bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5026: Loss of microRNA-143/145 disturbs cell growth of cancers by impairing the MDM2-p53 feedback loop
Authors: Chen Wantao , Zhang Jianjun , Sun Qiang 
Published: August 2012

Abstract
BACKGROUND: Dysregulated microRNAs (miRNAs) play an important role in many malignant tumors, including epithelial cancers, but little is known about the molecular mechanisms and clinical significances of miRNAs dysregulation. The aim is to identify and determine the miR-143 and miR-145 how to specifically be involved in controlling MDM2 expression in a tumor tissue-specific manner. METHODS: Using real-time PCR, the expression of miR-143, miR-145 and MDM2 were evaluated and analyzed in epithelial cancer cell lines and oral cancer specimens. The different PCR-derived fragments and mutagenesis from the MDM2 mRNA 3′ UTR were inserted into the pGL3 vector to generate the luciferase reporters and the reporter activities were assayed by luciferase assay kits. The effects of overexpression of miR-143 and miR-145 on MDM2 and p53 levels were analyzed by western blot. The effects of miR-143 and miR-145 on cell proliferation and cell cycle were determined by the EdU assay and flow cytometry analysis. The effects of miR-143 and miR-145 on tumorigenicity in vivo were investigated with HNSCC cell xenograft models and the cell apoptotic rate as well as mechanism were tested by TUNEL and apoptosis-protein expression in the tumor tissues. RESULTS: The results showed that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is post-transcriptionally activated by up-regulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. CONCLUSIONS: These findings suggest that MDM2 dysregulation caused by down-regulation of miR-143 and miR-145 contributes to epithelial cancer development and palys a key role in regulating cellular proliferation and apoptosis. Recruitment of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers. KEYWORDS: miRNA-143, miRNA-145, MDM2, p53, epithelial cancers. ACKNOWLEDGMENTS: This study was supported by the National Natural Science Foundation of China (Grant No. 30973343 and 81101515), Projects of the Shanghai Science and Technology Committee (Grant No. 08JC1414400 and 10XD1402500), the Shanghai Leading Academic Discipline Project (S30206). *The first two authors contributed equally to this work.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5026. doi:1538-7445.AM2012-5026
Abstract 503: Investigating the role of Tks5 and invadopodia in prostate tumor progression
Authors: Burger Karen L. , Learman Brian S. , Boucherle Amy K. , Seals Darren F. 
Published: August 2012

Abstract
Much of the morbidity and mortality in prostate cancer patients occurs strictly in response to metastatic disease. While ongoing efforts are examining the therapeutic value of Src kinase inhibitors, the mechanism by which Src activates invasive cell behavior within the context of this disease are not well-understood. Invadopodia are cytoskeletal structures formed by cancer cells that enable binding to, proteolytic degradation of, and invasion through the extracellular matrix. We and others have previously demonstrated that the Src tyrosine kinase substrate and adaptor protein Tks5 is important for invadopodia formation and function. Here we demonstrate that Src is activated and Tks5 up-regulated in prostate tumor specimens and invasive cell lines. Remarkably, overexpression of Tks5 alone is sufficient to form invadopodia structures and enhance invadopodia-associated gelatin degradation and invasion in the LNCaP cell line. We further show that this increase in invasive behavior likely depends on Src kinase activity and Tks5 phosphorylation. Our results predict a role for Src-Tks5 signaling in prostate tumor progression. This hypothesis will be tested in future studies using (i) mouse xenografts to monitor tumor development from Tks5-modified prostate cancer cell lines, and (ii) human prostate tumor tissue sections to measure Tks5 staining relative to tumor grade.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 503. doi:1538-7445.AM2012-503
Abstract 5034: Healthy and cancerous serum RNA profiling by the novel RNA extraction reagent and highly sensitive DNA chip
Authors: Takizawa Satoko , Ichikawa Makiko , Sudo Hiroko , Ueda Yoji , Akiyama Hideo 
Published: August 2012

Abstract
Proteins, metabolites and DNA are already known as components of serum or plasma biomarkers, however RNA has not been a strong biomarker candidate because of its instability. Exosomes that are small vesicles secreted by various cells are recently reported to play important roles in intercellular communications by transferring proteins, DNA and also RNA to distant cells through circulatory system. Surprisingly, the exosomal RNA in serum preserves its integrity and thus holds a potential to be a new blood biomarkers. In this report, we show the exhaustive analysis of miRNA and mRNA in serum by DNA chip for the highly purified RNA extracted with a novel reagent. Serum contains various types of nucleic acids, mainly small RNA, mRNA, and also short DNA fragment. We suppose that the contamination of DNA to the extracted RNA often causes a discrepancy between the DNA chip analysis and qRT-PCR validation. The novel reagent was able to extract RNA from serum without contamination of short DNA fragment, resulting in better RNA quantification and decreasing DNA-related noise outputs. Using this novel RNA extraction reagent and the highly sensitive DNA chip “3D-Gene,” we analyzed healthy and cancerous serum miRNA profiles. Over 500 miRNAs are detected in healthy and cancerous sera reproducibly, and some miRNAs were detected specifically in cancerous sera, such as breast, gastric, cervix cancer. In addition, we detected over 19,000 mRNAs from amplified RNA which were similarly extracted from healthy serum and detected by the DNA chip. This indicates that not only serum miRNA but also serum mRNA have a potential capability to be a biomarker.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5034. doi:1538-7445.AM2012-5034
Abstract 5039: Comparative analysis of miRNA in hormonal refractory prostate cancer
Authors: Lee Min Jin , Cha Youn Jin , Kang Suki , Ham Wonsik , Choi Young Deuk , Cho Nam Hoon 
Published: August 2012

Abstract
Background: Nucleotides 2-7 within mature miRNAs, short RNA molecule of between 19 and 22, create the ‘seed region’ that specifies the specific mRNA. To date, miRNAs have been linked to the etiology, progression and prognosis of cancer. The gain or loss of specific miRNAs can function as an oncogene or tumor suppressor. Design: By using recently developed miRNA 14K array (Agilent), we designed to compare miRNA expression between HRPCa cell line (PC3) and sensitive cell line (LNCaP). As validation for target mRNA following bioinformatics, candidates were applied on the neoadjuvant bicalutamide treated radical prostatectomized specimens using immunohistochemistry. Results: Amongst 57 upregulated miRNAs (ratio &gt;2.0), oncomirs-miRNAs that are amplified or overexpressed in PC3, includes miR-31, -27a, -23a, -9, -100, -29a, -24, let 7i, -21, -221, 29b, -222, -181a. Probable candidates for target mRNAs to each oncomir are tumor suppressor gene family, including p27, PTEN, apoptosis related genes (DAXX, PDCD4, caspase recruitment domain 10/11), ECM adhesion genes (Integrin β4, ADAMTS 7/8), SOCS 6. In 23 downregulated miRNAs (ratio&gt;2.0), tumor suppressor miRNAs that are downregualted or deleted from chromosomes acting as tumor suppressor genes, include miR-141, -200 a/b/c, -148a, -429, -34a, -195, -99a, -203, -125b-2. Possible candidates for target mRNAs are oncogeneic family are EMT-related genes including ZEB1, cell cycle related genes (Wee1, cyclin E1, CDK6), prostate specific proteins (STEAP1, prostein), RTK family (AXL, Rab-38, Rab-9A), transcriptional factor promotion (EIF2, SOX6), mitogen activator (MAP p38), secretory protein (SDF2). Among the top-listed candidates, STEAP1, prostein, ZEB1, and cyclin E1 were relatively overexpressed in the refractory PCa to compare with regressing cancer cells. Conclusion: Complicated networks of miRNA play substantial and crucial roles in the regulation of hormonal refractory prostate cancer, predominantly by virtue of STEAP1, prostein, ZEB1, cyclin E1 overexpression, and suppression of apoptosis-related genes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5039. doi:1538-7445.AM2012-5039
Abstract 5194: Heterogenous expression of chemokine receptors in primary patient-derived GBM lines; association of CXCR3, CXCR4, and CXCR7 with a slow cycling sub-population
Authors: Pham Kien , Liu Che , Luo Defang , Reynolds Brent A. , Harrison Jeffrey K. 
Published: August 2012

Abstract
WHO class IV glioblastoma multiforme (GBM) is one of the most malignant and aggressive forms of primary brain tumors and despite multimodal treatments patients have modest survival rates. The poor prognosis and therapy resistance of glioblastoma are believed to be a consequence of a subpopulation of glioma stem-like cells. As such, targeting functions associated with this cell population is likely to yield new therapeutic strategies. Roles for CXCR3, CXCR4, and CXCR7 in glioblastoma are well documented although previously published studies involved primarily the characterization of glioma cell lines grown in the presence of serum. Our studies were undertaken to understand the roles of chemokine receptors CXCR4 and CXCR7, and their ligands CXCL11 and CXCL12, in modulating glioblastoma stem-like cell functions. Tumors xenografts developed from patient-derived primary GBM cells cultured as gliomaspheres in serum-free conditions expressed CXCR4, CXCR7, CXCL11, and CXCL12 in a manner similar to expression patterns of these genes in human GBM tissues. Flow cytometry analysis of CXCR4 and CXCR7 on various patient-derived primary GBM lines indicated marked heterogenous expression of these receptors. Variable percentages of CXCR4+, CXCR7+, and CXCR4+/CXCR7+ (double positive) populations were evident. In contrast, chemokine receptors CCR3 and CXCR3 were co-expressed on a small but similar percentage of cells in all cell lines. RT-PCR indicated that all lines expressed CXCL11 while none expressed CXCL12. A slow cycling sub-population of cells, which express stem-like cell markers and exhibit high tumorigenic frequencies, were enriched for CXCR3, CXCR4, and CXCR7. CXCR4+ and CXCR7+ subpopulations were capable of forming spheres in serum-free culture conditions and exhibited plasticity in regenerating the cellular heterogeneity of their parental phenotype. In addition, both CXCR4+ and CXCR7+ cells were able to initiate the formation of intracranial tumors. In vitro functional studies showed that while CXCL12, but not CXCL11, stimulated the migration of GBM cell lines, both of these ligands were able to promote short-term proliferation. Collectively, the results suggest that CXCR4 and CXCR7 may regulate the stem-like properties of GBM cells. The high degree of heterogeneity in CXCR4 and CXCR7 expression both within and between glioblastomas suggests that personalized treatment of glioblastoma patients using selective antagonists that target CXCR4 and CXCR7 may need to consider the complex expression patterns and specific functions of these receptors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5194. doi:1538-7445.AM2012-5194
Abstract 5198: Elucidation of dynamic prostate epithelial hierarchy: Insights into transcriptional and epigenetic regulatory mechanisms
Authors: Rane Jayant K. , Pellacani Davide , Droop Alastair P. , Ylipää Antti , Stower Michael J. , Simms Matthew S. , Mann Vincet M. , Visakorpi Tapio , Collins Anne T. , Maitland Norman J. 
Published: August 2012

Abstract
The aim of present investigation is to elucidate the complex stem cell dynamics within prostate cancer, which can be utilized to design novel diagnostic and therapeutic strategies for the management of prostate cancer. In order to determine precise transcriptional and microRNA regulatory mechanisms modulating stem cell self-renewal and differentiation, unique cellular assays have been developed in our lab that utilize homogeneous fractionated cell populations enriched from primary patient prostate cultures. Using a prospective bioinformatic analysis of gene expression data from Birnie et. al., 2008, we have identified LCN2, CEACAM6, and S100p as candidate genes for regulation of prostate stem cell differentiation. Their over-expression in differentiated cells, as compared to stem cells, was validated in respective cells enriched from cultures obtained from BPH, cancer and castration resistant prostate cancer samples and from primary human prostate cancer xenografts. Interestingly, the analysis of 25,000 published human Affymetrix microarray chips revealed that LCN2, CEACAM6, and S100p have a more similar expression pattern than that of any other genes in the entire human genome, suggesting that they may have common function and are co-regulated. Indeed, the promoter analysis showed that the promoters (1kb from TSS) of all these genes have common binding sites for 40 transcription factors with very high affinity and P &lt; 0.001. Most of these transcription factors have a well-documented role in cell differentiation (RA, AR, and NANOG) and prostate carcinogenesis (NF-kB). Significant up-regulation in the expression of these genes in prostate cell lines after treatment with all-trans retinoic acid and androgen analogue R1881 further suggested the role of AR and RA in prostate differentiation. Along with transcriptional regulation, Agilent v3 miRNA microarray data revealed obviously distinct miRNA expression profiles in stem and differentiated prostate epithelial cells, confirming crucial role of miRNA in main taining epithelial hierarchies, in prostate. We anticipate that evaluation of integrative transcriptional (LCN2-CEACAM6-S100p)-microRNA regulatory network, with further functional studies, will comprehensively establish a detailed knowledge base for potential regulatory mechanisms involved in prostate stem cell and prostate cancer stem cell differentiation. These insights will be valuable to formulate efficient ‘differentiation therapy’ for the management of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5198. doi:1538-7445.AM2012-5198
Abstract 5199: Tumor vascularization by endothelial differentiation of endometrial cancer stem cells
Authors: Nakamura Mitsuhiro , Kyo Satoru , Zhang Xivzhi , Takakura Masahiro , Maida Yoshiko , Mizumoto Yasunari , Bono Yukiko , Sasagawa Toshiyuki , Inoue Masaki 
Published: August 2012

Abstract
Evidence for existence of cancer stem cells (CSCs) has been reported in several malignant tumors. CSCs have properties of self-renewal, tumorigenesis and multilineage differentiation. Many studies about CSCs have focused on self-renewal, tumorigenesis. However, it is unclear about multilineage differentiation. Our previous study showed CD133 was a CSC marker and a critical prognostic marker in endometrial cancer. In that study, we demonstrated that CD133+ cells were capable of generating both CD133+ and CD133- cells, whereas CD133 cells did not generate CD133+ cells, indicating that CD133+ CSCs have a differential ability. The present study investigated endothelial differentiation of endometrial cancer cells. We have established endometrial cancer cells from normal human endometrial epithelial cells by introduction of HPV16 E6/E7, hTERT and K-ras genes (EM-E6/E7/hTERT/K-ras cells). Histological findings of tumors formed from EM-E6/E7/hTERT/K-ras cells showed that tumors were composed of solid and vascular regions. Vascular regions were stained human-specific anti-CD31 antibody, suggesting that EM-E6/E7/hTERT/K-Ras cells are capable of differentiating to endothelial cells. Subcutaneous xenografts from clinical samples in endometrial cancer also demonstrated that human endometrial tumors contained human vessels labeled by human-specific anti-CD31 antibody. Endothelial tube formation assay (in vitro angiogenesis) revealed that isolated CD133+ endometrial cancer cells could show tube formation while CD133- cells could not, indicating that CD133+ endometrial cancer cells had an ability of endothelial differentiation. Furthermore, western blot analysis showed high expression of VEGFR1 in CD133+ cells. We demonstrated a new function of CSCs in endometrial cancer cells. These findings shed light on the establishment of new target therapy to endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5199. doi:1538-7445.AM2012-5199
Abstract 5202: Bone marrow-derived epithelial cells contribute to chronic skin inflammation and skin tumor formation in the mouse
Authors: Park Heuijoon , Readio Nyssa , Jin Guang , Asfaha Samuel , Singh Anupama , Singh Ashok , Yang Xiangdong , Patterson Kelly S. , Trempus Carol , Wang Timothy C. , Morris Rebecca J. 
Published: August 2012

Abstract
Although a stem cell origin for tumors was postulated nearly 200 years ago, a critical role of keratin-15 expressing hair follicle stem cells in skin tumorigenesis has only recently been established. In addition to tissue stem cells, bone marrow cells can play a reparative function in damaged organs and contribute to cancer development as recently demonstrated in a gastric cancer model of Helicobacter felis-induced chronic inflammation. We report here that bone marrow derived cells (BMDCs) are an exogenous source of epithelial cells in tumor development in the multistage skin carcinogenesis model following gender mismatched allogeneic bone marrow transplantation. First, clusters of BMDCs were detected in the epithelium of 37.78% papilloma samples with a genetic marker (EGFP) indicating their bone marrow donor origin. Second, clusters of keratin immunoreactive BMDCs were located primarily in the basal epithelium of the papillomas. Third, a subset of BMDCs in the basal epithelium was found to be highly proliferative as measured by incorporation of BrdU and expression of Ki67. Furthermore, a significant contribution of BMDCs was identified in 53.06% of ulcer-associated dysplastic skin samples by immunostaining and confirmed by presence of a Y chromosome. Moreover, an enhanced contribution of bone marrow-derived epithelial cells was observed in the dysplastic epidermis. Therefore, these results demonstrate that a subset of BMDCs participates as a new epithelial cell source in chronically damaged skin lesions including papillomas and ulcers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5202. doi:1538-7445.AM2012-5202
Abstract 5205: Iron metabolism informs glioblastoma stem cell maintenance
Authors: Schonberg David L. , Rich Jeremy N. 
Published: August 2012

Abstract
Glioblastoma is a highly lethal cancer that is characterized by florid angiogenesis, invasion into normal brain, and therapeutic resistance. Glioblastomas display cellular hierarchies with a self-renewing, tumorigenic glioblastoma stem cell (GSC) at the apex. The significance of GSCs in tumor biology has been supported by work from our group and others showing that GSCs are relatively resistant to conventional therapies, promote tumor angiogenesis, and are highly invasive. By comparing GSCs to matched differentiated tumor bulk, we have identified a number of molecular targets that function in maintenance of the cellular hierarchy and tumor growth. We have now identified increased iron metabolism as a characteristic of GSCs. Normal glial progenitors accumulate iron to increase migration and proliferation. Brain tumors accumulate iron and iron regulators are associated with poor survival. As hypoxia induces iron regulators and maintains the cellular hierarchy, we are investigating iron regulation in GSCs. Ectopic delivery of iron to GSCs increases tumorsphere growth while disrupting iron metabolism in GSCs using shRNA reduces cell growth and decreases the expression of angiogenic growth factors. Collectively, these results suggest that iron metabolism is important for GSC maintenance and tumorigenic potential.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5205. doi:1538-7445.AM2012-5205
Abstract 5207: The chemokine 25 and chemokine receptor 9 axis suppresses colon cancer invasion and metastasis
Authors: Chen Huanhuan , Tucci Serena , Gümüs Zeynep , Shen Xiling , Lipkin Steven M. 
Published: August 2012

Abstract
Chemokines help regulate tumor cell invasion and metastasis. Here, we show that the Chemokine 25/Chemokine Receptor 9 (CCL25/CCR9) axis suppresses colon cancer (CRC) invasion and metastasis. CCR9 protein expression levels are highest in colon adenomas, and progressively decrease in invasive and metastatic CRCs. CCR9 is expressed in both primary tumor cell cultures and colon cancer initiating cell lines (CCIC) derived from early stage (I/II) CRCs. CCL25 stimulates cell proliferation through a network of transcription factors downstream of AKT signaling. In vivo, systemically injected CCR9+ early stage CCIC spontaneously form orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling prevents CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extra-intestinal tumor multiplicity. NOTCH signaling, which promotes CRC metastasis, increases extra-intestinal tumor multiplicity by stimulating CCR proteosomal degradation. These data provide insights into the mechanisms that regulate CRC progression, invasion and metastasis and describe a novel in vivo experimental system to study these processes. Our findings also raise a safety concern for ongoing Inflammatory Bowel Disease clinical trials using CCR9 antagonists.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5207. doi:1538-7445.AM2012-5207