bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3905: Identification of new tumor-specific splice variants in NSCL cancers by whole genome exon arrays
Authors: Ghoneim Christelle , Kaoma Tony , Nicot Nathalie , François Bernardin , Nazarov Petr , Muller Arnaud , Birembaut Philippe , Vallar Laurent 
Published: June 2012

Abstract
Although lung cancer is one of the major causes of cancer death in men and women worldwide, the molecular pathogenesis of this disease remains elusive. The contribution of alternative splicing (AS) to cancer pathogenesis and progression is emerging as an area of considerable interest. Cancer-specific splice variants seem to play a key role in disease mechanism and etiology.
In this study, we analyzed 20 matched pairs of tumor specimens of Adenocarcinomas (AC), Squamous Cell Carcinomas (SCC) and adjacent normal tissue using Affymetrix GeneChip Exon microarrays. With this technology, it is possible to profile simultaneously gene expression and alternative splicing patterns for the entire genome using a single array. At the exon level, multiple probes for each exon enable the discrimination among different isoforms of a gene. Total RNA from tumors or normal tissue samples were amplified using the Ambion whole transcript expression kit and were hybridized onto GeneChip Human Exon 1.0 ST Array®. Data generated were normalized using RMA and were subjected to several layers of filtering (DABG filter, Multiple mRNAs filter). The delta splice index (ΔSI) was calculated, and alternative splicing events were detected using MIDAS and Rank Product method. Probesets were ranked based on their SI p-values.
By comparing tumor samples to the corresponding normal subgroups, we generated a list of 1689 splice variant candidates for SCC and 1010 for AC showing significant differential expression between normal and tumor tissues. Top candidates in each tumor subtype were selected based on their ΔSI for manual inspection and further bioinformatics analysis. Study of alternatively spliced candidates revealed that approximately 30 % of the genes were detected in both types of cancer. Gene function analysis combining text mining and knowledge-based approaches indicated that the largest subset (70 %) of these genes was related to cancer. Within this group, 30% of genes were related to lung cancers. Interestingly the major part (85%) of variant candidates was not previously associated with AS events in cancer. We focused our attention on this latter group and, through validation by RT/PCR, confirmed the existence of new specific alternative splicing events occurring in each cancer type. In addition, we identified biological pathways and gene networks that are specifically altered in AC or SCC. The cancer-specific AS variants and pathways identified in our study are promising biomarkers and targets for diagnostic or therapeutic purposes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3905. doi:10.1158/1538-7445.AM2011-3905
Abstract 397: LPA promotes ovarian cancer mesothelial invasion by regulating VCAM-1 expression
Authors: Slack-Davis Jill K. , Lynch Kevin R. 
Published: June 2012

Abstract
Ovarian cancers metastasize by attaching to and invading through the mesothelium, a single cell layer of mesothelial cells lining the peritoneal cavity. The presence of invasive peritoneal metastases is associated with a poor prognosis for ovarian cancer (5 yr survival &lt;25%). Lysophosphatidic acid (LPA) is abundant in malignant ascites where it regulates ovarian cancer cell growth, migration and response to chemotherapy. Using a cell culture model system of mesothelial invasion, treatment with a LPA receptor antagonist resulted in a dose-dependent decrease in mesothelial invasion. Eliminating LPA1 expression in mesothelial cells using siRNA blocked mesothelial invasion (70% inhibition relative to control) and resulted in decreased expression of VCAM-1. We have shown previously that VCAM-1 is expressed preferentially on the mesothelium of ovarian cancer patients where it regulates mesothelial invasion and ovarian cancer metastatic progression. Re-expression of VCAM-1 in mesothelial cells lacking LPA1 expression rescued mesothelial invasion. Together, these observations implicate a role for LPA in modulating the tumor microenvironment to regulate ovarian cancer progression. Furthermore, they specifically point to a role for LPA in the regulation of VCAM-1 expression in ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 397. doi:10.1158/1538-7445.AM2011-397
Abstract 3973: MiR-21 modulates hTERT through a STAT3-dependent manner on glioblastoma cell growth
Authors: Sun Guan , Wang Yingyi , Zhang Junxia , Wang Xiefeng , Sun Lihua , Pu Peiyu , Kang Chunsheng , Liu Ning , Fu Zhen , You Yongping 
Published: June 2012

Abstract
MiRNAs, are small noncoding RNA molecules of approximately 20-22 nucleotides in length, regulate protein expression by cleaving or repressing the translation of targets mRNA. MiR-21, as an oncogene, has been reported to be dyregulated in a variety of cancer. Our recent data have verified that miR-21 is one of the most frequently over-expressed miRNA in human glioblastoma (GBM) cell lines. However, the mechanism of miR-21 involved in gliomagenesis is still unknown. In this study, reduction of miR-21 by antisense oligonucleotide induced cell apoptosis and inhibited cell growth in U87 and LN229 GBM cells, with a decreased expression of human telomerase reverse transcriptase (hTERT). Knockdown of hTERT expression using lentiviral vector mediated delivery of hTERT-siRNA triggered cell apoptosis and cell cycle G1/G0 arrest in U87 and LN229 cells. In order to explore the molecular regulation of hTERT by miR-21, we found that STAT3 could be an important mediator between miR-21 and hTERT. Reduction of miR-21 repressed STAT3 expression and STAT3 phosphorylation. STAT3 inhibitor WP1066 led to a remarkable depletion of hTERT both at mRNA and protein levels. To determine the functional interaction between STAT3 and hTERT, ChIP showed the presence of STAT3-binding sites in the hTERT gene. Luciferase reporter assay revealed that the hTERT gene promoter was direct bound by STAT3. Furthermore, we evaluated the status of STAT3 in hTERT regulation by miR-21. U87 and LN229 cells that treated with miR-21 antisense oligonucleotide and IL-6 which could elevate the expression of STAT3 showed a significant increase of hTERT expression, whereas cells that treated with miR-21 oligonucleotide and STAT3 inhibitor WP1066 displayed a reduction of hTERT expression. Finally, knockdown of miR-21 considerably inhibited tumor growth and diminished the expression of STAT3, pSTAT3 and hTERT in xenograft model. Taken together, we have demonstrated that miR-21 inhibits cell growth through regulating hTERT expression in a STAT3-dependent pathway in GBM cells. These results suggest that modulation of the mechanism responsible for miR-21 in GBM could be used as a therapeutic strategy for GBM treatment and warrants further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3973. doi:10.1158/1538-7445.AM2011-3973
Abstract 3977: Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells
Authors: Östling Päivi , Leivonen Suvi-Katri , Aakula Anna , Kohonen Pekka , Mäkelä Rami , Hagman Zandra , Edsjö Anders , Kangaspeska Sara , Edgren Henrik , Nicorici Daniel , Bjartell Anders , Ceder Yvonne , Perälä Merja , Kallioniemi Olli 
Published: June 2012

Abstract
Androgen receptor (AR) is expressed in all stages of prostate cancer progression and its levels increase in the castration-resistant tumors. However, the mechanisms regulating AR expression remain poorly understood. Here, our aim was to determine the role of miRNAs in regulating AR protein. To this end, we performed a systematic gain-of function screen for 1129 miRNA molecules in prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. We identified 71 unique miRNAs that influenced the level of AR in LNCaP, LAPC-4, 22Rv1, CWR-1R and MDA-PCa-2B cells. Our RNA-sequencing data showed that the 3’UTRs of many genes, including the AR, are much longer than currently used by target prediction programs. Our analyses predicted that the majority of the miRNA regulation of AR would occur through the extended 6 kb 3’UTR. 3’UTR-binding assays validated 13 miRNAs (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371-3p, miR-421, miR-449a, miR-449b, miR-634, miR-654-5p, and miR-9) as direct AR regulators. Fifteen AR down-regulating miRNAs decreased androgen-induced proliferation of prostate cancer cells in vitro. Negative correlation of miR-34a and miR-34c expression with AR levels was also found in clinical prostate cancers. To conclude, our results demonstrate that miRNAs interacting with the long 3’UTR of the AR gene are important regulators of AR protein levels. This could be applied for developing novel therapeutic strategies to inhibit AR function and androgen-dependent cell growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3977. doi:10.1158/1538-7445.AM2011-3977
Abstract 3979: Identification of microRNA 885-5p as a novel regulator of tumor metastasis in colorectal cancer
Authors: Lam CSC 
Published: June 2012

Abstract
Introduction: MicroRNAs (miRNAs) are a class of small non-coding RNAs that play a crucial role in cellular proliferation, differentiation and apoptosis by regulating gene expression. They are involved in the regulation of human diseases as well as colorectal cancer (CRC). CRC is the third most common cancer in the world and second leading cause of cancer death in the Hong Kong. Liver is the most common site of distant metastasis with poor prognosis for CRC patients. Recent evidences suggested that miRNAs affect the cell invasiveness of various cancers and regulate key steps in metastatic cascade. Moreover, studies also demonstrated that miRNAs play critical roles in the regulation of drug resistance. The study of miRNAs mechanism in liver metastasis may provide some new strategies for cancer treatment.
Method: Microarrays were used for screening the expression differences of miRNAs between normal colon, CRC and liver metastasis. Lentiviral transduced colon cell lines were sorted with flow cytometer high-speed sorter by green fluorescent protein signal. Functional assay such as wound healing and invasion chamber were used to study the metastatic property (migration and invasion) in vitro. GeneChip expression was used to study the mRNA expression differences between gain-of-function and control. Orthotopic implantation of mi-885-5p-expressing CRC cells into the cecal wall of nude mice was performed to investigate their tumorigenic and metastatic capacity in vivo.
Results: We quantified the expression levels of miRNAs in 14 liver metastasis samples and 12 colorectal cancer tissues, and identified hsa-miR-885-5p whose expression levels were significantly up-regulated in liver metastasis samples compared with the CRC samples. Over-expressed miR-885-5p cell line showed more invasive and migratory when comparing with control. 67% of the mice developed liver metastasis with orthotopic implantation of a CRC cell line overexpressing miR-885-5p, as compared with 33% of metastatic incidence in mice injected with the vector-expressing CRC cell line. GeneChip array showed that VCAM1 may be one of a possible target of miR-885-5p, which was comparable with the online database.
Conclusion: We conclude that over expression of miR-885-5p is observed in liver metastasis has an important role in regulating the metastatic capacity of CRC cells vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3979. doi:10.1158/1538-7445.AM2011-3979
Abstract 3980: Hypoxia-induced microRNA-424 targets CUL2 to stabilize HIF-α isoforms and promotes angiogenesis
Authors: Subramanian Indira V. , Ghosh Goutam , Nguyen Julia , Zhang Xiaoxiao , Joshi Hemant P. , Zeng Yan , Ramakrishnan Sundaram 
Published: June 2012

Abstract
Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Adaptive changes to oxygen availability are critical for cell survival and homeostasis. Cells respond to hypoxia by modulating oxygen-sensing transducers that stabilize the transcription factor hypoxia-inducible factor 1α (HIF-1α), which transactivates genes governing angiogenesis and metabolic pathways. Oxygen-dependent changes in HIF-1α levels are regulated by proline hydroxylation and proteasomal degradation. Here we provide evidence for a novel mechanism regulating HIF-1α and HIF-2α levels in endothelial cells during hypoxia. Hypoxia differentially increased microRNA-424 (miR-424) levels in microvascular EC, HUVEC and EC progenitor cells purified from the blood. miR-424 targeted cullin 2 (CUL2), a scaffolding protein critical to the assembly of the ubiquitin ligase system, thereby stabilizing HIF-α isoforms. Hypoxia-induced miR-424 in EC was regulated by PU.1-dependent transactivation. PU.1 expression was in turn controlled by RUNX-1 and C/EBPα. Knocking down either C/EBPα or RUNX-1 or PU.1 attenuated hypoxia-driven expression of miR-424 and nuclear translocation of HIF-1α. Furthermore, miR-424 promoted angiogenesis in vitro and in mice, which was blocked by specific morpholinos. These results suggest that miR-424 plays an important physiological role in angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3980. doi:10.1158/1538-7445.AM2011-3980
Abstract 3985: MicroRNA-21 regulates Sox2 expression and tumor self-renewal in PDGF-driven glioma
Authors: Roswall Pernilla , Põlajeva Jelena , Swartling Fredrik J. , Jiang Yiwen , Singh Umashankar , Uhrbom Lene , Westermark Bengt 
Published: June 2012

Abstract
The Platelet-Derived Growth Factor (PDGF) has a known role in the progression of malignant primary brain tumors, glioma, but the mechanisms behind PDGF-driven brain tumor development are still not clarified. MicroRNAs regulate many genes in our genome at a post-transcriptional level. We recently identified microRNA-21 (miR-21) as a target in a retroviral screen for candidate brain tumor initiating genes in mice. To explore a role for miR-21 in brain tumors we used Northern blot and in situ hybridization to show that the expression levels of miR-21 in PDGF-induced mouse brain tumors and primary mouse glioma cell lines were strongly increased as compared to normal mouse brain. In normal fibroblasts, the expression of miR-21 was induced by a number of growth factors, including PDGF-B, suggesting miR-21 is downstream of PDGF signaling. By inhibiting PDGF-B with siRNA in Sox2-expressing mouse glioma initiating cells, we showed that miR-21 expression could be suppressed, followed by a decrease in tumor cell self-renewal. To understand the mechanisms of miR-21 in normal development, we identified miR-21 to be highly expressed during embryonic development and in newborn brain with its expression turned off before postnatal day 7 (P7) in the mouse brain. The expression of miR-21 overlapped with Sox2 expression in embryonic and newborn normal mouse brain, whose expression levels similarly decreased at P7. In situ hybridization of miR-21 and IHC staining of Sox2 showed consistent co-expression in mouse brain tumor specimens. Irreversible depletion of miR-21 by using an LNA-modified siRNA was shown to repress Sox2 in primary mouse brain tumor cells but also in human glioma cell lines. Our data suggest that miR-21 regulates Sox2, maintains the tumor initiating cell population and the progression of PDGF-driven brain tumors which insinuates miR-21 as a promising target for future treatment of glioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2011-3985
Abstract 3988: Identification of miR-132 and miR-290-3p as putative tumor and metastasis suppressor microRNAs in breast cancer
Authors: Goldberger Natalie E. , Kim Chang Hee , Walker Renard , Hunter Kent 
Published: June 2012

Abstract
Several microRNAs (miRNAs) have been classified as regulators of breast cancer metastasis [1], yet additional unidentified miRNAs may also exist that regulate metastasis. Most interesting, we propose that germline genetic changes may exist which create a predisposition towards developing breast cancer metastasis through the dysregulation of miRNAs. Thus, to identify novel miRNAs associated with a germline predisposition towards breast cancer metastasis, highly metastatic FVB/N-TgN (MMTV-PyMT) mice were crossed with 25 AKXD RI (AKR/J × DBA/2J) strains to produce F1 progeny displaying primary mammary tumors with varying degrees of pulmonary metastasis. The miRNA expression levels within all mammary tumors were evaluated using a miRNA microarray and correlated with the metastatic index for each strain. The analysis produced 27 candidate miRNAs possessing a significant p-value (p &lt; 0.05). To further validate the microarray findings, the expression levels for the most promising miRNAs were measured in mammary tumors from highly metastatic AKR/J and poorly metastatic DBA/2J strains. Downregulation of miR-132 and miR-290-3p was observed in the AKR/J strain versus the DBA/2J strain, consistent with the negative correlation coefficients produced during microarray analysis. In addition, miR-132 miRNA was downregulated in normal breast tissue from the AKR/J compared to the DBA/2J strain (p &lt; 0.00029), thus supporting a predisposition towards tumorigenesis. Most importantly, ectopic expression of miR-290-3p and miR-132 in highly metastatic murine breast cancer cell lines (Mvt-1 and 6DT1) reduced the mammary tumor burden and the number of pulmonary metastasis in FVB/NJ mice after orthotopic injection in the mammary fat pad. Overall, these findings suggest somatic or germline genetic changes that downregulate either miR-132 or miR-290-3p may create a predisposition towards breast cancer development and metastasis.
1. Hurst, D.R., M.D. Edmonds, and D.R. Welch, Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res, 2009. 69(19): p. 7495-8.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3988. doi:10.1158/1538-7445.AM2011-3988
Abstract 3993: Stromal and epithelial microRNA signatures of early breast lesions linked to cancer progression
Authors: Nilsson Sofie , Allred Craig , Howell Anthony , Landberg Göran 
Published: June 2012

Abstract
Columnar cell hyperplasia (CCH) is considered to originate in normal terminal duct lobular units (TDLUs) and is potentially the first histologically identifiable alteration in the development of breast cancer. These lesions have been characterized to have a higher proliferation rate but the underlying mechanisms have not been studied. In order to detect early changes in breast cancer progression we therefore investigated microRNA (miRNA) expression profiles in TDLUs and CCH. Epithelial cells and surrounding stroma of TDLUs and CCH from formalin-fixed paraffin embedded tissue from four patients with high risk of developing breast cancer were laser capture microdissected and RNA was extracted. MiRNA expression profiles were obtained using a qRT-PCR-based array analyzing 667 human miRNAs.
Interestingly, array analysis indicated substantial downregulation of several miRNAs in both the epithelial and the stromal compartments of CCH. MiRNA array analysis of paired samples from specimens with both TDLUs and CCH resulted in significant (p&lt;0.05) decreased levels of 15 miRNAs in epithelial cells of CCH (miR-532-3p, miR-92a, miR-886-3p, let-7c, miR-150, miR-27a, miR-491-5p, miR-130a, miR-365, miR-886-5p, miR-204, miR-135a*, miR-494, miR-29c, miR-768-3p) and downregulation of 18 miRNAs in the stroma (miR-195, miR-296-5p, miR-99a, miR-100, miR-224, let-7c, miR-19b, miR-423-5p, miR-26a, miR-511, miR-128, miR-203, miR-30b, miR-374a, miR-374b, miR-29b, let-7e, miR-10a). We next downregulated miR-27a and miR-92a in a CCH derived cell line and observed a significantly increased proliferation. Opposite effect was observed when the miRs were overexpressed altogether suggesting a proliferative inhibitory function for the selected miRNAs. The miRNA signatures indicate concordant early changes in the epithelial and stromal compartment and the findings could be useful in identifying early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3993. doi:10.1158/1538-7445.AM2011-3993