tumor in the world and is a common cause of tumor-related death. The development of esophageal cancer is a complex process involving many pathogenetic factors, multiple stages and accumulation of multiple gene mutations and interactions. This study aimed to investigate the effects of Raf kinase inhibitor protein (RKIP) on the proliferation, apoptosis and invasion of TE-1 esophageal cancer cells. Surgical specimens from esophageal cancer patients were classified into esophageal cancer tissues, tumor-adjacent tissues and normal esophageal tissues. The tissues were fixed in 4% paraformaldehyde solution for hematoxylin and eosin and immunohistochemical staining. RKIP expression in esophageal tissues was detected by immunohistochemical staining. The esophageal cancer cell line TE-1 was exposed to four different viruses: RKIP-RNAi-AD, NC-RNAi-GFP-AD, RKIP-AD and GFP-AD. Cell proliferation was detected by MTT assay and cell apoptosis was detected by flow cytometry. Cell invasion was determined by a Transwell coated with Matrigel. RKIP, phospho-RKIP, Raf-1, phospho-Raf-1, ERK1/2, phospho-ERK1/2, GRK-2 and GAPDH expression was assayed by western blotting. LIN28 and MMP-14 mRNA was assayed by qPCR. The results showed that RKIP expression was reduced in esophageal cancer tissues in comparison with expression in normal esophageal epithelium tissues and tumor-adjacent tissues. Reduced RKIP expression was associated with lymph node or distant metastasis in esophageal cancer. RKIP inhibited the invasive and metastatic abilities of esophageal cancer cell line TE-1 by downregulating mRNA expression of LIN28 and MMP-14. RKIP had no effect on the MAPK signaling pathway in the esophageal cancer cell line TE-1, but was involved in the G protein-coupled signaling pathway. Our findings clearly demonstrate that RKIP inhibits esophageal cancer cell invasion by downregulating the expression of GRK-2, LIN28 and MMP-14.

Related: Apoptosis Cancer of the Esophagus Esophageal Cancer


Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Related: Signal Transduction Stomach Cancer Gastric Cancer


Salnikova LE, Belopolskaya OB, Zelinskaya NI, Rubanovich AV
The potential effect of gender in CYP1A1 and GSTM1 genotype-specific associations with pediatric brain tumor.
Tumour Biol. 2013; 34(5):2709-19 [PubMed] Related Publications
Brain tumors are the common site for solid tumors in childhood. Very few studies have investigated genes with low penetrance in relation to pediatric brain tumor (pBT) development. Brain tumors do occur more frequently in males compared to females regardless of age, tumor histology, or region of the world. Taken into account these facts, we have designed a study aimed to analyse the contribution of some genetic factors to pBP in males and females. Patients with glial and embryonic brain tumors (160 males, 124 females) and healthy controls (277 males, 187 females) were included in the study. All subjects were genotyped for eight polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), repair ERCC2 (rs1799793, rs13181), and folate pathway MTHFR (rs1801133). Genotype-specific risks of pBT were sex-dependent. GSTM1 deletion and dual deletions in GSTM1-GSTT1 loci were associated with brain tumor in males (P = 1.2 × 10(-5); odds ratio (OR) = 2.56; 95 % confidence interval (CI), 1.45-3.85 and P = 4.9 × 10(-4); OR = 3.09; 95 % CI, 1.63-5.89, relatively). The increased risk of brain tumors was evident for CYP1A1 rs2606345 (P = 0.0028; OR = 2.06; 95 % CI, 1.27-3.34) and minor haplotypes rs2606345-rs1048943-rs4646903 in females (global haplotype association P value, 0.0011). This study provides first evidence for the different pronounced pBT associations in males and females. This phenomenon possibly reflects the sexual dimorphism as an important determinant of brain tumor biology.

Related: Childhood Brain Tumours Childhood Brain Tumors GSTT1 GSTM1


Martinho O, Pinto F, Granja S, et al.
RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy.
PLoS One. 2013; 8(3):e59104 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
Cervical cancer is one of the most common cancers in women worldwide, being high-risk group the HPV infected, the leading etiological factor. The raf kinase inhibitory protein (RKIP) has been associated with tumor progression and metastasis in several human neoplasms, however its role on cervical cancer is unclear. In the present study, 259 uterine cervix tissues, including cervicitis, cervical intraepithelial lesions and carcinomas, were analyzed for RKIP expression by immunohistochemistry. We found that RKIP expression was significantly decreased during malignant progression, being highly expressed in non-neoplastic tissues (54% of the samples; 73/135), and expressed at low levels in the cervix invasive carcinomas (∼15% (19/124). Following in vitro downregulation of RKIP, we observed a viability and proliferative advantage of RKIP-inhibited cells over time, which was associated with an altered cell cycle distribution and higher colony number in a colony formation assay. An in vitro wound healing assay showed that RKIP abrogation is associated with increased migratory capability. RKIP downregulation was also associated with an increased vascularization of the tumors in vivo using a CAM assay. Furthermore, RKIP inhibition induced cervical cancer cells apoptotic resistance to cisplatin treatment. In conclusion, we described that RKIP protein is significantly depleted during the malignant progression of cervical tumors. Despite the lack of association with patient clinical outcome, we demonstrate, in vitro and in vivo, that loss of RKIP expression can be one of the factors that are behind the aggressiveness, malignant progression and chemotherapy resistance of cervical cancer.

Related: Angiogenesis and Cancer Cervical Cancer


Doyle B, Hagan S, Al-Mulla F, et al.
Raf kinase inhibitor protein expression combined with peritoneal involvement and lymphovascular invasion predicts prognosis in Dukes' B colorectal cancer patients.
Histopathology. 2013; 62(3):505-10 [PubMed] Related Publications
AIMS: There is controversy regarding the use of adjuvant therapy in patients with Dukes' B colorectal cancer (CRC). New markers, identifying high-risk Dukes' B patients, are needed. Here, we examine the utility of Raf kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation.
METHODS AND RESULTS: We used a tissue microarray of 220 patients with Dukes' B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status.RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator, along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing.
CONCLUSIONS: Raf kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes' B CRC patients.This demonstrates the potential utility of RKIP in identifying 'high-risk' Dukes' B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy.

Related: Colorectal (Bowel) Cancer


Wang K, Jiang Y, Zheng W, et al.
Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma.
PLoS One. 2013; 8(2):e56829 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma.

Related: Apoptosis Rituximab (Mabthera)


Lasithiotaki I, Antoniou KM, Derdas SP, et al.
The presence of Merkel cell polyomavirus is associated with deregulated expression of BRAF and Bcl-2 genes in non-small cell lung cancer.
Int J Cancer. 2013; 133(3):604-11 [PubMed] Related Publications
Polyomaviruses such as BK virus (BKV), JC virus (JCV) and Merkel cell polyomavirus (MCPyV) are typically nononcogenic, although they have been detected in a variety of human neoplasms. The aim of our study was to determine the frequency of the most common polyomaviruses MCPyV, BKV and JCV as well as the gene expression profile of genes involved in oncogenesis including K-ras, BRAF, RKIP, Bax, Bcl-2, p53 and RB1 in a cohort of non-small cell lung cancer (NSCLC) patients. Real-time and nested polymerase chain reaction (PCR) were used to assess the presence of polyomaviruses DNA in tissue biopsies from 110 patients with primary NSCLC and 14 tissue specimens from macroscopically healthy sites of their lung. Real-time PCR was also used to determine the mRNA expression of K-ras, BRAF, RKIP, Bax, Bcl-2, p53 and RB1 in selected samples. Results showed that ten NSCLC specimens were positive for the presence of MCPyV DNA (10/110, 9.1%), whereas no control sample was tested positive for the virus. The MCPyV-positive samples were predominantly obtained from male smokers (9/10). BKV and JCV DNA were not detected either in lung tissues biopsies or the control specimens. Interestingly, gene expression analysis revealed increased mRNA and protein expression of BRAF gene in association with BRAF phosphorylation in the MCPyV-positive samples, whereas Bcl-2 gene expression was downregulated in the same type of samples. The detected MCPyV prevalence in NSCLC in combination with the deregulated expression of BRAF and Bcl-2 genes suggests that these events are likely to contribute to the pathogenesis of NSCLC.

Related: Non-Small Cell Lung Cancer Lung Cancer Merkel Cell Polyomavirus BRAF gene TP53 KRAS gene


Martinho O, Simões K, Longatto-Filho A, et al.
Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients.
Oncol Rep. 2013; 29(2):690-6 [PubMed] Related Publications
Gastric cancer is a leading cause of cancer-related mortality, and the presence of lymph node metastasis an important prognostic factor. Downregulation of RKIP has been associated with tumor progression and metastasis in several types of neoplasms, being currently categorized as a metastasis suppressor gene. Our aim was to determine the expression levels of RKIP in gastric tissues and to evaluate its impact in the clinical outcome of gastric carcinoma patients. RKIP expression levels were studied by immunohistochemistry in a series of gastric tissues. Overall, we analysed 222 non-neoplastic gastric tissues, 152 primary tumors and 42 lymph node metastasis samples. We observed that RKIP was highly expressed in ~83% of non-neoplastic tissues (including normal tissue and metaplasia), was lost in ~56% of primary tumors and in ~90% of lymph node metastasis samples. Loss of RKIP expression was significantly associated with several markers of poor clinical outcome, including the presence of lymph node metastasis. Furthermore, the absence of RKIP protein constitutes an independent prognostic marker for these patients. In conclusion, RKIP expression is significantly lost during gastric carcinoma progression being almost absent in lymph node metastasis samples. Of note, we showed that the absence of RKIP expression is associated with poor outcome features of gastric cancer patients, this being also an independent prognostic marker.

Related: Stomach Cancer Gastric Cancer


Poma P, Labbozzetta M, Vivona N, et al.
Analysis of possible mechanisms accounting for raf-1 kinase inhibitor protein downregulation in hepatocellular carcinoma.
OMICS. 2012; 16(11):579-88 [PubMed] Related Publications
Abstract Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor that promotes drug-induced apoptosis in cancer cells. It is frequently downregulated, both at the mRNA and protein level, in hepatocellular carcinoma (HCC), but the mechanisms leading to this reduction are obscure. We sequenced the whole RKIP gene in three human HCC cell lines (HA22T/VGH, HepG2, and Hep3B), and in five clinical HCC samples, but could not find any gene variant that might account for their low RKIP levels. We also examined whether gene methylation may be responsible for the altered RKIP expression. No methylation of the RKIP gene was found in the tumor samples, while among the cell lines only Hep3B showed methylation of the gene, which was reduced by treatment with 5-aza-2'-deoxycytidine (5-AZA). The same treatment caused upregulation of RKIP at the mRNA, but not at the protein level, indicating that gene methylation is not a principal mechanism of the decrease in RKIP in the Hep3B cells. Furthermore, different elements consistently suggested that RKIP may be a target repressed by miR-224, a miRNA that is frequently and specifically upregulated in HCC, but our results excluded that this occurs, at least in the HCC cell lines. Factors like Snail, EZH2, and HDAC, have been implicated in the RKIP downregulation present in breast and prostate tumors, though some of our results from the cell lines do not support that they play such a role in HCC; however, this aspect is worthy of further study. However, recent results of ours and others suggest a significant involvement of proteosomal degradation and of its pharmacological inhibition. In conclusion, the causes of RKIP downregulation in HCC remain incompletely understood. However, we think that the present observations will be useful to generate further research, with the ultimate possible goal of devising specific approaches to restore the relevant antitumor function of the factor.

Related: Azacitidine Liver Cancer


Guo W, Dong Z, Lin X, et al.
Decreased expression and aberrant methylation of Raf kinase inhibitory protein gene in esophageal squamous cell carcinoma.
Cancer Invest. 2012; 30(10):703-11 [PubMed] Related Publications
Raf kinase inhibitory protein (RKIP) gene is considered to be a suppressor of metastasis involved in various carcinomas. In the present study, we observed that promoter methylation repressed the expression of RKIP in TE-13 cell line. 5-Aza treatment and stable transfection of RKIP resulted in a significant inhibition of TE-13 cell proliferation. The promoter hypermethylation of RKIP was found to occur in dysplastic tissues and a close correlation was noted between RKIP methylation and the loss of mRNA and protein expression of the gene in ESCC specimens. In summary, RKIP may act as a tumor suppressor gene in esophageal cancer.

Related: Cancer of the Esophagus Esophageal Cancer


Das SK, Bhutia SK, Sokhi UK, et al.
Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.
Cancer Res. 2012; 72(23):6217-26 [PubMed] Article available free on PMC after 03/01/2015 Related Publications
Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor, RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored a hypothesized inverse relationship between MDA-9 and RKIP in melanoma. Tumor array and cell line analyses confirmed an inverse relationship between expression of MDA-9 and RKIP during melanoma progression. We found that MDA-9 transcriptionally downregulated RKIP in support of a suggested cross-talk between these two proteins. Furthermore, MDA-9 and RKIP physically interacted in a manner that correlated with a suppression of FAK and c-Src phosphorylation, crucial steps necessary for MDA-9 to promote FAK/c-Src complex formation and initiate signaling cascades that drive the MDA-9-mediated metastatic phenotype. Finally, ectopic RKIP expression in melanoma cells overrode MDA-9-mediated signaling, inhibiting cell invasion, anchorage-independent growth, and in vivo dissemination of tumor cells. Taken together, these findings establish RKIP as an inhibitor of MDA-9-dependent melanoma metastasis, with potential implications for targeting this process therapeutically.

Related: Melanoma Signal Transduction


Guo W, Dong Z, Guo Y, et al.
Aberrant methylation and loss expression of RKIP is associated with tumor progression and poor prognosis in gastric cardia adenocarcinoma.
Clin Exp Metastasis. 2013; 30(3):265-75 [PubMed] Related Publications
Raf kinase inhibitory protein (RKIP) has been identified as a member of a novel class of molecules which implicated in cancer progression and suppress the metastatic spread of tumors. The aim of this study was to investigate the promoter methylation and expression of RKIP, determine the prognostic significance of RKIP in gastric cardia adenocarcinoma (GCA). MSP approach and immunohistochemistry methods were used respectively to examine methylation status and protein expression of RKIP in GCA tissues. The frequency of RKIP methylation in GCA tumor tissues (62.1 %) was significantly higher than that in corresponding normal tissues (4.1 %) and was associated with TNM stage, histological differentiation, depth of invasion, LN metastasis, distant metastasis or recurrence, and upper gastrointestinal cancers (UGIC) family history. Positive staining of RKIP in GCA tumor tissues (34.5 %) was significantly decreased than that in corresponding normal tissues (84.1 %) and was associated with RKIP methylation. RKIP may act as a tumor suppressor gene in GCA by regulation of the Raf-1/MEK/ERK signaling pathway. GCA patients in stage III and IV, with positive UGIC family history, and hypermethylation and down-expression of RKIP were most likely to develop metastatic disease and also showed the worse survival. RKIP methylation in GCA was an independent prognostic marker for survival using multivariate Cox regression analysis (P = 0.04). In all, aberrant hypermethylation of RKIP may be one of the mechanisms that lead to loss or down expression of the gene in GCA especially in individuals with UGIC family history. Additionally, hypermethylation and loss of RKIP expression may be used as a marker to predict clinical outcome of GCA.

Related: Stomach Cancer Gastric Cancer


Giovannetti E, Labots M, Dekker H, et al.
Molecular mechanisms and modulation of key pathways underlying the synergistic interaction of sorafenib with erlotinib in non-small-cell-lung cancer (NSCLC) cells.
Curr Pharm Des. 2013; 19(5):927-39 [PubMed] Related Publications
Combination of drugs with different targets is a logical approach to overcome multilevel cross-stimulation among key pathways in NSCLC progression such as EGFR, K-Ras and VEGFR. The sorafenib-erlotinib combination showed clinical activity and acceptable safety. Therefore, we evaluated mechanisms underlying sorafenib-erlotinib interaction in seven NSCLC cell lines selected for their heterogeneous pattern of EGFR and Raf-kinase-inhibitor protein (RKIP) expression, and EGFR/K-Ras mutations. Pharmacologic interaction was studied using MTT/SRB assays and the combination index (CI) method, while effects on EGFR, Erk1/2 and Akt phosphorylation, cell cycle and apoptosis were studied with western-blot, ELISA, and flow cytometry. Intracellular drug concentrations were measured with LC-MS/MS, whereas kinase activity profiles were generated on tyrosine kinase peptide substrate arrays. Synergism was detected in all cell lines, with CIs < 0.6 in K-Ras mutated A549, SW1573 and H460, as well as in H1975 (EGFR-T790M) cells. Sorafenib slowed cell cycle progression and induced apoptosis, which was significantly increased in the combination. Moreover, sorafenib reduced Akt/ERK phosphorylation in erlotinib-resistant cells, associated with significant RKIP up-regulation. No direct drug interaction was detected by LC-MS/MS measurement, while lysates from A549 and H1975 cells exposed to erlotinib+sorafenib showed a significant inhibition in the phosphorylation of 16 overlapping peptides, including sites from RAF, VEGFR2, PDGFR, CDK2 and SRC, suggesting new markers to identify NSCLC patients who are likely to respond to this treatment. In conclusion, several mechanisms, including apoptosis-induction, modulation of expression/phosphorylation of RKIP and crucial kinases contribute to erlotinib-sorafenib synergistic interaction and should be evaluated in future trials for the rational development of this combination in NSCLC.

Related: Apoptosis Non-Small Cell Lung Cancer Lung Cancer Sorafenib (Nexavar) Erlotinib (Tarceva)


Yan L, Gu H, Li J, et al.
RKIP and 14-3-3ε exert an opposite effect on human gastric cancer cells SGC7901 by regulating the ERK/MAPK pathway differently.
Dig Dis Sci. 2013; 58(2):389-96 [PubMed] Related Publications
BACKGROUND: Raf-1 kinase inhibitor protein (RKIP) inhibits Raf (a key element in the ERK/MAPK pathway) and is regarded as anti-tumoral. In contrast, 14-3-3 is considered protumoral. However, the pathogenetic role of RKIP and 14-3-3ε in gastric cancer is unclear.
AIM: The purpose of this study was to examine the influence of 14-3-3ε and RKIP on SGC7901, the regulation of the ERK/MAKP pathway by both, and the interaction between the two proteins.
METHODS: RKIP and 14-3-3ε genes were introduced into SGC7901 cells using gene cloning technique, then, the bioactivities including the proliferation, migration and invasion of the cells were assessed by MTT and migration assays. ERK/MAKP pathway's activity was examined using real-time quantitative RT-PCR, western blot, immunoprecipitation and 3D-immunolocalization techniques.
RESULTS: Our results showed that RKIP inhibited SGC7901 cells' bioactivities whereas 14-3-3ε upregulated them through the involvement of the ERK/MAPK pathway. RKIP inactivated this pathway, but 14-3-3ε activated it. RKIP and 14-3-3ε were co-localized in the cells and interacted with each other; this attributed to their opposite influence on the ERK/MAPK pathway and the cells bioactivities.
CONCLUSIONS: The ERK/MAPK pathway is involved in the pathogenesis of gastric cancer; RKIP and 14-3-3ε exert an opposite effect on this pathway and the cells possibly via both direct and indirect reactions with the elements in this pathway. The interaction between RKIP and 14-3-3ε may also contribute to their pathogenetic roles in gastric cancer.

Related: Stomach Cancer Gastric Cancer


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Cite this page: Cotterill SJ. PEBP1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/PEBP1.htm Accessed: date

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