bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1120: Role and relevance of TrkB mutations and expression in non-small cell lung cancer
Authors: Harada Taishi , Wang Yisong , Yatabe Yasushi , Takeshita Masafumi , Koga Takaomi , Yano Tokujiro , Giaccone Giuseppe 
Published: June 2012

Abstract
Purpose: TrkB oncogene has been involved in poor cancer outcome. TrkB mutations have been reported in non-small cell lung cancer. In this study, we aimed at characterizing the role of 3 potentially sensitizing mutations previously reported in TrkB in lung cancer.
Experimental design: We characterized three activation loop mutants of TrkB (M713I, R715G and R734C) in terms of pathway activation/phosphorylation, migration, anchorage independent growth and sensitivity to a Trk inhibitor, using NIH3T3 cells and Baf3 cells. We also sequenced the tyrosine kinase domain of TrkB in a large number of lung cancer samples and cell lines.
Results: None of the mutants were constitutively active in NIH3T3 transformation and migration assays. M713I and R734C mutants showed low levels of autophosphorylation in comparison with wild-type TrkB. Although R715G showed similar level of autophosphorylation to wild-type TrkB upon BDNF stimulation, the mutant was not as competent as wild-type TrkB in supporting IL-3 independent growth of Baf3 cells. In addition, the Trk inhibitor inhibited wild-type TrkB induced cell migration and cell growth, whereas the mutants were relatively resistant to the Trk inhibitor compared to wild-type TrkB. We could not confirm the presence of non-synonymous mutation in 78 lung cancer samples and 29 cell lines.
Conclusions: Wild-type TrkB but not its activation loop mutations enhances cell migration and transformation. Our study suggests that TrkB mutations should not be used for selection of patients with lung cancer treated with Trk inhibitors. High expression of wild-type TrkB might be beneficial for studies of Trk inhibitors.
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 1120. doi:10.1158/1538-7445.AM2011-1120
Abstract 1126: The L858R mutation of the EGFR gene might be associated with smoking in non-small cell lung cancer
Authors: Buyru Nur , Baykara Onur , Tansarikaya Merve , Ulutin Turgut 
Published: June 2012

Abstract
Lung cancer, which involves malignant proliferation of the epithelial lining of the lower respiratory tract is the most common cause of cancer death in men and is second only to breast cancer in women. Smoking is considered to be one of the principal causes of lung cancer. However, as only a subgroup of smokers ever develop the disease, it has been suggested that genetic susceptibility may contribute to the risk. Recent studies have shown that some non-small cell lung cancer (NSCLC) patients harbor gain-of-function mutations in the epidermal growth factor receptor gene (EGFR). Phosphorylated EGFR triggers the activation of intracellular signal transduction pathways such as RAS-MAPK, PI3K-Akt and STAT. On the other hand, point mutations in codons 12, 13 or 61 of the K-Ras gene inactivate the GTPase activity of the K-Ras resulting in continuous stimulation of autonomous growth and contribute to neoplastic development.
The aim of this study was to investigate the presence and relationship of EGFR and K-Ras mutations with smoking history in a series of 50 primary NSCLC tumors.
DNA was isolated by digestion of tissue samples using a DNA isolation kit. EGFR and K-ras mutations were investigated by Real Time-PCR assay. To confirm the mutations exons 18-21 of the EGFR gene and the whole K-ras gene were also analyzed by cycle sequencing in the samples found positive by the real-time PCR assay.
In four patients (8%) EGFR mutations were detected. Two of these mutations were L858R and the remaining two were deletion mutations spanning codons from 746 to 750. The L858R mutation was significantly associated with smoking status (p=0.003). K-ras codon 12 and 61 mutations were also observed in 4 patients. However, no association was observed between K-ras mutations and tumor staging, sex, histology and smoking status of the patients.
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 1126. doi:10.1158/1538-7445.AM2011-1126
Abstract 1145: Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis
Authors: Chen Kexin , Cheng Hanyin , Zhang Lina , Cogdell David E. , Zheng Hong , Schetter Aaron J. , Nykter Matti , Harris Curtis C. , Hamilton Stanley R. , Zhang Wei 
Published: June 2012

Abstract
Background: Colorectal cancer (CRC) remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs), have recently identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers.
Methodology/Principle Findings: By using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV CRC in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in a cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced CRC.
Conclusions/Significance: We propose that plasma miR-141 is a novel biomarker that complements CEA in detecting CRC with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis.
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 1145. doi:10.1158/1538-7445.AM2011-1145
Abstract 1151: microRNAs affect therapeutic sensitivity of human gliobastoma to temozolomide
Authors: Quintavalle Cristina , Garofalo Michela , Romano Giulia , Iaboni Margherita , Donnarumma Elvira , Nuovo Gerard , Croce Carlo M. , Condorelli Gerolama 
Published: June 2012

Abstract
Glioma is among the most deadly type of cancer. In spite of the enormous improvements made the prognosis of malignant glioma has remained poor over the last decade. Many glial-derived tumors seem to be particularly resistant to apoptosis following DNA damage. MicroRNAs (miRNA) represent a novel class of small RNAs that might play a fundamental role in tumorigenesis, cell proliferation, migration and apoptosis. Temozolomide is an alkylating agent used in glioma patients that alkylates/methylates DNA. The alkylation damages the DNA and triggers the death of tumor cells. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme which removes DNA adducts. MGMT activity is frequently lost in glioblastoma in the presence of CpG island hypermethylation in the promoter region. The methylation status of the MGMT promoter is considered to be indicative of a good outcome in patients with malignant gliomas. However, in some studies the correlation between MGMT promoter methylation and MGMT expression levels are contradictory. Other possible mechanisms of MGMT modulation should exist. Therefore, we investigated the role of miRs on the regulation of MGMT expression levels.
We analyzed temozolomide sensitivity of human glioma cell lines, T98G and U87MG. T98G resulted resistant to temozolomide, whereas U87MG cells were sensitive. Through a microarray analysis we provided evidences that miR-221/222 are differentially expressed in U87MG compared to T98G cells. Bioinformatics analysis through RNA Hybrid indicated a possible match between MGMT 3’UTR and miR-221/222. Luciferase assay confirmed that miR-221/222 are capable to bind the 3’UTR of MGMT and to impair its mRNA translation. Western blot and RT-PCR analysis upon synthetic pre-miR-221/222 transfection of T98G cells indicated that MGMT levels were significantly decreased. At the contrar, the transfection of U87MG cells with anti-miR-221/222 induced an increase of MGMT levels. Therefore this data indicate that MGMT is a new target of miRs -221/222. The analysis of cell death with MTT, Annexin V and colony assay upon temozolomide treatment in cells whose miR-221/222 levels were modulated, demonstrated an important role of those miRs in temozolomide sensitivity.
All these data indicate that miR-221/222 might represent a new strategy for regulation of MGMT expression levels and thus temozolomide sensitivity and an improvement in chemotherapy strategy for glioblastoma patients.
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 1151. doi:10.1158/1538-7445.AM2011-1151
Abstract 1174: Genetic variations in microRNA biogenesis pathway genes as susceptibility loci for lung cancer risk
Authors: Ye Yuanqing , Spitz Margaret R. , Yang Hushan , Wu Xifeng 
Published: June 2012

Abstract
Many studies have demonstrated that genetic susceptibility played an important role in lung cancer etiology. It has been estimated that microRNAs (miRNAs) may regulate the expression of one third of all human genes and are related to carcinogenesis through their function as oncogenes or tumor suppressors. To test the hypothesis that common sequence variants in microRNA pathways may affect individuals’ lung cancer susceptibility, we assessed the association of 75 haplotype tagging and potential functional single nucleotide polymorphisms (SNPs) in 8 miRNA biogenesis pathway genes with lung cancer risk in a case control study of 1135 lung cancer cases and 803 healthy controls among Caucasians. Overall, SNP rs2302905 from RNASEN exhibited the strongest association and remained significant after adjusting for multiple comparisons using q value at 10% level. Individuals carrying the variant allele of rs2302905 showed a 1.40-fold increased risk of lung cancer (95% CI = 1.11- 1.77; P = 0.0042). Interestingly, similar to rs2302905, two additional SNPs (rs10805564 and rs639174) from RNASEN also showed increased risk of lung cancer (OR = 1.29, 95% CI = 1.04- 1.60; and OR = 1.24, 95% CI = 1.00- 1.53). Two SNPs (rs197412 and rs85276) from DDX20 had significantly reduced lung cancer risk (OR = 0.80, 95% CI = 0.65- 1.00; and OR = 0.78, 95% CI = 0.61- 1.00). Stratified analyses by age, gender, and smoking status identified several additional SNPs that were associated with lung cancer risks in sub-populations. We also counted the number of unfavorable genotypes in each individual to assess the cumulative effect of the top 5 SNPs on lung cancer risk and found a significant gene-dosage effect (P for trend = 0.00028). Compared to the individuals with ≤ 3 unfavorable genotypes in the low risk group, carriers of 4 and 5 unfavorable genotypes had increased risk of lung cancer (OR = 1.30, 95% CI = 0.96 to 1.77; and OR = 2.09, 95% CI = 1.47 to 2.98, respectively). In conclusion, genetic variants in miRNA biogenesis pathway genes may affect the risk of lung 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 1174. doi:10.1158/1538-7445.AM2011-1174
Abstract 1183: miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines
Authors: Henry Jon C. , Park Jong-Kook , Jiang Jinmai , Kim Ji Hye , Roberts Lewis R. , Nagorney David M. , Banerjee Soma , Schmittgen Thomas D. 
Published: June 2012

Abstract
Previous work by us and others reported decreased expression of miR-199a-3p in hepatocellular carcinoma (HCC) tissues compared to adjacent benign tissue. We report here a significant reduction of miR-199a-3p expression in 7 HCC cell lines (Huh7, HepG2, SNU182, PLC/PRF/5, Hep3B, SNU423 and SNU449) compared to primary hepatocytes. To determine if miR-199a-3p has a tumor suppressive role, miR-199a-3p mimetic was transfected into the 7 HCC cell lines. miR-199a-3p mimetic reduced cell proliferation by approximately 60% compared to control oligonucleotide in only two cell lines (SNU449 and SNU423); the proliferation of the other 5 treated cell lines was similar to control oligonucleotide. A miR-199a-3p mimetic formulated with chemical modifications to enhance stability while preserving processing reduced cell proliferation in SNU449 and SNU423 to the same extent as the commercially available miR-199a-3p mimetic. Furthermore, only the duplex miR-199a-3p mimetic, and not the guide strand alone, was effective at reducing cell viability. Since a CD44 variant was essential for c-Met signaling (Orian-Rousseau, et al., Genes Dev. 2002) and c-Met is a known miR-199a-3p target, we hypothesized that miR-199a-3p may also target CD44. Indeed, miRNA target algorithms predict miR-199a-3p to be a putative target of CD44. Immunoblotting confirmed that only the HCC lines that were sensitive to the effects of miR-199a-3p mimetic (SNU449 and SNU423) were CD44+. Direct targeting of CD44 by miR-199a-3p was confirmed using luciferase reporter assays and immunoblotting. Transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin; both effects were enhanced when hyaluronic acid was added to the cell cultures. An inverse correlation between the expression of miR-199a-3p and CD44 protein was noted in primary HCC tissue specimens. The anti-proliferative and anti-invasive properties of miR-199a-3p mimetic on CD44+ HCC may be a useful targeted therapy for CD44+ HCC.
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 1183. doi:10.1158/1538-7445.AM2011-1183
Abstract 1198: Connexin 43 is an estrogen receptor β1 regulated gene in breast cancer
Authors: Badiani Ketan , McLachlan Elizabeth , Ung Kanyarat , Ung Charles , Murphy Leigh C. 
Published: June 2012

Abstract
Connexins are a family of transmembrane proteins that allow direct cell to cell communication. Normal human mammary epithelium expresses both connexin 43 (Cx43) and connexin 26 (Cx26) and when overexpressed, these connexins have been shown to act as tumor suppressors in human breast cancer. We have previously characterized two human breast cancer cells lines that inducibly overexpress estrogen receptor β1 (ERβ1) and we utilize these cells to examine the regulation of Cx43 by ERβ1 in human breast cancer. We observe that in both MCF7 and MDA-MB-231 cells that inducibly overexpress ERβ1, upon estradiol (E2) stimulation, there is a 4-fold or greater increase in Cx43 protein, regardless of whether cells are grown in two-dimensional (2D) or organotypic three-dimensional (3D) cell culture. Cx43 mRNA increases 2-fold upon ERβ1 induction and E2 stimulation of MDA-MB-231 cells with no co-incident change in Cx26 mRNA. Cx43 protein significantly increases upon treatment of cells with selective ERβ agonists, like DPN or genistein, but not with the ERα agonist PPT. Treatment of cells with ICI 182780 inhibits the E2 stimulated increase in Cx43 protein, while, the E2 stimulated increase was still seen in the presence of the anti-progestin RU486. Moreover, we observe a morphological shift in the appearance of MDA-MB-231 cells that overexpress ERβ1 when grown in 3D culture to that of a more differentiated-like organoid. Further work will involve an analysis of the interaction between ERβ1 and the Cx43 promoter. Taken together, the data suggests that Cx43 is an ERβ1 regulated gene. This research is funded by grants from CBCRA (Canadian Breast Cancer Research Alliance), CIHR (Canadian Institutes for Health Research), and CCMF (CancerCare Manitoba Foundation). EM is the recipient of a post-doctoral research fellowship from the Canadian Cancer Society Research Institute – Terry Fox Foundation.
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 1198. doi:10.1158/1538-7445.AM2011-1198
Abstract 120: Over-expression of microRNA-221 causes neoplastic cell transformation through induction of the epithelial-mesenchymal transition in non-tumorigenic liver cells
Authors: Tryndyak Volodymyr P. , Beland Frederick A. , Pogribny Igor P. 
Published: June 2012

Abstract
MicroRNAs (miRNAs) are negative regulators of gene expression with immense significance in cancer progression. In cancer cells, aberrant expression of miRNAs has been associated with every aspect of tumor biology, including tumor progression, invasiveness, metastasis, and acquisition of resistance of malignant cells to chemotherapeutic agents. MicroRNA miR-221 is frequently up-regulated in several major human cancers, including liver cancer. More importantly, up-regulated miR-221 is capable of enhancing liver carcinogenesis; it is not clear, however, if over-expression of any given miRNA, including miR-221, is sufficient to initiate neoplastic cell transformation. The goal of our study was to determine the tumorigenic potential of the miR-221 on normal non-transformed liver cells. Non-tumorigenic TRL-1215 rat liver cells were transfected with 20 nM of either scrambled RNA oligonucleotide (control) or pre-miR-221. At 72 hours post-transfection, adherent cells were harvested, re-seeded, and transfection was repeated, a process that was repeated for 10 months. After 1, 2, 4, and 10 months, control and miR-221-transfected cells were collected for subsequent analyses. Ectopic transfection of miR-221 for 1, 2, and 4 months resulted in significant down-regulation of the experimentally confirmed targets of the miR-221, including p27, Ddit4, and Esr1 genes and a number of newly predicted target genes. Previous reports have linked the oncogenic properties of miR-221 in liver carcinogenesis to down-regulation of critical cancer-related genes p27, Ddit4, and Esr1; however, despite a profound and early inhibition of these target genes, we did not find any evidence of neoplastic cell transformation until 10 months of pre-miRNA-221 transfection. At that time, we detected substantial morphological changes in the miR-221-transfected cells and the accumulation of neoplastic phenotypic features (i.e., soft agar colony formation and increase in cell invasiveness). These changes were accompanied by a significant decrease in the levels of plasma membrane E-cadherin. Array-based RT-PCR analysis demonstrated changes in the expression of a number of extracellular matrix and adhesion genes, including more than a 50 fold up-regulation of the mesenchymal cell marker N-cadherin (Cdh2) gene. In conclusion, our results demonstrate that the up-regulation of miR-221 not only enhances liver tumorigenesis, but also initiates the neoplastic cell transformation of the normal liver cells.
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 120. doi:10.1158/1538-7445.AM2011-120
Abstract 1201: Role of the chemokine CXCL12 in the estrogen response of breast cancer cells
Authors: Hawsawi Nahed M. 
Published: June 2012

Abstract
The purpose of this study was to investigate the extent to which CXCL12 mediates the effects of estrogen in estrogen-responsive breast cancer cells. Expression microarray studies have identified CXCL12 as a gene regulated consistently by estrogen in estrogen-responsive breast cancer cells in our own and other laboratories and it has been reported that CXCL12 mediates the proliferative effects of estrogen. CXCL12 activates two seven transmembrane G protein-coupled receptors, CXCR4 and CXCR7, that transducer signals via heterotrimeric G-proteins. CXCR4 has long been accepted, whereas CXCR7 was identified more recently as a potential CXCL12 receptor.
Methods: Expression of CXCL12, CXCR4 and CXCR7 was measured in five estrogen-responsive and five estrogen-nonresponsive breast cancer cell lines by qRT-PCR and western transfer analysis. The effects of CXCL12 on proliferation of the cells were assessed by DNA quantification and on migration in a modified Boyden chamber assay. The ability of CXCL12 to activate the downstream signalling molecules, MAPK and Akt, was measured by western transfer analysis with a phospho-specific antibodies. The motogenic responses of different breast cancer cell lines to CXCL12 were measured in modified Boyden chamber and in vitro wounding assays. The relative importance of CXCR4 in the CXCL12 response was probed with a specific inhibitor of CXCR4 receptor.
Results: The expression of CXCL12, CXCR4 and CXCR7 varied greatly between the ten breast cancer cell lines analyzed. CXCL12 expression was highest in estrogen-responsive T-47D cells whereas CXCR4 and CXCR7 expression was highest in estrogen-nonresponsive MDA-MB-231 cells. CXCL12 was detected after secretion into medium conditioned by T-47D and MCF-7 breast cancer cells. CXCL12 did not stimulate the proliferation of MCF-7 or T-47D cells in the absence or presence of estrogen. CXCL12 did stimulate breast cancer cell migration in a concentration-dependent manner and cells that express high concentrations of the CXCL12 receptor were more responsive to CXCL12. CXCL12 stimulated Phosphorylation of both MAPK and Akt in estrogen-responsive and non-responsive breast cancer cells.
Conclusion: This study shows that CXCL12 does not mediate the proliferative effects of estrogen on breast cancer cells. CXCL12 does however stimulate the migration of both estrogen-responsive and estrogen non-responsive breast cancer cells. CXCL12 mediates it effects in breast cancer cells by activation on both the MAPK and Akt signal transduction pathways.
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 1201. doi:10.1158/1538-7445.AM2011-1201