Gene Summary

Gene:PEBP1; phosphatidylethanolamine binding protein 1
Aliases: PBP, HCNP, PEBP, RKIP, HCNPpp, PEBP-1, HEL-210, HEL-S-34, HEL-S-96
Summary:This gene encodes a member of the phosphatidylethanolamine-binding family of proteins and has been shown to modulate multiple signaling pathways, including the MAP kinase (MAPK), NF-kappa B, and glycogen synthase kinase-3 (GSK-3) signaling pathways. The encoded protein can be further processed to form a smaller cleavage product, hippocampal cholinergic neurostimulating peptide (HCNP), which may be involved in neural development. This gene has been implicated in numerous human cancers and may act as a metastasis suppressor gene. Multiple pseudogenes of this gene have been identified in the genome. [provided by RefSeq, Jul 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:phosphatidylethanolamine-binding protein 1
Source:NCBIAccessed: 31 August, 2019


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

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.

  • Proto-Oncogene Proteins p21(ras)
  • Lymphatic Metastasis
  • BRAF
  • TNF-Related Apoptosis-Inducing Ligand
  • Phosphorylation
  • Chromosome 12
  • Receptor, erbB-2
  • ras Proteins
  • Transfection
  • Neoplasm Invasiveness
  • Transcription Factors
  • Skin Cancer
  • Tissue Array Analysis
  • Down-Regulation
  • Triple Negative Breast Cancer
  • Colorectal Cancer
  • Mutation
  • Promoter Regions
  • Cell Movement
  • Apoptosis
  • MicroRNAs
  • Neoplasm Metastasis
  • Melanoma
  • Tumor Suppressor Proteins
  • NF-kappa B
  • Protein Binding
  • Biomarkers, Tumor
  • Cell Proliferation
  • Antineoplastic Agents
  • Breast Cancer
  • snail family transcription factors
  • raf Kinases
  • ROC Curve
  • Tumor Microenvironment
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Western Blotting
  • Immunohistochemistry
  • Phosphatidylethanolamine Binding Protein
  • Staging
  • Prostate Cancer
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: PEBP1 (cancer-related)

Liu X, Bao Y, Meng W, et al.
TROY interacts with RKIP to promote glioma development.
Oncogene. 2019; 38(9):1544-1559 [PubMed] Free Access to Full Article Related Publications
TROY is a component of the Nogo receptor complex and plays the key role in neuronal survival, migration, and differentiation. Here, we show the up-regulation of TROY in human glioma tissues and cells. Inhibition of TROY expression slowed glioma development in vivo and in vitro. Raf kinase inhibitor (RKIP) was found to interact with TROY. The physical interaction of TROY/RKIP was confirmed via co-immunoprecipitation (co-IP) assays. Furthermore, we found that the TROY/RKIP interaction was enhanced by fetal bovine serum (FBS) exposure, and TROY knockdown also led to down-regulation of NF-κB. Finally, disruption of the TROY/RKIP interaction using the TAT-TROY (234-371 aa) protein reduced the glioma development in xenografted mice. This suggests the TROY/RKIP interaction is a potential target for therapy of gliomas.

Bonavida B
Linking Autophagy and the Dysregulated NFκB/ SNAIL/YY1/RKIP/PTEN Loop in Cancer: Therapeutic Implications.
Crit Rev Oncog. 2018; 23(5-6):307-320 [PubMed] Free Access to Full Article Related Publications
The role of autophagy in the pathogenesis of various cancers has been well documented in many reports. Autophagy in cancer cells regulates cell proliferation, viability, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, and responses to chemotherapeutic and immunotherapeutic treatment strategies. These manifestations are the result of various regulatory gene products that govern autophagic, biochemical, and molecular mechanisms. In several human cancer cell models, the presence of a dysregulated circuit-namely, NFκB/SNAIL/YY1/RKIP/PTEN-that plays a major role in the regulation of tumor cell unique characteristics just listed for autophagy-regulated activities. Accordingly, the autophagic mechanism and the dysregulated circuit in cancer cells share many of the same properties and activities. Thus, it has been hypothesized that there must exist a biochemical/molecular link between the two. The present review describes the link and the association of each gene product of the dysregulated circuit with the autophagic mechanism and delineates the presence of crosstalk. Crosstalk between autophagy and the dysregulated circuit is significant and has important implications in the development of targeted therapies aimed at either autophagy or the dysregulated gene products in cancer cells.

Wang Y, Bonavida B
A New Linkage between the Tumor Suppressor RKIP and Autophagy: Targeted Therapeutics.
Crit Rev Oncog. 2018; 23(5-6):281-305 [PubMed] Free Access to Full Article Related Publications
The complexities of molecular signaling in cancer cells have been hypothesized to mediate cross-network alterations of oncogenic processes such as uncontrolled cell growth, proliferation, acquisition of epithelial-to-mesenchymal transition (EMT) markers, and resistance to cytotoxic therapies. The two biochemically exclusive processes/proteins examined in the present review are the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP) and the cell-intrinsic system of macroautophagy (hereafter referred to as autophagy). RKIP is poorly expressed in human cancer tissues, and low expression levels are correlated with high incidence of tumor growth, metastasis, poor treatment efficacy, and poor prognoses in cancer patients. By comparison, autophagy is a conserved cytoprotective degradation pathway that has been shown to influence the acquisition of resistance to hypoxia and nutrient depletion as well as the regulation of chemo-immuno-resistance and apoptotic evasion. Evidently, a broad library of cancer-relevant studies exists for RKIP and autophagy, although reports of the interactions between pathways involving RKIP and autophagy have been relatively sparse. To circumvent this limitation, the coordinate regulatory and effector mechanisms were examined for both RKIP and autophagy. Here, we propose three putative pathways that demonstrate the inherent pleiotropism and relevance of RKIP and the microtubule-associated protein 1 light chain 3 (MAP1LC3, LC3) on cell growth, proliferation, senescence, and EMT, among the hallmarks of cancer. Our findings suggest that signaling modules involving p53, signal transducer and activator of transcription 3 (STAT3), nuclear factor-κB (NF-κB), and Snail highlight the novel roles for RKIP in the control of autophagy and vice versa. The suggested potential crosstalk mechanisms are new areas of research in which to further study RKIP and autophagy in cancer models. These should lead to novel prognostic motifs and will provide alternative therapeutic strategies for the treatment of unresponsive aggressive cancer types.

Kim JS, Choi GH, Jung Y, et al.
Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines.
J Cancer Res Clin Oncol. 2018; 144(8):1487-1501 [PubMed] Related Publications
PURPOSE: Although sorafenib enhances overall survival, sorafenib resistance has been reported to be a significant limiting factor for improved prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to identify the mechanism of sorafenib resistance. This study aimed to identify the causative factor of sorafenib resistance and suggest methods for overcoming it.
METHODS: The sensitivity to sorafenib was compared in human HCC cell lines and patient-derived HCC primary cells. Based on its cytotoxicity, signaling pathways altered by sorafenib and the causative factors were examined through assays. The mechanism by which sorafenib modified the sorafenib-resistance inducer through gene or protein expression or stability was also investigated. We also designed a treatment option to overcome sorafenib resistance.
RESULTS: Sorafenib activated the Raf/MEK/ERK pathway and caused sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Sorafenib reactivated the MAPK pathway by down-regulating RKIP at the post-translational level. Knockdown of RKIP increased phosphorylated ERK and thus suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy for patients with sorafenib resistance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing apoptosis efficacy.
CONCLUSION: Reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms behind sorafenib resistance in HCC. Sequential combination treatment with sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.

Yang K, Li Y, Lian G, et al.
KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer.
Int J Cancer. 2018; 142(11):2323-2334 [PubMed] Related Publications
Oncogenic KRAS plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. However, the mechanism has not been clearly elucidated. RKIP is a tumor repressor, and loss of RKIP has been shown in PDAC. Here, we found that KRAS expression was inversely correlated with RKIP expression in PDAC fresh tissue regardless of the KRAS mutant status. The negative correlation between KRAS and RKIP was further confirmed in our PDAC tissue microarray. KRAS overexpression and RKIP downregulation were associated with poor clinical outcomes. Knockdown or overexpression of KRAS in PDAC cell lines robustly increased or decreased, respectively, RKIP protein and mRNA levels. Furthermore, the MAPK-ERK pathway was involved in the regulation of RKIP. KRAS-regulated RKIP expression, which in turn affected the expression of pivotal epithelial-mesenchymal transition (EMT) and apoptosis factors. The biological function of the KRAS-RKIP axis was demonstrated in human pancreatic cancer cells in vitro and in vivo. KRAS knockdown increased RKIP expression and inhibited metastasis and chemoresistance. Moreover, the feature of metastasis and chemoresistance was rescued in the KRAS-knockdown cells through the inhibition of RKIP by RNA interference. In conclusion, our studies demonstrate how KRAS inhibits the tumor suppressor RKIP, thus offering novel justification for targeting RKIP as a strategy to overcome KRAS-induced tumor metastasis and chemoresistance in PDAC.

Liu S, Li X, Lin Z, et al.
SEC-induced activation of ANXA7 GTPase suppresses prostate cancer metastasis.
Cancer Lett. 2018; 416:11-23 [PubMed] Free Access to Full Article Related Publications
Annexin A7 (ANXA7) is a suppressor of tumorigenesis and metastasis in prostate cancer. Activated ANXA7 GTPase promotes prostate cancer cell apoptosis. However, the role and underlying mechanism of ANXA7 GTPase in prostate cancer metastasis have not been established. RKIP is a metastatic suppressor and downregulated in prostate cancer metastases. The binding of RKIP and its target proteins could inhibit the activation of its interactive partners. However, the effect of RKIP on ANXA7 GTPase activation is not clear. Here, we report that activation of ANXA7 GTPase by a small molecule SEC ((S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3- (4-methoxyphenyl)-1H-pyrazole-5-carboxylate) effectively inhibited prostate cancer metastasis. Mechanistically, activated ANXA7 promoted AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes, including CCL2, APLN, and IL6ST. Conversely, RKIP interacted with ANXA7 and impaired activation of ANXA7 GTPase by SEC and its downstream signaling pathway. Notably, SEC treatment suppressed metastasis of prostate cancer cells in in vivo orthotopic analysis. Together, our findings provide a novel insight into how metastasis of prostate cancer with low RKIP expression is suppressed by SEC-induced activation of ANXA7 GTPase via the AMPK/mTORC1/STAT3 signaling pathway.

Shvartsur A, Givechian KB, Garban H, Bonavida B
Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma.
J Exp Clin Cancer Res. 2017; 36(1):62 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) is poorly expressed in the majority of cancers and is often almost absent in metastatic tumors. RKIP inhibits the Raf/MEK/ERK1/2 and the NF-κB pathways. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our recent findings demonstrated that RKIP is overexpressed primarily in its inactive phosphorylated form in MM cell lines and patient-derived tumor tissues. The underlying mechanism of RKIP overexpression in MM, in contrast to other tumors, is not known. We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the co-expression of RKIP and other gene products in both pre-MM and MM. The transcription of several gene products was found to be either commonly overexpressed (i.e., RKIP, Bcl-2, and DR5) or underexpressed (i.e., Bcl-6 and TNFR2) in both pre-MM and MM. Noteworthy, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF-α and underexpression of YY1 versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF-α. Based on the analysis on mRNA levels and reported studies on protein levels of the above various genes, we have constructed various schemes that illustrate the possible cross-talks between RKIP (active/inactive) and the identified gene products that underlie the mechanism of RKIP overexpression in MM. Clearly, such cross-talks would need to be experimentally validated in both MM cell lines and patient-derived tumor tissues. If validated, the differential molecular signatures between pre-MM and MM might lead to a more precise diagnosis/prognosis of the disease and disease stages and will also identify novel molecular therapeutic targets for pre-MM and MM.

Wang SC, Zhou F, Zhou ZY, et al.
Knockdown of PEBP4 suppresses proliferation, migration and invasion of human breast cancer cells.
Biomed Pharmacother. 2017; 90:659-664 [PubMed] Related Publications
Phosphatidylethanolamine-binding protein 4 (PEBP4), a member of the PEBP family, plays a pivotal role in tumor progression. However, the roles of PEBP4 in breast cancer remain unclear. Therefore, in the present study, we investigated the effects of PEBP4 on breast cancer cell proliferation, migration and invasion, and the underlying mechanism was also explored. Our results showed that the expression of PEBP4 was significantly up-regulated in breast cancer cell lines. Knockdown of PEBP4 inhibited breast cancer cell proliferation in vitro and tumor growth in vivo. Furthermore, knockdown of PEBP4 suppressed breast cancer cell migration and invasion with prevented EMT. Mechanistically, knockdown of PEBP4 inhibited breast cancer cell proliferation and migration through the inactivation of PI3K/Akt signaling pathway. In conclusion, the present study demonstrated for the first time that knockdown of PEBP4 inhibited the proliferation, invasion and tumorigenesis in breast cancer cells. Thus, PEBP4 may serve as a potential therapeutic target for the treatment of breast cancer.

Lee S, Wottrich S, Bonavida B
Crosstalks between Raf-kinase inhibitor protein and cancer stem cell transcription factors (Oct4, KLF4, Sox2, Nanog).
Tumour Biol. 2017; 39(4):1010428317692253 [PubMed] Related Publications
Raf-kinase inhibitor protein has been reported to inhibit both the Raf/mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase and nuclear factor kappa-light-chain of activated B cells pathways. It has also been reported in cancers that Raf-kinase inhibitor protein behaves as a metastatic suppressor as well as a chemo-immunosensitizing factor to drug/immune-mediated apoptosis. The majority of cancers exhibit low or no levels of Raf-kinase inhibitor protein. Hence, the activities of Raf-kinase inhibitor protein contrast, in part, to those mediated by several cancer stem cell transcription factors for their roles in resistance and metastasis. In this review, the existence of crosstalks in the signaling pathways between Raf-kinase inhibitor protein and several cancer stem cell transcription factors (Oct4, KLF4, Sox2 and Nanog) was assembled. Oct4 is induced by Lin28, and Raf-kinase inhibitor protein inhibits the microRNA binding protein Lin28. The expression of Raf-kinase inhibitor protein inversely correlates with the expression of Oct4. KLF4 does not interact directly with Raf-kinase inhibitor protein, but rather interacts indirectly via Raf-kinase inhibitor protein's regulation of the Oct4/Sox2/KLF4 complex through the mitogen-activated protein kinase pathway. The mechanism by which Raf-kinase inhibitor protein inhibits Sox2 is via the inhibition of the mitogen-activated protein kinase pathway by Raf-kinase inhibitor protein. Thus, Raf-kinase inhibitor protein's relationship with Sox2 is via its regulation of Oct4. Inhibition of extracellular signal-regulated kinase by Raf-kinase inhibitor protein results in the upregulation of Nanog. The inhibition of Oct4 by Raf-kinase inhibitor protein results in the failure of the heterodimer formation of Oct4 and Sox2 that is necessary to bind to the Nanog promoter for the transcription of Nanog. The findings revealed that there exists a direct correlation between the expression of Raf-kinase inhibitor protein and the expression of each of the above transcription factors. Based on these analyses, we suggest that the expression level of Raf-kinase inhibitor protein may be involved in the regulation of the cancer stem cell phenotype.

Wottrich S, Kaufhold S, Chrysos E, et al.
Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer.
Drug Resist Updat. 2017; 30:28-38 [PubMed] Related Publications
Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post-translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-κB/Snail/YY1, p38/MAPK/RKIP/GSK3β/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1's negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo-immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life.

Du Y, Liu XH, Zhu HC, et al.
MiR-543 Promotes Proliferation and Epithelial-Mesenchymal Transition in Prostate Cancer via Targeting RKIP.
Cell Physiol Biochem. 2017; 41(3):1135-1146 [PubMed] Related Publications
BACKGROUND/AIMS: MicroRNAs (miRNAs, miRs) have emerged as important post-transcriptional regulators in various cancers. miR-543 has been reported to play critical roles in hepatocellular carcinoma and colorectal cancer, however, the role of miR-543 in the pathogenesis of prostate cancer has not been fully understood.
METHODS: Expression of miR-543 and Raf Kinase Inhibitory Protein (RKIP) in clinical prostate cancer specimens, two prostate cancer cell lines, namely LNCAP and C4-2B, were determined. The effects of miR-543 on proliferation and metastasis of tumor cells were also investigated with both in vitro and in vivo studies.
RESULTS: miR-543 was found to be negatively correlated with RKIP expression in clinical tumor samples and was significantly upregulated in metastatic prostate cancer cell line C4-2B compared with parental LNCAP cells. Further studies identified RKIP as a direct target of miR-543. Overexpression of miR-543 downregulated RKIP expression and promoted the proliferation and metastasis of cancer cells, whereas knockdown of miR-543 increased expression of RKIP and suppressed the proliferation and metastasis of cancer cells in vitro and in vivo.
CONCLUSION: Our study demonstrates that miR-543 promotes the proliferation and metastasis of prostate cancer via targeting RKIP.

Tsao DA, Shiau YF, Tseng CS, Chang HR
Expression of Raf kinase inhibitor protein in human hepatoma tissues by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight methods.
Indian J Cancer. 2016 Apr-Jun; 53(2):216-219 [PubMed] Related Publications
PURPOSE: Hepatocellular carcinoma (HCC) is the most common malignant liver tumor. To reduce the mortality and improve the effectiveness of therapy, it is important to search for changes in tumor-specific biomarkers whose function may involve in disease progression and which may be useful as potential therapeutic targets. Materials and Mehtods: In this study, we use two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to observe proteome alterations of 12 tissue pairs isolated from HCC patients: Normal and tumorous tissue. Comparing the tissue types with each other, 40 protein spots corresponding to fifteen differentially expressed between normal and cancer part of HCC patients.
RESULTS: Raf kinase inhibitor protein (RKIP), an inhibitor of Raf-mediated activation of mitogen-activated protein kinase/extracellular signal-regulated kinase, may play an important role in cancer metastasis and cell proliferation and migration of human hepatoma cells. RKIP may be considered as a marker for HCC, because its expression level changes considerably in HCC compared with normal tissue. In addition, we used the methods of Western blotting and real time-polymerase chain reaction to analysis the protein expression and gene expression of RKIP. The result showed RKIP protein and gene expression in tumor part liver tissues of HCC patient is lower than peritumorous non-neoplastic liver tissue of the corresponding HCC samples.
CONCLUSION: These results strongly suggest that RKIP may be considered to be a marker for HCC and RKIP are down-regulated in liver cancer cell.

Bainer R, Frankenberger C, Rabe D, et al.
Gene expression in local stroma reflects breast tumor states and predicts patient outcome.
Sci Rep. 2016; 6:39240 [PubMed] Free Access to Full Article Related Publications
The surrounding microenvironment has been implicated in the progression of breast tumors to metastasis. However, the degree to which metastatic breast tumors locally reprogram stromal cells as they disrupt tissue boundaries is not well understood. We used species-specific RNA sequencing in a mouse xenograft model to determine how the metastasis suppressor RKIP influences transcription in a panel of paired tumor and stroma tissues. We find that gene expression in metastatic breast tumors is pervasively correlated with gene expression in local stroma of both mouse xenografts and human patients. Changes in stromal gene expression elicited by tumors better predicts subtype and patient survival than tumor gene expression, and genes with coordinated expression in both tissues predict metastasis-free survival. These observations support the use of stroma-based strategies for the diagnosis and prognosis of breast cancer.

Ye C, Shen Z, Wang B, et al.
A novel long non-coding RNA lnc-GNAT1-1 is low expressed in colorectal cancer and acts as a tumor suppressor through regulating RKIP-NF-κB-Snail circuit.
J Exp Clin Cancer Res. 2016; 35(1):187 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The role of long non-coding RNAs (lncRNAs) in colorectal cancer (CRC) progression has not fully been elucidated. This study was designed to report the identification of a novel lncRNA, lnc-GNAT1-1, and its functional role in CRC progression.
METHODS: lncRNA expression profile microarray was performed in three paired primary and liver metastatic tissues of CRC, and a novel lncRNA, lnc-GNAT1-1, was identified to be a potential functional lncRNA. Quantitative real-time PCR was used to detect its expression in CRC tissues, cell lines, and patients' plasma, cell fractionation was used to evaluate its subcellular location. lnc-GNAT1-1 was knockdown by siRNA or overexpressed by a lentivirus vector, then in vitro an vivo experiments were performed to evaluate its biological role and the underlying mechanisms in CRC.
RESULTS: Expression of lnc-GNAT1-1 was decreased in liver metastasis than the primary tumor, while the later one is lower than the paired normal mucosa. Decreased lnc-GNAT1-1 expression was associated unfavorable clinicopathological features and a poor prognosis of CRC patients. In multivariate analysis, lnc-GNAT1-1 was proved to be an independent prognostic factor. In plasma, lnc-GNAT1-1 was significant decreased in CRC patients than healthy donors, and with the TNM stages advanced, the plasma lnc-GNAT1-1 level decreased; Receiver operating characteristic curve (ROC curve) showed that plasma lnc-GNAT1-1 had a moderate to well diagnostic efficiency for CRC. In vitro experiments showed that knockdown of lnc-GNAT1-1 could inhibit the aggressive phenotypes of CRC cell lines. In vivo study showed that overexpression of lnc-GNAT1-1 could suppress the liver metastasis of CRC cells. Finally, we explored the underlying mechanism of the role lnc-GNAT1-1 plays in CRC, and found a positive correlation between lnc-GNAT1-1 and Raf kinase inhibitor protein (RKIP) expression both in cells and in patients' tissues. We further found that lnc-GNAT1-1 could regulate the RKIP-NF-κB-Snail circuit in CRC.
CONCLUSIONS: We have demonstrated in this study that a novel lncRNA, lnc-GNAT1-1, is low expressed in colorectal cancer tissues and plasma, and acts as a tumor suppressor through regulating RKIP-NF-κB-Snail circuit.

Cheng XK, Yu GZ, Li XD, Ren XQ
Molecular mechanism of hepatitis B virus (HBV) on suppression of raf kinase inhibitor protein (RKIP) expression.
Oncotarget. 2017; 8(1):1132-1140 [PubMed] Free Access to Full Article Related Publications
Raf kinase inhibitor protein (RKIP) has been shown to be a suppressor of the mitogen-activated protein kinase pathway and is reported to be involved in human malignancy. However, the molecular mechanism of hepatitis B virus (HBV) in regulating RKIP expression is not yet clarified. In this study, we compared RKIP expression in 107 pairs of matched liver cancer and adjacent non-cancerous liver tissues. Among seven HBV-encoded proteins, we found HBV X (HBX) protein could significantly inhibit the expression level of RKIP, indicating that HBV could suppress RKIP expression through regulating HBX. To further elucidate the mechanism, analyses on transcriptional regulation and promoter methylation inhibition were conducted in Huh7 cells. Our results showed that HBX can interact with AP1 protein to inhibit the RKIP transcription. Moreover, we observed that the promoter methylation level of RKIP could be enhanced by HBV. In conclusion, our study revealed that RKIP could act as a molecular marker for HBV-infected liver cancer, but had no tumor-suppressing effect.

Zou Q, Wu H, Fu F, et al.
RKIP suppresses the proliferation and metastasis of breast cancer cell lines through up-regulation of miR-185 targeting HMGA2.
Arch Biochem Biophys. 2016; 610:25-32 [PubMed] 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 anti-metastasis strategy. In this study, we found the expression of RKIP and miR-185 in breast cancer tissues was significantly lower than that of in normal breast tissues. Over-expression of RKIP up-regulated miR-185 expression, inhibited breast cancer cell growth and invasion, and inhibited miR-185 target gene High-mobility group AT-hook 2 (HMGA2). HMGA2 is encoded by HMGA2 gene, which encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. Moreover, RKIP knockdown attenuated the inhibition of breast cancer cell invasion and the expression of HMGA2 by miR-185. Forced HMGA2 overexpression could partly restore the inhibitory effect of miR-185 on breast cancer cell growth and invasion. Our findings newly described RKIP/miR-185 to HMGA2 link and provided a potential mechanism for breast cancer cell growth and invasion. It may illustrate the potential therapeutic utility of signaling pathway signatures.

Li S, Liu T, Mo W, et al.
Prognostic value of phosphorylated Raf kinase inhibitory protein at serine 153 and its predictive effect on the clinical response to radiotherapy in nasopharyngeal carcinoma.
Radiat Oncol. 2016; 11(1):121 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Radiation is an effective treatment against nasopharyngeal carcinoma (NPC). However, radioresistance-induced locoregional recurrence remains as a major cause of treatment failure. Therefore, radiosensitivity indicators prior to treatment should be developed to screen radioresistant patients. Previous studies revealed that RKIP (Raf kinase inhibitor protein) is associated with NPC prognosis and radiosensitivity. However, the relationship of p-Ser153 RKIP (RKIP in a phosphorylated form at residue serine153) expression with the effect of radiation and prognosis of NPC patients is not elucidated. Thus, these clinical implication of the phosphorylated RKIP in NPC has yet to be described.
METHODS: The effect of p-Ser153 RKIP on locoregional relapse-free survival (LRRFS) was first analyzed in a retrospective cohort of NPC patients without distant metastasis at initial diagnosis. They received radical intensity-modulated radiotherapy alone. Of 180 patients were enrolled in the ongoing matched pair study. The patients were re-classified into radioresistant group or radiosensitive group on the basis of the specified criteria. Patients in the two groups were matched in terms of radiosensitivity-related factors. p-Ser153 RKIP was examined by immunohistochemical staining on a NPC tissue microarray before radiotherapy. The relationship between the expression of p-Ser153 RKIP and the effect of radiotherapy was also analyzed.
RESULTS: In this study, a retrospective cohort with 733 cases who received radical radiotherapy alone was established. Using the cohort, we validated that the p-Ser153 RKIP expression observed through immunohistochemical staining in a pretreatment NPC tissue microarray was an independent prognostic factor of LRRFS and OS; we also confirmed that endemic patients with a positive p-Ser153 RKIP expression benefited from irradiation alone in terms of locoregional relapse-free survival. A total of 180 patients were enrolled in a matched pair study. Both groups were well matched in terms of radiosensitivity-related factors. On the basis of the p-Ser153 RKIP expression, we predicted the following data: 80.0 % sensitivity, 73.3 % specificity, 76.7 % accuracy, 75.0 % positive predictive value, and 78.6 % negative predictive value.
CONCLUSIONS: Our results revealed for the first time that positive p-Ser153 RKIP expression was a favorable prognostic factor. It was also positively correlated with the radiosensitivity of NPC. p-Ser153 RKIP could also be used as a biomolecular marker with good availability and authenticity to preliminarily screen NPC-related clinical radiosensitivity.

Alaiya AA, Aljurf M, Shinwari Z, et al.
Protein signatures as potential surrogate biomarkers for stratification and prediction of treatment response in chronic myeloid leukemia patients.
Int J Oncol. 2016; 49(3):913-33 [PubMed] Free Access to Full Article Related Publications
There is unmet need for prediction of treatment response for chronic myeloid leukemia (CML) patients. The present study aims to identify disease-specific/disease-associated protein biomarkers detectable in bone marrow and peripheral blood for objective prediction of individual's best treatment options and prognostic monitoring of CML patients. Bone marrow plasma (BMP) and peripheral blood plasma (PBP) samples from newly-diagnosed chronic-phase CML patients were subjected to expression-proteomics using quantitative two-dimensional gel electrophoresis (2-DE) and label-free liquid chromatography tandem mass spectrometry (LC-MS/MS). Analysis of 2-DE protein fingerprints preceding therapy commencement accurately predicts 13 individuals that achieved major molecular response (MMR) at 6 months from 12 subjects without MMR (No-MMR). Results were independently validated using LC-MS/MS analysis of BMP and PBP from patients that have more than 24 months followed-up. One hundred and sixty-four and 138 proteins with significant differential expression profiles were identified from PBP and BMP, respectively and only 54 proteins overlap between the two datasets. The protein panels also discriminates accurately patients that stay on imatinib treatment from patients ultimately needing alternative treatment. Among the identified proteins are TYRO3, a member of TAM family of receptor tyrosine kinases (RTKs), the S100A8, and MYC and all of which have been implicated in CML. Our findings indicate analyses of a panel of protein signatures is capable of objective prediction of molecular response and therapy choice for CML patients at diagnosis as 'personalized-medicine-model'.

Li W, Dong Y, Zhang B, et al.
PEBP4 silencing inhibits hypoxia-induced epithelial-to-mesenchymal transition in prostate cancer cells.
Biomed Pharmacother. 2016; 81:1-6 [PubMed] Related Publications
Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Phosphatidylethanolamine-binding protein 4 (PEBP4) is a member of the PEBP family and has been reported to be upregulated in various cancer types. The definite function of PEBP4 in regulating the EMT of prostate cancer, however, is still unclear. Here, we examined the functional role of PEBP4 and the underlying molecular mechanisms in hypoxia-induced EMT in prostate cancer cells. Our results showed that PEBP4 mRNA and protein expression was markedly increased in the human prostate cancer tissues and cell lines. Knockdown of PEBP4 significantly inhibited hypoxia-induced migration/invasion and EMT program. Furthermore, knockdown of PEBP4 prevented hypoxia-induced the expression of p-Akt and p-mTOR in prostate cancer cells. Taken together, this study reported here provided evidence that knockdown of PEBP4 inhibited hypoxia-induced EMT in prostate cancer cells. Our study uncovered a novel role for PEBP4 in prostate cancer progression, which might support the potential for PEBP4 targeting in prostate cancer therapy.

Kowalczewska M, Piotrowski J, Jędrzejewski T, Kozak W
Polysaccharide peptides from Coriolus versicolor exert differential immunomodulatory effects on blood lymphocytes and breast cancer cell line MCF-7 in vitro.
Immunol Lett. 2016; 174:37-44 [PubMed] Related Publications
The protein-bound polysaccharides (PBP), isolated from Coriolus versicolor (CV) fungus, are considered as natural compounds with potential therapeutic applications. The immunopotentiating and antitumor activity of polysaccharopeptides has been previously examined, however similar findings could not be achieved. The source of PBP, variations in extraction process as well as environmental factors seems to affect the biological properties of these active CV components. Since further analysis are needed to draw more definite conclusion, the present study aimed to investigate the immunomodulatory properties of the PBP extract, isolated from commercially available capsules of C. versicolor. Our results revealed that the effect mediated by PBP extract depends on the target cells. We reported that the polysaccharopeptides induced a significant decrease in breast cancer MCF-7 cells growth, which was TNF-α-dependent phenomenon. Interestingly, the level of two others cytokines, IL-1β and IL-6 was not affected. On the other hand, in this study we noticed that protein-bound polysaccharides extracted from CV significantly augmented the proliferative response of blood lymphocytes in a time-dependent manner, which was associated with IL-6 and IL-1β mRNA upregulation. Moreover we found that the cells response to PBP stimuli might be inversely related to its concentration.

Lee TY, Liu CL, Chang YC, et al.
Increased chemoresistance via Snail-Raf kinase inhibitor protein signaling in colorectal cancer in response to a nicotine derivative.
Oncotarget. 2016; 7(17):23512-20 [PubMed] Free Access to Full Article Related Publications
A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.

Genrich G, Kruppa M, Lenk L, et al.
The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1.
BMC Cancer. 2016; 16:155 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nuclear factor E2 related factor-2 (Nrf2) is an oxidative stress inducible transcription factor being essential in regulating cell homeostasis. Thus, acute induction of Nrf2 in epithelial cells exposed to inflammation confers protection from oxidative cell damage and mutagenesis supporting an anti-tumorigenic role for Nrf2. However, pancreatic ductal adenocarcinoma (PDAC) is characterized by persistent Nrf2 activity conferring therapy resistance which points to a pro-tumorigenic role of Nrf2. A similar dichotomous role in tumorigenesis is described for the Transforming Growth Factor-beta 1 (TGF-β1). The present study therefore aimed at elucidating whether the switch of Nrf2 function towards a tumor promoting one relates to the modulation of TGF-β1 induced cell responses and whether this might occur early in PDAC development.
METHODS: In situ analysis comprised immunohistochemical stainings of activated (phosphorylated) Nrf2 and Ki67 in pancreatic tissues containing normal ducts and pancreatic intraepithelial neoplasia (PanINs). In vitro, Nrf2 levels in benign (H6c7-pBp), premalignant (H6c7-kras) and malignant (Colo357) pancreatic ductal epithelial cells were modulated by Nrf2 specific siRNA or Nrf2 overexpression. Then, the effect of Nrf2 alone and in combination with TGF-β1 on cell growth and survival was investigated by cell counting, Ki67 staining and apoptosis assays. The underlying cell signaling was investigated by western blotting. Statistical analysis was performed by Shapiro-Wilk test for normal distribution. Parametric data were analyzed by one-way ANOVA, while non-parametric data were analyzed by Kruskal-Wallis one-way ANOVA on ranks.
RESULTS: Significantly elevated expression of activated Nrf2 and Ki67 could be detected in PanINs but not in normal pancreatic ductal epithelium. While the effect of Nrf2 on basal cell growth of H6c7-pBp, H6c7-kras and Colo357 cells was minor, it clearly attenuated the growth inhibiting effects of TGF-β1 in all cell lines. This enhanced Nrf2-mediated cell survival was predominantly based on an enhanced proliferative activity. Accordingly, expression of p21 expression along with expression of phospho-p38 and phospho-Smad3 was diminished whereas Erk-phosphorylation was enhanced under these conditions.
CONCLUSIONS: Overall, our data demonstrate that Nrf2 being elevated in early precursor lesions counteracts the growth inhibiting function of TGF-β1 already in benign and premalignant pancreatic ductal epithelial cells. This could represent one fundamental mechanism underlying the functional switch of both- TGF-β1 and Nrf2 - which may manifest already in early stages of PDAC development.

Kim GE, Kim NI, Lee JS, et al.
Reduced RKIP Expression is Associated With Breast Neoplastic Progression and is Correlated With Poor Outcomes and Aberrant Methylation in Breast Carcinoma.
Appl Immunohistochem Mol Morphol. 2017; 25(7):467-474 [PubMed] Related Publications
Raf kinase inhibitor protein's (RKIP) downregulation can predict poor outcome in patients with various types of malignancy. In this study, we aimed to assess the potential involvement of RKIP in breast carcinogenesis and to evaluate its association with outcome variables and aberrant promoter methylation in breast carcinoma (BC). Tissue microarray sections were immunostained for RKIP in 26 normal breasts, 25 usual ductal hyperplasia, 76 ductal carcinoma in situ, and 198 BC specimens. The methylation status of RKIP was also determined in BC. In addition, the mRNA and protein level of RKIP was analyzed in 8 pairs of BC tissues and surrounding normal tissues by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. RKIP mRNA and protein expression was significantly downregulated in BC tissues compared with the surrounding normal tissues (P<0.05 and P<0.01, respectively). Reduced RKIP expression seemed to increase progressively from normal breast to BC (P<0.001). Reduced RKIP expression was significantly associated with metastatic relapse (P<0.001) and was identified as an independent adverse prognostic indicator for disease-free survival (P=0.003). Reduced RKIP expression in BC was significantly correlated with its aberrant promoter methylation (P<0.05). In conclusion, downregulation of RKIP plays an important role in the breast neoplastic progression and correlates with poor prognosis in patients with BC. Aberrant RKIP methylation is one of the mechanisms that lead to downregulation of RKIP in BC.

Lei X, Chang L, Ye W, et al.
Raf kinase inhibitor protein (RKIP) inhibits the cell migration and invasion in human glioma cell lines in vitro.
Int J Clin Exp Pathol. 2015; 8(11):14214-20 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To investigate the effects and the potential mechanisms of RKIP on cell migration, invasion and proliferation in human glioma cell lines in vitro.
METHODS: The RKIP over-expressing and RKIP knockdown human U87 glioma cells were used to reveal the effects of RKIP on human glioma cells migration, invasion and proliferation. After the recombinant plasmid pcDNA3.0-RKIP or RKIP-shRNA was transfected into the cell lines U87 by the means of liposome assay, the cells migration, invasion and proliferation were detected by wound healing, Transwell and MTT assay. Then, the levels of RKIP, MMP-3, MMP-9 and HMGA2 mRNA transcription were measured by means of RT-qPCR and levels of proteins expressions were determined using Western blot.
RESULTS: The results of MTT assay suggested that the PKIP have little inhibitive effects on glioma cells proliferation (P>0.05). The present paper showed that the migration distances in the group of RKIP-shRNA were markedly increased compared to the pcDNA3.0-RKIP and control. Similarly, the results showed that the numbers of invasion cells in RKIP-shRNA were remarkably increased than the pcDNA3.0-RKIP group and control group. Western blot and RT-qPCR suggested that over-expressions of RKIP lessened the MMP-2, MMP-9 and HMGA2 expression, however, turning down the RKIP expression showed the inverse effects.
CONCLUSION: RKIP inhibits the cells migrations and invasions. Meanwhile, RKIP might inhibit the glioma cells through inhibiting MMPs and HMAG2 expression. Therefore, we demonstrated that RKIP is an underlying target for the treatment of glioma.

Noh HS, Hah YS, Ha JH, et al.
Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity.
Oncotarget. 2016; 7(4):4632-46 [PubMed] Free Access to Full Article Related Publications
Raf kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, has been implicated as a suppressor of metastasis and a prognostic marker in cancers. However, how RKIP acts as a suppressor during metastasis is not fully understood. Here, we show that RKIP activity in cervical and stomach cancer is inversely correlated with endogenous levels of the Notch1 intracellular domain (NICD), which stimulates the epithelial to mesenchymal transition (EMT) and metastasis. The levels of RKIP were significantly decreased in tumor tissues compared to normal tissues, whereas NICD levels were increased. Overexpression of RKIP in several cell lines resulted in a dramatic decrease of NICD and subsequent inhibition of several mesenchymal markers, such as vimentin, N-cadherin, and Snail. In contrast, knockdown of RKIP exhibited opposite results both in vitro and in vivo using mouse models. Nevertheless, knockdown of Notch1 in cancer cells had no effect on the expression of RKIP, suggesting that RKIP is likely an upstream regulator of the Notch1 pathway. We also found that RKIP directly interacts with Notch1 but has no influence on the intracellular level of the γ-secretase complex that is necessary for Notch1 activation. These data suggest that RKIP plays a distinct role in activation of Notch1 during EMT and metastasis, providing a new target for cancer treatment.

Wei H, Gao HQ, Li HB, et al.
Correlation among RKIP expression, NF-κB p65 levels, and T-lymphocyte subsets in gastric cardia adenocarcinoma.
Genet Mol Res. 2015; 14(4):16491-6 [PubMed] Related Publications
The aim of this study was to characterize variations in Raf kinase inhibitor protein (RKIP) expression and related signaling molecules in gastric cardia adenocarcinoma. Cancerous and precancerous tissues were collected from patients with gastric cardia adenocarcinoma and normal tissue was collected from healthy controls. RKIP expression was detected in these tissues and the serum levels of NF-κB p65 and T-lymphocyte subsets were measured. Positive RKIP expression was higher in gastric cardia adenocarcinoma tissues than in precancerous tissues. The serum level of total NF-κB p65 was higher in patients with gastric cardia adenocarcinoma than in healthy controls. Levels of NF-κB p65 did not correlate with positive and negative expression of RKIP, but were higher in patients with lymph node metastasis than in those without it. The cellular immune function of the gastric cardia adenocarcinoma group was lower than in normal controls, particularly in cases with negative RKIP expression. RKIP is downregulated in gastric cardia adenocarcinoma tissues, which is related to the occurrence, progression, invasion, and metastasis of tumors. The possible mechanism for this may be the inhibition of NF-κB activity and cellular immune function, which allows for the escape of tumor cells from immune surveillance.

Farooqi AA, Li Y, Sarkar FH
The biological complexity of RKIP signaling in human cancers.
Exp Mol Med. 2015; 47:e185 [PubMed] Free Access to Full Article Related Publications
The Raf kinase inhibitory protein (RKIP) has been demonstrated to modulate different intracellular signaling pathways in cancers. Studies have shown that RKIP is frequently downregulated in cancers; therefore, attempts have been made to upregulate the expression of RKIP using natural and synthetic agents for the treatment of human malignancies. Moreover, various regulators such as specific proteins and microRNAs (miRNAs) that are involved in the regulation of RKIP expression have also been identified. RKIP mechanistically modulates the apoptotic regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling. Because of its critical role in human cancers, RKIP has drawn much research attention, and our understanding is expanding rapidly. Here, we summarize some of the biological complexities of RKIP regulation. However, we restrict our discussion to selected tumors by focusing on TRAIL, miRNAs and natural agents. Emerging evidence suggests a role for natural agents in RKIP regulation in cancer cells; therefore, naturally occurring agents may serve as cancer-targeting agents for cancer treatment. Although the literature suggests some advancement in our knowledge of RKIP biology, it is incomplete with regard to its preclinical and clinical efficacy; thus, further research is warranted. Furthermore, the mechanism by which chemotherapeutic drugs and novel compounds modulate RKIP and how nanotechnologically delivered RKIP can be therapeutically exploited remain to be determined.

Rapozzi V, Della Pietra E, Bonavida B
Dual roles of nitric oxide in the regulation of tumor cell response and resistance to photodynamic therapy.
Redox Biol. 2015; 6:311-317 [PubMed] Free Access to Full Article Related Publications
Photodynamic therapy (PDT) against cancer has gained attention due to the successful outcome in some cancers, particularly those on the skin. However, there have been limitations to PDT applications in deep cancers and, occasionally, PDT treatment resulted in tumor recurrence. A better understanding of the underlying molecular mechanisms of PDT-induced cytotoxicity and cytoprotection should facilitate the development of better approaches to inhibit the cytoprotective effects and also augment PDT-mediated cytotoxicity. PDT treatment results in the induction of iNOS/NO in both the tumor and the microenvironment. The role of NO in cytotoxicity and cytoprotection was examined. The findings revealed that NO mediates its effects by interfering with a dysregulated pro-survival/anti-apoptotic NF-κB/Snail/YY1/RKIP loop which is often expressed in cancer cells. The cytoprotective effect of PDT-induced NO was the result of low levels of NO that activates the pro-survival/anti-apoptotic NF-κB, Snail, and YY1 and inhibits the anti-survival/pro-apoptotic and metastasis suppressor RKIP. In contrast, PDT-induced high levels of NO result in the inhibition of NF-kB, Snail, and YY1 and the induction of RKIP, all of which result in significant anti-tumor cytotoxicity. The direct role of PDT-induced NO effects was corroborated by the use of the NO inhibitor, l-NAME, which reversed the PDT-mediated cytotoxic and cytoprotective effects. In addition, the combination of the NO donor, DETANONOate, and PDT potentiated the PDT-mediated cytotoxic effects. These findings revealed a new mechanism of PDT-induced NO effects and suggested the potential therapeutic application of the combination of NO donors/iNOS inducers and PDT in the treatment of various cancers. In addition, the study suggested that the combination of PDT with subtoxic cytotoxic drugs will result in significant synergy since NO has been shown to be a significant chemo-immunosensitizing agent to apoptosis.

Datar I, Feng J, Qiu X, et al.
RKIP Inhibits Local Breast Cancer Invasion by Antagonizing the Transcriptional Activation of MMP13.
PLoS One. 2015; 10(8):e0134494 [PubMed] Free Access to Full Article Related Publications
Raf Kinase Inhibitory Protein or RKIP was initially identified as a Raf-1 binding protein using the yeast 2-hybrid screen. RKIP inhibits the activation phosphorylation of MEK by Raf-1 by competitively inhibiting the binding of MEK to Raf-1 and thus exerting an inhibitory effect on the Raf-MEK-Erk pathway. RKIP has been identified as a metastasis suppressor gene. Expression of RKIP is low in cancer metastases. Although primary tumor growth remains unaffected, re- expression of RKIP inhibits cancer metastasis. Mechanistically, RKIP constrains metastasis by inhibiting angiogenesis, local invasion, intravasation, and colonization. The molecular mechanism of how RKIP inhibits these individual steps remains undefined. In our present study, using an unbiased PCR based screening and by analyzing DNA microarray expression datasets we observe that the expression of multiple metalloproteases (MMPs) including MMP1, MMP3, MMP10 and MMP13 are negatively correlated with RKIP expression in breast cancer cell lines and clinical samples. Since expression of MMPs by cancer cells is important for cancer metastasis, we hypothesize that RKIP may mediate suppression of breast cancer metastasis by inhibiting multiple MMPs. We show that the expression signature of RKIP and MMPs is better at predicting high metastatic risk than the individual gene. Using a combination of loss- and gain-of-function approaches, we find that MMP13 is the cause of RKIP-mediated inhibition of local cancer invasion. Interestingly expression of MMP13 alone is not sufficient to reverse the inhibition of breast cancer cell metastasis to the lung due to the expression of RKIP. We find that RKIP negatively regulates MMP13 through the Erk2 signaling pathway and the repression of MMP13 by RKIP is transcription factor AP-1 independent. Together, our findings indicate that RKIP inhibits cancer cell invasion, in part, via MMP13 inhibition. These data also implicate RKIP in the regulation of MMP transcription, suggesting a potential mechanism by which RKIP inhibits tumor progression and metastasis.

Frankenberger C, Rabe D, Bainer R, et al.
Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.
Cancer Res. 2015; 75(19):4063-73 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP(+) tumors, relative to metastatic RKIP(-) tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP(+) tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics.

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