bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5007: Nuclear targeted Deleted in liver cancer 1 exhibited reduced tumor suppressive function both in vitro and in vivo
Authors: Chan Lo Kong , Ko Frankie Chi Fat , Ng Irene Oi Lin , Yam Judy Wai Ping 
Published: February 2011

Abstract
The tumor suppressor Deleted in liver cancer 1 (DLC1) protects cell from transformation by catalyzing the GTP hydrolysis of active RhoA. Besides the RhoGAP activity, accumulating evidences have supported that localization at focal adhesions and interaction with tensin protein are key factors guiding the tumor suppressive activity of DLC1. In this study, we provided new evidence that DLC1 was a dynamic protein which shuttles between cytoplasm and nucleus instead of statically staying in the cytoplasm. Subcellular fractionation assay showed that DLC1 protein can be detected in cytoplasmic and nuclear fractions. Treatment of Leptomycin B (LMB), a nuclear export blocker, could lead to the nuclear retention of exogenous and endogenous DLC1 in different human cancer cell lines. Detail examination of relevant DLC1 mutants had shown that the center region of DLC1 was necessary and sufficient for its nuclear localization. We transiently expressed a NLS fusion DLC1 (NLS-DLC1) with preferential nuclear localization in SMMC HCC cells and found that NLS-DLC1 was less potent in suppressing colony formation and actin stress fiber formation. To study the tumor suppressive function of nuclear DLC1 both in vitro and in vivo, we employed retroviral transduction to stably express NLS-DLC1 in a p53−/− RasV12 hepatoblast model. We found that NLS-DLC1 expressing cells proliferated faster in vitro and exhibited increased tumorigenicity upon nude mice injection when compared with the non-nuclear targeted DLC1. Although the function of nuclear DLC1 remains to be answered, our results clearly demonstrated that nuclear localization of DLC1 may serve as a potential mechanism in negatively regulating its tumor suppressive activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5007.
Abstract 5009: Analyses of human specimens and knockout mouse model reveal a tumor suppressor function of EphA2 in liver
Authors: Guo Hong , Miao Hui , Chen Xin , Iida Hiroshi , Kaneko Shuichi , Wang Bingcheng 
Published: February 2011

Abstract
EphA2 kinase is highly expressed in normal mammalian liver, but its functions are poorly defined. Here we show that EphA2 expression was down-regulated in majority of human hepatocellular carcinoma (HCC) from three different populations. In mice, EphA2 deletion led to enhanced susceptibility to hepatocarcinogenesis induced by diethylnitrosamine (DEN) in tumor multiplicity and burden compared with wild type mice. Acute DEN treatment induced EphA2 expression upregulation, concomitant with mitotic arrest in wild type liver. EphA2-null liver displayed significantly increased apoptosis compared with wild type. Further, acute DEN treatment caused substantially elevated Akt and ERK1/2 kinase activities in EphA2-null but not in wild type liver. Ephrin-A1 stimulation inhibited AKT and ERK1/2 and suppressed cell proliferation in vitro. Re-expression of EphA2 fully restored its function. Liver development displayed stable EphA2 expression and kinase activation increase by age coinciding with upregulated ephrin-A1. Human HCC and the mouse model show that EphA2 suppresses hepatocarcinogenesis by facilitating mitotic arrest in response to carcinogenic insults; inhibition of Akt and ERK is one possible mechanism involved in tumor progression. Together, these finding provide a mechanistic link between EphA2 and liver tumor development.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5009.
Abstract 501: A novel PDT system consisting of a DDS-type photosensitizer and a newly developed fiber probe for homogenous irradiation
Authors: MIYAZAKI Kozo , MORIMOTO Yuji , MURAOKA Miho , KUMAGAI Michiaki , HORIE Souta , FUKUSHIMA Shigeto , SHINOMIYA Nariyoshi , NISHIYAMA Nobuhiro , KATAOKA Kazunori 
Published: February 2011

Abstract
Introduction:
Photodynamic therapy (PDT) has already been established as anti-cancer therapy. However, since some types of cancer proliferate multifocally and/or diffusely, topical irradiation of light by a conventional optical fiber results in an insufficient PDT effect. Moreover, using a conventional fiber, we cannot irradiate minimal tumors that escape from detection by conventional diagnostic approaches. When PDT is applied to the lesions of hollow organs, if we homogenously irradiate a wide area of the organ wall, undetectable minimal tumors and multifocally proliferating tumors can be treated simultaneously. In order to realize this concept, we have developed a novel fiber probe that provides homogenous light irradiation on the mucosa of hollow organs. In this study, we fabricated a homogenous irradiation fiber probe (HIFP) for illuminating the bladder by the use of state-of-the-art processing technology (torsional deformation of a fiber core, conical shaping of fiber tip, etc). We evaluated the PDT effect on a rat orthotopic bladder tumor model using the HIFP and a dendrimer phthalocyanine micelle (DPc/m) that we developed as a DDS-type photosensitizer.
Materials and Methods:
The property of spatial distribution of light emitted from the HIFP was measured. Using the HIFP, PDT was carried out on a rat orthotopic bladder tumor model 24 h after administration of a photosensitizer (Photofrin or DPc/M) and PDT effects were pathologically evaluated.
Results:
Preliminarily examination of ultrasonic imaging revealed that the shape of the rat bladder approximates an ellipsoidal body with a long radius of 7.5 mm and a short radius of 5 mm. Analysis of spatial distribution showed that the light emitted from the HIFP covered 90% of the whole luminal area of the approximate ellipsoidal body, while the light emitted from a control fiber (CF) (NA=0.41; flat cleaved end) covered only 15%. Pathological study of the PDT-treated rat using the CF revealed that an anti-tumor effect occurred only in the local area proximate to the focal point of the CF with no anti-tumor effect in tumors in other areas of the bladder wall. In contrast, pathological study of the PDT-treated rat using the HIFP revealed that light was distributed over 60 −80% of the mucosa of the bladder and tumor proliferation was widely suppressed.
Conclusion:
Widespread and homogenous irradiation in the mucosa of the bladder was achieved using the newly developed fiber probe. PDT using a combination of the fiber probe and DPc/M enhanced the anti-tumor effect without bladder shrinking.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 501.
Abstract 5011: Potential tumor suppressor role of PHD2 : functional study of mutations identified in germline DNA of patients with congenital polycythemia with or without paraganglioma
Authors: Gardie Betty , Ladroue Charline , Carcenac Romain , Gad Sophie , Barrois Michel , Bombled Johny , Hermine Olivier , Leporrier Michel , Baruchel André , Jean-Claude Kiladjian , Giraud Sophie , Mazure Nathalie , Pouyssegur Jacques , Richard Stéphane 
Published: February 2011

Abstract
The Hypoxia Inducible Factor (HIF) plays a major role in tissue response to hypoxia. HIF induces expression of many genes involved in anaerobic glycolysis, angiogenesis, erythropoiesis and cell proliferation. HIF-alpha subunit is tightly regulated by a family of specific hydroxylases in normoxia. PHD (prolyl-hydroxylase domain) proteins hydroxylate HIF-alpha, thereby allowing its attachment to the VHL protein, a component of an E3 ubiquitin ligase complex involved in protein ubiquitination and degradation. Mutations in HIF regulators have been described and lead to the stabilization of HIF, activation of target genes and development of either tumors or polycythemia. Heterozygous germline mutations in the VHL gene predispose to the von Hippel-Lindau disease characterized by a panel of highly vascularized tumors (central nervous system and retinal hemangioblastomas, pheochromocytomas, renal cell carcinoma, pancreatic endocrine tumors) whereas homozygous or compound heterozygous VHL mutations are responsible for isolated polycythemia (”Chuvash polycythemia”) with high circulating erythropoietin levels. Recently, heterozygous germline mutations in the PHD2 gene have been described in few patients with such congenital polycythemia and a particular mutation (H374R) has been identified in a patient with a polycythemia and a recurrent paraganglioma1. This observation raised the question of a possible role of PHD2 loss of function in the genesis of tumors usually seen in the VHL disease. We report here four new heterozygous PHD2 germline mutations in patients with familial or apparently sporadic polycythemia. We performed a functional study of these mutants compared to the H374R mutant and we showed differences in the capacity of the PHD2 mutants to downregulate HIF-alpha. These differences, tested in various conditions, are highly reproducible and suggest that there may be a genotype/phenotype correlation for the PHD2 mutants like the VHL mutants with their different ability to regulate HIF associated with different phenotypes in the VHL disease.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5011.
Abstract 5013: FOXP3 is an X-linked prostate tumor suppressor gene that represses MYC
Authors: Lizhong Wang , Liu Runhua , Katoh Hiroto , Liu Yang , Zheng Pan 
Published: February 2011

Abstract
Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene in human prostate cancer. We first evaluated expression of FOXP3 in both normal and prostate tissue and a reduced FOXP3 expression was wide-spread among prostate cancer samples. We then used fluorescence in situ hybridization (FISH) and determined the deletion of the FOXP3 in the 14% prostate cancer tissues. Our sequencing analyses identified single base-pair changes in 5/20 prostate cancer samples and these somatic mutations of the FOXP3 are functionally inactivating. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. The targeted mutation of the FoxP3 in prostate tissue is sufficient to initiate the process of prostate cancer development. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is the first X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a new paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5013.
Abstract 5014: Identification and analysis of critical domains within the neuroblastoma tumor suppressor gene CASZ1
Authors: Virden Ryan A. , Liu Zhihui , Thiele Carol J. 
Published: February 2011

Abstract
Neuroblastoma (NB) is an enigmatic pediatric cancer for which highly successful therapies have been developed for tumors displaying favorable characteristics, while poor prognoses persist for unfavorable tumors. Chromosome 1p36 is frequently lost in the tumors of many patients with unfavorable prognoses and harbors the locus of the zinc finger (ZF) transcription factor CASZ1. Low CASZ1 expression is significantly associated with lower overall patient survival in NB. Functionally, CASZ1 suppresses NB tumor cell growth and regulates a number of key genes important in neural development (e.g. TrkA, p75 and tyrosine hydoxylase [TH]). It has been shown that high expression of TrkA and p75 are both independently associated with good prognoses in NB patients. Despite the important role of CASZ1 in neural development and NB tumor suppression, the key domains that mediate the activation role of CASZ1 have never been elucidated. In order to address this question, we performed a detailed analysis of CASZ1 protein isoform A (CASZ1a), which contains five ZF's. Abrogation of CASZ1a function was determined by loss of the ability to induce endogenous TrkA, p75 and TH mRNA transcription as well as by loss of the ability to activate a TH promoter-luciferase reporter construct. Using site-directed mutagenesis, we individually mutated each of the five ZF's and discovered that loss of any one of ZF1-4 resulted in a 72-98% loss of function compared to wild-type CASZ1a (p &lt; 0.001), without altering protein stability or nuclear localization. Also, deletion of the C-terminal sequence AA728-1166 (a 38% truncation of the protein) did not appreciably alter function. However, a series of N-terminal truncations revealed a novel nuclear localization signal (NLS) at AA23-29, and it was found that CASZ1a depends on this NLS to localize to the nucleus. In addition, a critical activation domain was mapped to AA31-185 of the N-terminus, which also coincides with a newly identified CASZ1a homodimerization domain. Loss of this activation domain resulted in a complete loss of CASZ1a-mediated induction of the target genes TrkA, p75 and TH (p &lt; 0.001), without affecting protein stability or nuclear localization. Therefore, the discovery and analysis of critical domains in this study has linked CASZ1a loss of function to the loss of induction of the positive NB prognostic factors p75 and TrkA. This demonstrates how the loss of CASZ1a may contribute to the pathogenesis and abysmal survivability of high stage neuroblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5014.
Abstract 5018: Transcriptional and functional analysis of the CHD5 gene in Colorectal Cancer
Authors: Fatemi Mehrnaz , Brim Hassan , kumar Krisham , Ashktorab Hassan 
Published: February 2011

Abstract
Background: CHD5 is a family member of chromatin remodeling factors that functions as a tumor suppressor in neuroblastoma and ovarian cancer. The transcriptional activity of CHD5 is silenced by hypermethylation. It has been found that CHD5 is a biomarker in colon carcinogenesis. In this study, we have investigated the transcriptional regulation and function of the CHD5 in CRC.
Methods: The transcriptional activity of CHD5 was tested by reporter luciferase assay. The 1kb large fragment upstream of CHD5 transcription start site (TSS) showed luciferase activity; while the 400 bp subfragment upstream of TSS was inactive in both RKO (CHD5 endogenous non-expressing) and HCT116 (CHD5 endogenous expressing) cell lines. This suggests that the transcriptionally active sites of CHD5 are located within −400 to −1000. There are two consensus TCF binding sites in the 1 kb promoter region. In order to investigate whether Wnt pathway affects the CHD5 transcriptional activity, we treated the RKO and HCT116 cell lines with 6-bromoindirubin-3′oxime (BIO), the GSK-3a inhibitor, which activates the β-Catenin. We tested the Wnt pathway activity in RKO and HCT116 cell lines by using the TCF/LEF responsive luciferase construct. Methylation profiles of CHD5 in 51 CRC and 6 adenomas from African Americans analyzed by MSP. Microdeletion analysis of the CHD5 region (1p36) was performed by aCGH.
Results: The activity of TCF/LEF responsive element increased by 17.5 folds in RKO cell line and by 7.3 in HCT116 cell line after BIO treatment. Interestingly, the luciferase activity of 1kb CHD5 promoter increased after treating with BIO, and no changes were observed in activity of the 400 bp fragment. This suggests that the TCF/LEF and β-Catenin might act as coactivators for CHD5 transcriptional regulation. We also analyzed the proliferation of the RKO cell line after stably transfecting with CHD5 expressing plasmid (pcDNA). The results showed that the exogenous expression of CHD5 reduces the proliferation of the RKO cell line by two folds compared to the wild type and the mock controls. CHD5 was hypermethylated in 78% of the tested patients samples and deleted in 36%.
Conclusion: The function of CHD5 is not well understood in CRC. Here, we suggest that the wnt/β-catenin pathway may be involved in the transcriptional regulation of CHD5. In addition in vivo CHD5 microdeletion and methylation excrement suggest that CHD5 act as tumor suppressor in CRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5018.
Abstract 5019: Loss of the ETS transcription factor ESE3 induces epithelial-mesenchimal transition and generates cells with stem cell-like properties
Authors: Albino Domenico , Longoni Nicole , Ortelli Erica , Kunderfranco Paolo , Malek Anastasia , Catapano Carlo V. , Carbone Giuseppina MR 
Published: February 2011

Abstract
ETS transcription factors have emerged as important elements in the pathogenesis of prostate cancer. Most ETS factors promote cell proliferation, survival and transformation, while few others act as tumor suppressors. We have recently reported that the epithelial-specific ETS factor ESE3 is frequently down-regulated in prostate cancer, affects negatively cell proliferation and survival, and acts as tumor suppressor in prostate epithelial cells. ESE3 signatures extracted from prostate cancer clinical samples indicated a broad dedifferentiation program. Thus, we hypothesized that ESE3 maintains the differentiation state of prostate epithelial cells and that its loss leads to cell transformation. In this study, we report that stable knock-down of ESE3 in immortalized human prostate epithelial LHS cells (LHS-ESE3kd) resulted in the induction of epithelial-mesenchymal transition (EMT) with the acquisition of a fibroblast-like appearance. Concomitantly, LHS-ESE3kd cells acquired also ability to grow in anchorage-independent conditions in soft-agar and to form prostatosheres in sphere-forming assays. Expression of various stem-cell markers was also increased in LHS-ESE3kd compared to LHS cells. In a panel of prostate cell lines the ability to form prostatospheres was inversely correlated with ESE3 expression level, providing further support to the idea that the gene is an important regulator of the stem cell compartment. Consistently, re-expression of ESE3 in DU145 cells, which do not express ESE3, induced morphological changes consistent with a mesenchymal-epithelial transition, reduced the ability of the cells to migrate and to form prostatospheres. Cancer stem cells are reportedly to be drug resistant and drugs like taxol can select for drug-resistant cells with stem cell properties. We observed that resistance to taxol was inversely correlated with ESE3 expression in prostate cell lines. Furthermore, treatment of LHS-ESE3kd cells with taxol increased sphere formation, consistent with an enlargement of the stem-cell compartment by the ESE3 knock-down and increased selection by the drug. Collectively, these findings implicate that ESE3 controls the differentiation state and stem cell properties of prostate epithelial cells and that loss of ESE3 can be an important event in prostate tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5019.
Abstract 502: Cytokeratin staining for complete remission in rectal cancer after chemoradiation
Authors: Cho Yong Beom , Kim Hee Cheol , Yun Hae Ran , Kim Seok Hyung , Shin Hee Jeong , Yun Seong Hyeon , Lee Woo Yong , Chun Ho-Kyung 
Published: February 2011

Abstract
Purpose: Generally, pathologic complete remission (CR) of rectal cancer after neoadjuvant chemoradiation therapy (CRT) is confirmed by routine hematoxylin and eosin (H & E) staining. The aim of this study was to identify residual rectal cancer cells in primary lesions in patients with pathologic CR by staining immunohistochemically for cytokeratin.
Methods: The medical records of 358 rectal cancer patients that underwent neoadjuvant CRT prior to radical surgery between October 2002 and August 2007 were reviewed. The authors stained sections of resected specimens of the 58 (15.9%) patients (42 males; mean age 54 years) that achieved pathologic CR (as determined originally by H&E staining) with H&E and performed IHC using monoclonal cytokeratin antibody. These stained sections were then reviewed by a pathologist for residual rectal cancer cells.
Results: Of the 58 patients that achieved CR by initial pathologic examinations, 8 (13.8%) were found to contain tumor by cytokeratin IHC. Our H&E study in these 8, revealed that 6 were positive for cancer cells, but that the remaining 2, were negative for residual rectal cancer cells.
Conclusion: By better enabling the identification of residual rectal cancer cells cytokeratin IHC offers a means of improving staging accuracy, and thus, would be use to provide information for actual prognosis and treatment decision making of patients who had clinically CR in rectal cancer after CRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 502.