The role of ECE1 variants in cognitive ability in old age and Alzheimer's disease risk

The ß-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aß-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE e4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE e4 allele (P = 0.00036, ß = -0.19). Both results showed a trend towards significance after permutation (0.05 <P <0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z <0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE e4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.

PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells

Background: In recent years, much progress has been made in the treatment of multiple myeloma. However, a major limitation of existing chemotherapeutic drugs is the eventual emergence of resistance; hence, the development of novel agents with new mechanisms of action is pertinent. Here, we describe the activity and mechanism of action of pyrrolo-1,5-benzoxazepine-15 (PBOX-15), a novel microtubule-targeting agent, in multiple myeloma cells.

Methods: The anti-myeloma activity of PBOX-15 was assessed using NCI-H929, KMS11, RPMI8226, and U266 cell lines, and primary myeloma cells. Cell cycle distribution, apoptosis, cytochrome c release, and mitochondrial inner membrane depolarisation were analysed by flow cytometry; gene expression analysis was carried out using TaqMan Low Density Arrays; and expression of caspase-8 and Bcl-2 family of proteins was assessed by western blot analysis.

Results: Pyrrolo-1,5-benzoxazepine-15 induced apoptosis in ex vivo myeloma cells and in myeloma cell lines. Death receptor genes were upregulated in both NCI-H929 and U266 cell lines, which displayed the highest and lowest apoptotic responses, respectively, following treatment with PBOX-15. The largest increase was detected for the death receptor 5 (DR5) gene, and cotreatment of both cell lines with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the DR5 ligand, potentiated the apoptotic response. In NCI-H929 cells, PBOX-15-induced apoptosis was shown to be caspase-8 dependent, with independent activation of extrinsic and intrinsic apoptotic pathways. A caspase-8-dependent decrease in expression of Bim(EL) preceded downregulation of other Bcl-2 proteins (Bid, Bcl-2, Mcl-1) in PBOX-15-treated NCI-H929 cells.

Conclusion: PBOX-15 induces apoptosis and potentiates TRAIL-induced cell death in multiple myeloma cells. Thus, PBOX-15 represents a promising agent, with a distinct mechanism of action, for the treatment of this malignancy. British Journal of Cancer (2011) 104, 281-289. doi: 10.1038/sj.bjc.6606035 www.bjcancer.com Published online 21 December 2010 (C) 2011 Cancer Research UK

MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma

Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA (siRNA)-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs (miRNAs) in human OS cells compared to mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting miRNA in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, while 3UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3 mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel RUNX2-p53-miR34 network controls cell growth of osseous cells and is compromised in OS.

Electron-Impact Excitation Collision Strengths and Theoretical Line Intensities for Fine-Structure Transitions in S III

We present Maxwellian-averaged effective collision strengths for the electron-impact excitation of S III over a wide range of electron temperatures of astrophysical importance, log Te (K) = 3.0-6.0. The calculation incorporates 53 fine-structure levels arising from the six configurations—3s 23p 2, 3s3p 3, 3s 23p3d, 3s 23p4s, 3s 23p4p, and 3s 23p4d—giving rise to 1378 individual lines and is undertaken using the recently developed RMATRX II plus FINE95 suite of codes. A detailed comparison is made with a previous R-matrix calculation and significant differences are found for some transitions. The atomic data are subsequently incorporated into the modeling code CLOUDY to generate line intensities for a range of plasma parameters, with emphasis on allowed ultraviolet extreme-ultraviolet emission lines detected from the Io plasma torus. Electron density-sensitive line ratios are calculated with the present atomic data and compared with those from CHIANTI v7.1, as well as with Io plasma torus spectra obtained by Far-Ultraviolet Spectroscopic Explorer and Extreme-Ultraviolet Explorer. The present line intensities are found to agree well with the observational results and provide a noticeable improvement on the values predicted by CHIANTI.

Development and characterization of self-assembling nanoparticles using a bio-inspired amphipathic peptide for gene delivery

The design of a non-viral gene delivery vehicle capable of delivering and releasing a functional nucleic acid cargo intracellularly remains a formidable challenge. For systemic gene therapy to be successful a delivery vehicle is required that protects the nucleic acid cargo from enzymatic degradation, extravasates from the vasculature, traverses the cell membrane, disrupts the endosomal vesicles and unloads the cargo at its destination site, namely the nucleus for the purposes of gene delivery. This manuscript reports the extensive investigation of a novel amphipathic peptide composed of repeating RALA units capable of overcoming the biological barriers to gene delivery both in vitro and in vivo. Our data demonstrates the spontaneous self-assembly of cationic DNA-loaded nanoparticles when the peptide is complexed with pDNA. Nanoparticles were < 100 nm, were stable in the presence of serum and were fusogenic in nature, with increased peptide α-helicity at a lower pH. Nanoparticles proved to be non-cytotoxic, readily traversed the plasma membrane of both cancer and fibroblast cell lines and elicited reporter-gene expression following intravenous delivery in vivo. The results of this study indicate that RALA presents an exciting delivery platform for the systemic delivery of nucleic acid therapeutics.

Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study

Background: Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population based cohort of lung cancer patients.
Methods: Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by statin use before and after diagnosis and to adjust these HRs for potential confounders.
Results: In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR=0.89, 95% CI 0.78, 1.02; P=0.09). Associations were more marked after 12 prescriptions (adjusted HR=0.81, 95% CI 0.67, 0.98; P=0.03) and when lipophilic statins were investigated (adjusted HR=0.81, 95% CI 0.70, 0.94; P=0.01) but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.83, 0.93; P<0.001).
Conclusions: There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality.
 Impact: These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients.

Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population

OBJECTIVES: Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.

METHODS: SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor-compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.

RESULTS: High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.

CONCLUSION: Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.

Particle-in-cell simulation study of the interaction between a relativistically moving leptonic micro-cloud and ambient electrons

Context. The jets of compact accreting objects are composed of electrons and a mixture of positrons and ions. These outflows impinge on the interstellar or intergalactic medium and both plasmas interact via collisionless processes. Filamentation (beam-Weibel) instabilities give rise to the growth of strong electromagnetic fields. These fields thermalize the interpenetrating plasmas. 

Aims. Hitherto, the effects imposed by a spatial non-uniformity on filamentation instabilities have remained unexplored. We examine the interaction between spatially uniform background electrons and a minuscule cloud of electrons and positrons. The cloud size is comparable to that created in recent laboratory experiments and such clouds may exist close to internal and external shocks of leptonic jets. The purpose of our study is to determine the prevalent instabilities, their ability to generate electromagnetic fields and the mechanism, by which the lepton micro-cloud transfers energy to the background plasma. 

Methods. A square micro-cloud of equally dense electrons and positrons impinges in our particle-in-cell (PIC) simulation on a spatially uniform plasma at rest. The latter consists of electrons with a temperature of 1 keV and immobile ions. The initially charge- and current neutral micro-cloud has a temperature of 100 keV and a side length of 2.5 plasma skin depths of the micro-cloud. The side length is given in the reference frame of the background plasma. The mean speed of the micro-cloud corresponds to a relativistic factor of 15, which is relevant for laboratory experiments and for relativistic astrophysical outflows. The spatial distributions of the leptons and of the electromagnetic fields are examined at several times. 

Results. A filamentation instability develops between the magnetic field carried by the micro-cloud and the background electrons. The electromagnetic fields, which grow from noise levels, redistribute the electrons and positrons within the cloud, which boosts the peak magnetic field amplitude. The current density and the moduli of the electromagnetic fields grow aperiodically in time and steadily along the direction that is anti-parallel to the cloud's velocity vector. The micro-cloud remains conjoined during the simulation. The instability induces an electrostatic wakefield in the background plasma. 

Conclusions. Relativistic clouds of leptons can generate and amplify magnetic fields even if they have a microscopic size, which implies that the underlying processes can be studied in the laboratory. The interaction of the localized magnetic field and high-energy leptons will give rise to synchrotron jitter radiation. The wakefield in the background plasma dissipates the kinetic energy of the lepton cloud. Even the fastest lepton micro-clouds can be slowed down by this collisionless mechanism. Moderately fast charge- and current neutralized lepton micro-clouds will deposit their energy close to relativistic shocks and hence they do not constitute an energy loss mechanism for the shock.

Late-time spectral line formation in Type IIb supernovae, with application to SN 1993J, SN 2008ax, and SN 2011dh

We investigate line formation processes in Type IIb supernovae (SNe) from 100 to 500 days post-explosion using spectral synthesis calculations. The modelling identifies the nuclear burning layers and physical mechanisms that produce the major emission lines, and the diagnostic potential of these. We compare the model calculations with data on the three best observed Type IIb SNe to-date - SN 1993J, SN 2008ax, and SN 2011dh. Oxygen nucleosynthesis depends sensitively on the main-sequence mass of the star and modelling of the [O I] lambda lambda 6300, 6364 lines constrains the progenitors of these three SNe to the M-ZAMS = 12-16 M-circle dot range (ejected oxygen masses 0.3-0.9 M-circle dot), with SN 2011dh towards the lower end and SN 1993J towards the upper end of the range. The high ejecta masses from M-ZAMS greater than or similar to 17 M-circle dot progenitors give rise to brighter nebular phase emission lines than observed. Nucleosynthesis analysis thus supports a scenario of low-to-moderate mass progenitors for Type IIb SNe, and by implication an origin in binary systems. We demonstrate how oxygen and magnesium recombination lines may be combined to diagnose the magnesium mass in the SN ejecta. For SN 2011dh, a magnesium mass of 0.02-0.14 M-circle dot is derived, which gives a Mg/O production ratio consistent with the solar value. Nitrogen left in the He envelope from CNO burning gives strong [N II] lambda lambda 6548, 6583 emission lines that dominate over Ha emission in our models. The hydrogen envelopes of Type IIb SNe are too small and dilute to produce any noticeable H alpha emission or absorption after similar to 150 days, and nebular phase emission seen around 6550 angstrom is in many cases likely caused by [N II] lambda lambda 6548, 6583. Finally, the influence of radiative transport on the emergent line profiles is investigated. Significant line blocking in the metal core remains for several hundred days, which affects the emergent spectrum. These radiative transfer effects lead to early-time blueshifts of the emission line peaks, which gradually disappear as the optical depths decrease with time. The modelled evolution of this effect matches the observed evolution in SN 2011dh.

The host galaxy and late-time evolution of the superluminous supernova PTF12dam

Superluminous supernovae (SLSNe) of Type Ic have a tendency to occur in faint host galaxies which are likely to have low mass and low metallicity. PTF12dam is one of the closest and best-studied superluminous explosions that has a broad and slowly fading light curve similar to SN 2007bi. Here we present new photometry and spectroscopy for PTF12dam from 200-500 d (rest frame) after peak and a detailed analysis of the host galaxy (SDSS J142446.21+461348.6 at z = 0.107). Using deep templates and image subtraction we show that the light curve can be fit with a magnetar model if escape of high-energy gamma rays is taken into account. The full bolometric light curve from -53 to +399 d (with respect to peak) cannot be fit satisfactorily with the pair-instability models. An alternative model of interaction with a dense circumstellar material (CSM) produces a good fit to the data although this requires a very large mass (˜13 M⊙) of hydrogen-free CSM. The host galaxy is a compact dwarf (physical size ˜1.9 kpc) and with Mg = -19.33 ± 0.10, it is the brightest nearby SLSN Ic host discovered so far. The host is a low-mass system (2.8 × 108 M⊙) with a star formation rate (5.0 M⊙ yr-1), which implies a very high specific star formation rate (17.9 Gyr-1). The remarkably strong nebular emission provide detections of the [O III] λ4363 and [O II] λλ7320, 7330auroral lines and an accurate oxygen abundance of 12 + log (O/H) = 8.05 ± 0.09. We show here that they are at the extreme end of the metallicity distribution of dwarf galaxies and propose that low metallicity is a requirement to produce these rare and peculiar SNe.

IGFBP7 promoter methylation and gene expression analysis in prostate cancer

PURPOSE: IGFBP7 belongs to a family of insulin-like growth factor-1 regulatory binding proteins. IGFBP7 hypermethylation is associated with its down-regulation in various carcinomas. In prostate cancer IGFBP7 down-regulation has been widely reported but to our knowledge the mechanisms behind this event are unknown. We performed a denaturing high performance liquid chromatography screening and validation strategy to profile the methylation status of IGFBP7 in prostate cancer.

MATERIALS AND METHODS: We combined denaturing high performance liquid chromatography and bisulfite sequencing to examine IGFBP7 methylation in a panel of prostate cancer cell lines. Quantitative methylation specific polymerase chain reaction was used to determine methylation levels in prostate tissue specimens of primary prostate cancer, histologically benign prostate adjacent to tumor, high grade prostatic intraepithelial neoplasia and benign prostatic hyperplasia. IGFBP7 gene expression was measured by quantitative methylation specific polymerase chain reaction in cell lines and tissue specimens.

RESULTS: IGFBP7 was methylated in the 4 prostate cancer cell lines DU145, LNCaP, PC-3 and 22RV1. Quantitative methylation specific polymerase chain reaction analysis revealed that promoter methylation was associated with decreased IGFBP7 expression. Quantitative methylation specific polymerase chain reaction showed that IGFBP7 methylation was more frequently detected in prostate cancer (60% (31/52)) and high grade prostatic intraepithelial neoplasia (40% (6/15)) samples compared to histologically benign prostate adjacent to tumor (10%) and benign prostatic hyperplasia (0%) samples.

CONCLUSIONS: To our knowledge this is the first report of aberrant IGFBP7 promoter hypermethylation and concurrent IGFBP7 gene silencing in prostate cancer cell lines. Results demonstrate that CpG methylation of IGFBP7 may represent a novel biomarker of prostate cancer and pre-invasive neoplasms. Thus, future examination of IGFBP7 methylation and expression in a larger patient cohort, including bodily fluids, is justified to further evaluate its role in a diagnostic and prognostic setting.

In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer

BACKGROUND: Aberrant DNA methylation has been implicated as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many cellular processes including apoptosis. Limited data is available on the methylation profile of apoptotic genes in prostate cancer (CaP). The aim of this study was to profile methylation of apoptotic-related genes in CaP using denaturing high performance liquid chromatography (DHPLC).

METHODS: Based on an in silico selection process, 13 genes were screened for methylation in CaP cell lines using DHPLC. Quantitative methylation specific PCR was employed to determine methylation levels in prostate tissue specimens (n = 135), representing tumor, histologically benign prostate, high-grade prostatic intraepithelial neoplasia and benign prostatic hyperplasia. Gene expression was measured by QRT-PCR in cell lines and tissue specimens.

RESULTS: The promoters of BIK, BNIP3, cFLIP, TMS1, DCR1, DCR2, and CDKN2A appeared fully or partially methylated in a number of malignant cell lines. This is the first report of aberrant methylation of BIK, BNIP3, and cFLIP in CaP. Quantitative methylation analysis in prostate tissues identified 5 genes (BNIP3, CDKN2A, DCR1, DCR2 and TMS1) which were frequently methylated in tumors but were unmethylated in 100% of benign tissues. Furthermore, 69% of tumors were methylated in at least one of the five-gene panel. In the case of all genes, except BNIP3, promoter hypermethylation was associated with concurrent downregulation of gene expression.

CONCLUSION: Future examination of this "CaP apoptotic methylation signature" in a larger cohort of patients is justified to further evaluate its value as a diagnostic and prognostic marker.

Recognition of O6MeG lesions by MGMT and mismatch repair proficiency may be a prerequisite for low-dose radiation hypersensitivity

Low-dose hyper-radiosensitivity (HRS) is the phenomenon whereby cells exposed to radiation doses of less than approximately 0.5 Gy exhibit increased cell killing relative to that predicted from back-extrapolating high-dose survival data using a linear-quadratic model. While the exact mechanism remains to be elucidated, the involvement of several molecular repair pathways has been documented. These processes in turn are also associated with the response of cells to O6-methylguanine (O6MeG) lesions. We propose a model in which the level of low-dose cell killing is determined by the efficiency of both pre-replicative repair by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) and post-replicative repair by the DNA mismatch repair (MMR) system. We therefore hypothesized that the response of cells to low doses of radiation is dependent on the expression status of MGMT and MMR proteins. MMR (MSH2, MSH6, MLH1, PMS1, PMS2) and MGMT protein expression signatures were determined in a panel of normal (PWR1E, RWPE1) and malignant (22RV1, DU145, PC3) prostate cell lines and correlated with clonogenic survival and cell cycle analysis. PC3 and RWPE1 cells (HRS positive) were associated with MGMT and MMR proficiency, whereas HRS negative cell lines lacked expression of at least one (MGMT or MMR) protein. MGMT inactivation had no significant effect on cell survival. These results indicate a possible role for MMR-dependent processing of damage produced by low doses of radiation.

Impact of fractionation on out-of-field survival and DNA damage responses following exposure to intensity modulated radiation fields

To limit toxicity to normal tissues adjacent to the target tumour volume, radiotherapy is delivered using fractionated regimes whereby the total prescribed dose is given as a series of sequential smaller doses separated by specific time intervals. The impact of fractionation on out-of-field survival and DNA damage responses was determined in AGO-1522 primary human fibroblasts and MCF-7 breast tumour cells using uniform and modulated exposures delivered using a 225 kVp x-ray source. Responses to fractionated schedules (two equal fractions delivered with time intervals from 4 h to 48 h) were compared to those following acute exposures. Cell survival and DNA damage repair measurements indicate that cellular responses to fractionated non-uniform exposures differ from those seen in uniform exposures for the investigated cell lines. Specifically, there is a consistent lack of repair observed in the out-of-field populations during intervals between fractions, confirming the importance of cell signalling to out-of-field responses in a fractionated radiation schedule, and this needs to be confirmed for a wider range of cell lines and conditions.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.

RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.

CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230-42. ©2015 AACR.