bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-708 Induces Apoptosis and Suppresses Tumorigenicity in Renal Cancer Cells
Authors: Saini Sharanjot , Yamamura Soichiro , Majid Shahana , Shahryari Varahram , Hirata Hiroshi , Tanaka Yuichiro , Dahiya Rajvir 
Published: August 2011

AbstractCancer pathogenesis is restricted by stresses that compromise cell division and survival. In this study, we identify miR-708, a little studied member of a set of microRNAs that have been implicated in stress control, as an important tumor suppressor in renal cell carcinoma (RCC). miR-708 expression was attenuated widely in human RCC specimens. Restoration of miR-708 expression in RCC cell lines decreased cell growth, clonability, invasion, and migration and elicited a dramatic increase in apoptosis. Moreover, intratumoral delivery of miR-708 was sufficient to trigger in vivo regression of established tumors in murine xenograft models of human RCC. Investigation of the targets of miR-708 identified the inhibitor of apoptosis protein survivin as important. siRNA-mediated knockdown of survivin partially phenocopied miR-708 overexpression suggesting that the proapoptotic role of miR-708 may be mediated primarily through survivin regulation. Additionally, we identified the E-cadherin regulators ZEB2 and BMI1 as likely miR-708 targets. Taken together, our findings define a major tumor suppressive role for miR-708, which may offer an attractive new target for prognostic and therapeutic intervention in RCC. Cancer Res; 71(19); 6208–19. ©2011 AACR.
Haploinsufficiency in the Prometastasis Kiss1 Receptor Gpr54 Delays Breast Tumor Initiation, Progression, and Lung Metastasis
Authors: Cho Sung-Gook , Wang Ying , Rodriguez Melissa , Tan Kunrong , Zhang Wenzheng , Luo Jian , Li Dali , Liu Mingyao 
Published: August 2011

Abstract
Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus–polyoma virus middle T antigen (MMTV-PyMT)–induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r+/+ and PyMT/Kiss1r+/− mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway. Cancer Res; 71(20); 6535–46. ©2011 AACR.
Early Detection of Tumor Cells by Innate Immune Cells Leads to Treg Recruitment through CCL22 Production by Tumor Cells
Authors: Faget Julien , Biota Cathy , Bachelot Thomas , Gobert Michael , Treilleux Isabelle , Goutagny Nadège , Durand Isabelle , Léon-Goddard Sophie , Blay Jean Yves , Caux Christophe , Ménétrier-Caux Christine 
Published: August 2011

AbstractIn breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (Treg) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45+ infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ–producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of Treg. As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits Treg to evade this early antitumor immune response. Cancer Res; 71(19); 6143–52. ©2011 AACR.
Oncogene AEG-1 Promotes Glioma-Induced Neurodegeneration by Increasing Glutamate Excitotoxicity
Authors: Lee Seok-Geun , Kim Keetae , Kegelman Timothy P. , Dash Rupesh , Das Swadesh K. , Choi Jung Kyoung , Emdad Luni , Howlett Eric L. , Jeon Hyun Yong , Su Zhao Zhong , Yoo Byoung Kwon , Sarkar Devanand , Kim Sung-Hoon , Kang Dong-Chul , Fisher Paul B. 
Published: August 2011

Abstract
Aggressive tumor growth, diffuse tissue invasion, and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. Astrocyte elevated gene-1 (AEG-1) is an oncogene that is overexpressed in several types of human cancers, including more than 90% of brain tumors. In addition, AEG-1 promotes gliomagenesis, particularly in the context of tumor growth and invasion, 2 primary characteristics of glioma. In the present study, we investigated the contribution of AEG-1 to glioma-induced neurodegeneration. Pearson correlation coefficient analysis in normal brain tissues and samples from glioma patients indicated a strong negative correlation between expression of AEG-1 and a primary glutamate transporter of astrocytes EAAT2. Gain- and loss-of-function studies in normal primary human fetal astrocytes and T98G glioblastoma multiforme cells revealed that AEG-1 repressed EAAT2 expression at a transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter. In addition, AEG-1–mediated EAAT2 repression caused a reduction of glutamate uptake by glial cells, resulting in induction of neuronal cell death. These findings were also confirmed in samples from glioma patients showing that AEG-1 expression negatively correlated with NeuN expression. Taken together, our findings suggest that AEG-1 contributes to glioma-induced neurodegeneration, a hallmark of this fatal tumor, through regulation of EAAT2 expression. Cancer Res; 71(20); 6514–23. ©2011 AACR.
ZNF668 Functions as a Tumor Suppressor by Regulating p53 Stability and Function in Breast Cancer
Authors: Hu Ruozhen , Peng Guang , Dai Hui , Breuer Eun-Kyoung , Stemke-Hale Katherine , Li Kaiyi , Gonzalez-Angulo Ana M. , Mills Gordon B. , Lin Shiaw-Yih 
Published: August 2011

Abstract
Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage–induced stabilization of p53. RNA interference–mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability. Cancer Res; 71(20); 6524–34. ©2011 AACR.
A Mutation Threshold Distinguishes the Antitumorigenic Effects of the Mitochondrial Gene MTND1, an Oncojanus Function
Authors: Gasparre Giuseppe , Kurelac Ivana , Capristo Mariantonietta , Iommarini Luisa , Ghelli Anna , Ceccarelli Claudio , Nicoletti Giordano , Nanni Patrizia , De Giovanni Carla , Scotlandi Katia , Betts Christine M. , Carelli Valerio , Lollini Pier Luigi , Romeo Giovanni , Rugolo Michela , Porcelli Anna Maria 
Published: August 2011

Abstract
The oncogenic versus suppressor roles of mitochondrial genes have long been debated. Peculiar features of mitochondrial genetics such as hetero/homoplasmy and mutation threshold are seldom taken into account in this debate. Mitochondrial DNA (mtDNA) mutations generally have been claimed to be protumorigenic, but they are also hallmarks of mostly benign oncocytic tumors wherein they help reduce adaptation to hypoxia by destabilizing hypoxia-inducible factor-1α (HIF1α). To determine the influence of a disassembling mtDNA mutation and its hetero/homoplasmy on tumorigenic and metastatic potential, we injected mice with tumor cells harboring different loads of the gene MTND1 m.3571insC. Cell cultures obtained from tumor xenografts were then analyzed to correlate energetic competence, apoptosis, α-ketoglutarate (α-KG)/succinate (SA) ratio, and HIF1α stabilization with the mutation load. A threshold level for the antitumorigenic effect of MTND1 m.3571insC mutation was defined, above which tumor growth and invasiveness were reduced significantly. Notably, HIF1α destabilization and downregulation of HIF1α-dependent genes occurred in cells and tumors lacking complex I (CI), where there was an associated imbalance of α-KG/SA despite the presence of an actual hypoxic environment. These results strongly implicate mtDNA mutations as a cause of oncocytic transformation. Thus, the antitumorigenic and antimetastatic effects of high loads of MTND1 m.3571insC, following CI disassembly, define a novel threshold-regulated class of cancer genes. We suggest these genes be termed oncojanus genes to recognize their ability to contribute either oncogenic or suppressive functions in mitochondrial settings during tumorigenesis. Cancer Res; 71(19); 6220–9. ©2011 AACR.
High-Dose Antiangiogenic Therapy for Glioblastoma: Less May Be More?
Authors: de Groot John F. 
Published: August 2011

Abstract
Targeting angiogenesis in glioblastoma rapidly reduces vascular permeability and contrast enhancement on MRI and prolongs progression-free survival. The long-term efficacy of bevacizumab and other antiangiogenic agents is limited, however, because of the rapid development of resistance. Alternative dosing approaches may be one mechanism of prolonging therapeutic efficacy. Clin Cancer Res; 17(19); 6109–11. ©2011 AACR.
AMPK Alpha 1-Induced RhoA Phosphorylation Mediates Vasoprotective Effect of Estradiol
Authors: Gayard Marion , Guilluy Christophe , Rousselle Anthony , Viollet Benoit , Henrion Daniel , Pacaud Pierre , Loirand Gervaise , Rolli-Derkinderen Malvyne 
Published: August 2011

Objective—
Estradiol (E2) mediates numerous beneficial effects assigned to estrogens, but whereas mechanisms have been described at the endothelial level, direct effects on vascular smooth muscle cells (VSMC) are poorly documented. As evidence accumulates regarding the role of RhoA in vascular pathophysiology and the benefit of RhoA-Rho associated protein kinase (Rock) pathway inhibition, we analyzed if E2 could inhibit it in VSMC.

Methods and Results—
We show that in VSMC, E2 inhibits the RhoA-Rock pathway in a time- and concentration-dependent manner. The inhibition of RhoA-Rock pathway results from E2-induced phosphorylation of the Ser188 of RhoA. Using pharmacological, transfection, and in vitro phosphorylation experiments, we demonstrate that AMP-activated protein kinase subunit alpha 1 (AMPKα1) is activated by estrogen receptor stimulation and catalyzes RhoA phosphorylation induced by E2. Ex vivo, ovariectomy leads to an increase in the amplitude of phenylephrine- or serotonine-induced contractions of aortic rings in wild-type mice but not in AMPKα1-knock-out mice or E2-supplemented animals. These functional effects were correlated with a reduced level of RhoA phosphorylation in the aorta of ovariectomized female, male, and AMPKα1 knock-out mice.

Conclusion—
Our work thus defines AMPKα1 as (1) a new kinase for RhoA and (2) a new mediator of the vasoprotective effects of estrogen.
Nitric Oxide Decreases the Expression of Endothelin-Converting Enzyme-1 Through mRNA Destabilization
Authors: Raoch Viviana , Rodríguez-Pascual Fernando , López-Martínez Vanesa , Medrano-Andrés Diana , Rodríguez-Puyol Manuel , Lamas Santiago , Rodríguez-Puyol Diego , López-Ongil Susana 
Published: August 2011

Objective—
Endothelial function depends on the equilibrium in the synthesis of vasoactive endothelial factors. It is well known that endothelin and nitric oxide (NO) exhibit reciprocal regulation. We assessed the ability of NO to regulate endothelin-converting enzyme-1 (ECE-1) expression in vascular endothelial cells.

Methods and Results—
Bovine aortic endothelial cells were incubated with 2 different NO donors as well as with a cyclic-GMP analog, dibutyryl-cGMP (dB-cGMP). ECE-1 protein content and mRNA expression were evaluated by Western blot and Northern blot, respectively, promoter activity by transfection experiments, ECE-1 activity by ELISA, and cGMP production by radioimmunoassay. Both NO donors decreased ECE-1 protein content, mRNA expression, and ECE-1 activity. ODQ, an inhibitor of soluble guanylyl cyclase, blocked those effects. NO donors raised cGMP levels, and dB-cGMP mimicked their effects on ECE-1 expression, which were blocked by KT5823, a nonspecific PKG inhibitor. The changes on ECE-1 expression were due to a destabilization on 3′-untranslated region (3′-UTR) of this mRNA, because the activity of a luciferase reporter construct containing the 3′-UTR of the ECE-1 gene was reduced by dB-cGMP in a PKG-dependent manner. The biological relevance of this regulation was confirmed in bovine aortic endothelial cells coincubated with macrophages in the presence of lipopolysaccharide, in eNOS-deficient mice, and in Wistar rats treated with NO donors. In every case, an inverse relationship was observed between NO and ECE-1 protein content.

Conclusion—
Our results support that NO regulates ECE-1 expression through a cGMP/PKG-dependent regulatory mechanism at the post-transcriptional level via the 3′-UTR of the ECE-1 gene.
Focal Adhesion Kinase–Related Nonkinase Inhibits Vascular Smooth Muscle Cell Invasion by Focal Adhesion Targeting, Tyrosine 168 Phosphorylation, and Competition for p130
Cas
Binding
Authors: Koshman Yevgeniya E. , Chu Miensheng , Engman Steven J. , Kim Taehoon , Iyengar Rekha , Robia Seth L. , Samarel Allen M. 
Published: August 2011

Objective—
Focal adhesion kinase–related nonkinase (FRNK), the C-terminal domain of focal adhesion kinase (FAK), is a tyrosine-phosphorylated, vascular smooth muscle cell (VSMC)–specific inhibitor of cell migration. FRNK inhibits both FAK and proline-rich tyrosine kinase 2 (PYK2) in cultured VSMCs, and both kinases may be involved in VSMC invasion during vascular remodeling.

Methods and Results—

Adenovirally mediated gene transfer of green fluorescent protein–tagged, wild-type (wt) FRNK into balloon-injured rat carotid arteries confirmed that FRNK overexpression inhibited both FAK and PYK2 phosphorylation and downstream signaling in vivo. To identify which kinase was involved in regulating VSMC invasion, adenovirally mediated expression of specific short hairpin RNAs was used to knock down FAK versus PYK2 in cultured VSMCs, but only FAK short hairpin RNA was effective in reducing VSMC invasion. The role of FRNK tyrosine phosphorylation was then examined using adenoviruses expressing nonphosphorylatable (Tyr168Phe-, Tyr232Phe-, and Tyr168,232Phe-) green fluorescent protein–FRNK mutants. wtFRNK and all FRNK mutants localized to FAs, but only Tyr168 phosphorylation was required for FRNK to inhibit invasion. Preventing Tyr168 phosphorylation also increased FRNK-paxillin interaction, as determined by coimmunoprecipitation, total internal reflection fluorescence microscopy, and fluorescence recovery after photobleaching. Furthermore, wtFRNK competed with FAK for binding to p130
Cas
(a critically important regulator of cell migration) and prevented its phosphorylation. However, Tyr168Phe-FRNK was unable to bind p130
Cas
.

Conclusion—

We propose a 3-stage mechanism for FRNK inhibition: focal adhesion targeting, Tyr168 phosphorylation, and competition with FAK for p130
Cas
binding and phosphorylation, which are all required for FRNK to inhibit VSMC invasion.
The Coronary Artery Disease–Associated 9p21 Variant and Later Life 20-Year Survival to Cohort Extinction
Authors: Dutta Ambarish , Henley William , Lang Iain A. , Murray Anna , Guralnik Jack , Wallace Robert B. , Melzer David 
Published: August 2011

Background—

Common variation at chromosome 9p21 (marked by
rs10757278
or
rs1333049
) is associated with coronary artery disease (CAD) and peripheral vascular disease. A decreasing effect at older age was suggested, and effects on long-term mortality are unclear. We estimated 9p21 associations with CAD and all-cause mortality in a CAD diagnosis–free older population. We also estimated classification gains on adding the variant to the Framingham Risk Score (FRS) for CAD.

Methods and Results—

DNA was from an Established Populations for Epidemiological Study of the Elderly–Iowa cohort from 1988 (participants >71 years), with death certificates obtained to 2008 for 92% of participants. Cox regression models were adjusted for confounders and CAD risk factors. Of 1095 CAD diagnosis–free participants, 52% were heterozygous (CG) and 22% were homozygous (CC) for the risk
C
allele
rs1333049
. Unadjusted CAD-attributed death rates in the CC group were 30 vs 22 per 1000 person-years for the GG group. The
C
allele was associated with all-cause (hazard ratio, 1.19; 95% CI, 1.08–1.30) and CAD (hazard ratio, 1.29; 95% CI, 1.08–1.56) mortality, independent of CAD risk factors. There was no association with stroke deaths. Variant associations with CAD mortality were attenuated after the age of 80 years (age-interaction term
P
=0.05). In age group 71 to 80 years, FRS classified as high risk 21% of respondents who died of CAD within 10 years; adding 9p21 identified 27% of respondents.

Conclusions—
In 71- to 80-year-old subjects free of CAD diagnoses, 9p21 is associated with excess mortality, mainly attributed to CAD mortality. Adding 9p21 to the FRS may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation.
Carbon Monoxide–Activated Nrf2 Pathway Leads to Protection Against Permanent Focal Cerebral Ischemia
Authors: Wang Bing , Cao Wangsen , Biswal Shyam , Doré Sylvain 
Published: August 2011

Background and Purpose—
Carbon monoxide (CO) is a gaseous second messenger produced when heme oxygenase enzymes catabolize heme. We have demonstrated that CO can be therapeutic in ischemia-reperfusion brain injury; however, it is unclear whether CO can also offer protection in permanent ischemic stroke or what mechanism(s) underlies the effect. Heme oxygenase-1 neuroprotection was shown to be regulated by Nrf2; therefore, we investigated whether CO might partially exert neuroprotection by modulating the Nrf2 pathway.

Methods—
To evaluate the potential protective effects of CO, we exposed male wild-type and Nrf2-knockout mice to 250 ppm CO or control air for 18 hours immediately after permanent middle cerebral artery occlusion. Infarct volume and neurologic deficits were assessed on day 7. Molecular mechanisms of Nrf2 pathway activation by CO were also investigated.

Results—
Mice exposed to CO after permanent ischemia had 29.6±12.6% less brain damage than did controls at 7 days, although amelioration in neurologic deficits did not reach significance. Additionally, 18-hour CO treatment led to Nrf2 dissociation from Keap1, nuclear translocation, increased binding activity of Nrf2 to heme oxygenase-1 antioxidant response elements, and elevated heme oxygenase-1 expression 6 to 48 hours after CO exposure. The CO neuroprotection was completely abolished in Nrf2-knockout mice.

Conclusions—
Low-concentration CO represent a neuroprotective agent for combination treatment of ischemic stroke, and its beneficial effect would be at least partially mediated by activation of the Nrf2 pathway.
Microembolism Versus Hemodynamic Impairment in Rosary-Like Deep Watershed Infarcts
Authors: Moustafa Ramez Reda , Momjian-Mayor Isabelle , Jones P. Simon , Morbelli Silvia , Day Diana J. , Aigbirhio Franklin I. , Fryer Tim D. , Warburton Elizabeth A. , Baron Jean-Claude 
Published: August 2011

Background and Purpose—
Deep watershed infarcts are frequent in high-grade carotid disease and are thought to result from hemodynamic impairment, particularly when adopting a rosary-like pattern. However, a role for microembolism has also been suggested, though never directly tested. Here, we studied the relationships among microembolic signals (MES) on transcranial Doppler, rosary-like deep watershed infarcts on brain imaging, and cerebral hemodynamic compromise on positron emission tomography (PET), all in severe symptomatic carotid disease. We hypothesized that rosary-like infarcts would be significantly associated with worse hemodynamic status, independent of the presence of MES.

Methods—

Sixteen patients with ≥70% carotid disease ipsilateral to recent transient ischemic attack/minor stroke underwent magnetic resonance imaging including diffusion-weighted imaging,
15
O-PET, and transcranial Doppler. Mean transit time, a specific marker for hemodynamic impairment, was obtained in the symptomatic and unaffected hemispheres.

Results—

Eleven of 16 patients had rosary-like infarcts (Rosary+) and 8 patients had MES. Mean transit time was significantly higher (
P
=0.008) in Rosary+ patients than in healthy controls (
n
=10), and prevalence of MES was not different between Rosary+ and Rosary− patients. Contrary to our hypothesis, however, the presence of MES within the Rosary+ subset was associated (
P
=0.03) with a better hemodynamic status than in their absence, with a significant (
P
=0.02) negative correlation between mean transit time and rate of MES/h.

Conclusions—
Contrary to mainstream understanding, rosary-like infarcts were not independent of presence and rate of MES, suggesting that microembolism plays a role in their pathogenesis, probably in association with hemodynamic impairment. Pending confirmation in a larger sample, these findings have management implications for patients with carotid disease and rosary-like infarcts.