bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 163: mRNA and miRNA profiling of platinum-resistant non-small cell lung cancer cell clones identifies potential targets involved in DNA metabolism and DNA replication
Authors: Salim Hogir M. , Lundholm Lovisa , Zong Dali , Hååg Petra , Mörk Birgitta , Viktorsson Kristina , Lewensohn Rolf 
Published: June 2012

Abstract
Non small cell lung cancer (NSCLC) constitutes the majority of lung cancer diagnoses and platinum-based chemotherapy regimen is the standard treatment. Unfortunately, a large proportion do not respond or relapse on such treatment regimens for yet only partly revealed mechanisms. We profiled residual clones of NSCLC cells after treatment with cisplatin. The mRNA and miRNA pattern was compared between untreated and cisplatin-resistant NSCLC clones using Affymetrix gene and miRNA expression arrays, respectively.
We found that around 1100 genes were up regulated (at least two fold) and about 1200 genes were down regulated (at least two fold) in the cisplatin-resistant clones compared with untreated NSCLCs. We then used the Gene Set Enrichment Analysis (GSEA) to find the over- and underrepresented gene sets in large datasets like, Gene Trail and Gene Ontology. We found that cisplatin-refractory NSCLCs showed increased expression of genes involved in different cellular mechanisms including DNA metabolic processes, DNA replication and DNA-dependent DNA replication initiation for example, XRCC2, FANCI, FANCD2, RRM1, MRE11A, BLM, RRM2 and TOP2A which were validated on RNA, protein and functional level for their role in cisplatin sensitivity of NSCLC.
We also found a few miRNAs that were up regulated in cisplatin refractory NSCLC by a least 1.3-fold e.g. miRNA-25 star and miRNA-1290. Interestingly, only 14 miRNAs were down regulated (by at least 1.3 fold) in the surviving cisplatin refractory NSCLC cells. Among these miRNAs were (miR-29b, miR-210, miR-486-3p, miR-324-5p, miR-572, miR-30a, e, miR-424, miR-449a, b, miR-301a, miR-153, miR-150 star and miR-34c-5p). We then looked for the predicted targets of these miRNAs using Target scan and microcosm and we found a large list of genes to be potential targets of the miRNAs among them are genes involved in apoptosis, cell cycle regulation, Wnt signaling pathway and other cellular processes (ex. VDAC, SMAD2, RAN, etc.). Correlation analysis between miRNA gene targets and gene expression data is ongoing with the aim to identify and validate putative targets on RNA, protein and functional level.
In conclusion, our data show that cisplatin refractory NSCLC tumors have dysregulated mRNAs and miRNAs. Among the dysregulated genes, are certain genes involved in DNA metabolism, DNA replication and DNA-dependent DNA replication initiation which may be novel targets for improved platinum-based therapy response of NSCLC.
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 163. doi:10.1158/1538-7445.AM2011-163
Abstract 1636: ErbB4 is a new therapeutic target for metastasis and anoikis resistance in Ewing's sarcoma
Authors: Mendoza-Naranjo Ariadna , Mistry Pitri , Lazic Nikola , Strauss Sandra J. , Sorensen Poul HB 
Published: June 2012

Abstract
Most Ewing sarcoma (ES)-related deaths occur as a result of metastatic disease. As a barrier to metastases, cells normally undergo a form of cell death called ‘‘anoikis” after they lose contact with the extracellular matrix or neighboring cells. Tumor cells that acquire malignant potential develop mechanisms to suppress anoikis. We previously demonstrated that ES tumors suppress anoikis and show prolonged survival as multicellular spheroids, which mimic micrometastases under anchorage-independent conditions. Here we have used the paired CHLA-9 primary tumor line established at diagnosis and the metastatic CHLA-10 line established from the same patient after four cycles of induction chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and etoposide, as well as high-throughput Affymetrix whole exon array platforms to screen for potential therapeutic targets to treat metastatic disease. We have identified ErbB4, a member of the epidermal growth factor receptor (EGFR) family, as a novel mediator of anoikis resistance in ES. We detected a 4-fold increase in ERBB4, along with enhanced ErbB4 protein expression and Tyr kinase activation (confirmed by P-Tyr kinase proteome arrays) in CHLA-10 cells grown under anchorage independent conditions, compared to CHLA-9 tumor cells under the same conditions. Upregulated ErbB4 expression was further confirmed in a panel of metastatic vs. primary ES cell lines at both the mRNA and protein levels. We are currently validating these findings in the clinical setting by analyzing ErbB4 expression in paired primary vs. metastatic biopsies from ES patients. shRNA-mediated knockdown of ErbB4, or treatment with the ErbB inhibitor Lapatinib, dramatically reduced proliferation, decelerated tumor invasion, and sensitized metastatic/chemoresistant ES tumors to chemotherapeutic drugs used to treat ES patients. Taken together, our findings identify ErbB4 as a novel target for metastasis and anoikis resistance in ES.
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 1636. doi:10.1158/1538-7445.AM2011-1636
Abstract 1657: A pivotal role for epithelial cell adhesion molecule (EpCAM) in survival of lung cancer cells
Authors: Hase Tetsunari , Sato Mitsuo , Yoshida Kenya , Takeyama Yoshihiro , Elshazley Momen , Sekido Yoshitaka , Gazdar Adi F. , Minna John D. , Kondo Masashi , Hasegawa Yoshinori 
Published: June 2012

Abstract
Introduction: Epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of human cancers, including lung cancer, and its contribution to increased proliferation through up-regulating cell cycle accelerators such as cyclin A/E is well demonstrated in breast and gastric cancers. Nevertheless, very little is known about its role in survival of cancer cells. In addition, functional role of EpCAM in the pathogenesis of lung cancer remains to be explored.
Matrials and methods: 18 human non-small cell lung cancer cell lines and an immortalized normal human bronchial epithelial cell (HBEC4) lines were used. EpCAM expression was measured by quantitative real-time PCR (qRT-PCR) and FACS. RNA interference (RNAi)-mediated gene silencing for EpCAM was done in three non-small cell lung cancer cell and HBEC4 lines. Cell proliferation was measured by WST-1 and clonogenic growth was measured by liquid and soft agar colony formation assays. Apoptosis was evaluated by annexin V/7-AAD staining. FACS with PI staining was done to examine apoptosis and cell cycle. p27kip1 expression was evaluated by western blot analysis. In vitro invasion assay was done by using transwell chambers layered with matrigel and invading cells were stained and counted.
Results: We analyzed the expression of EpCAM in a panel of lung cancer cell and HBEC4 lines and found that most of lung cancer cell lines expressed EpCAM. EpCAM knockdown suppressed proliferation and clonogenic growth of two EpCAM-expressing lung cancer cell lines in anchorage dependent and independent conditions. EpCAM knockdown suppressed invasiveness in a highly invasive line but not in a lowly invasive cell line. In addition, EpCAM knockdown induced massive apoptosis in both cell lines as well as another EpCAM-expressing lung cancer cell line but to a much lesser extent in HBEC4 line. EpCAM knockdown caused lung cancer cells to have increased responsiveness to contact inhibition in part through up-regulating p27kip1 cyclin dependent kinase inhibitor. Conclusion: These results demonstrate that EpCAM substantially contributes to the pathogenesis of lung cancer, especially in its survival, and the development of EpCAM-targeted therapy for lung cancer may have promise.
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 1657. doi:10.1158/1538-7445.AM2011-1657
Abstract 1675: Identification of KURO3 overexpressed in high-grade prostate cancer
Authors: Tamura Kenji , Furihata Mutsuo , Satake Hirofumi , Anchi Takashi , Ashida Shingo , Yamasaki Ichiro , Inoue Keiji , Shuin Taro 
Published: June 2012

Abstract
Prostate cancer is usually androgen-dependent and responds well to androgen ablation therapy. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype. These cancer cells are originally high-grade and show very poor response to any anticancer therapies. To characterize the molecular features of clinical high-grade prostate cancers, we analyzed gene-expression profiles by genome-wide cDNA microarray combined with microdissection and found dozens of trans-activated genes in clinical high-grade prostate cancers. Among them, we report the identification of a new biomarker, KURO3. We confirmed overexpression of KURO3 in high-grade prostate cancer cells by RT-PCR. Knockdown of KURO3 expression by siRNA in a prostate cancer cell line resulted in a drastic decrease of cell numbers. In contrast, KURO3 overexpression in a prostate cancer cell line promoted cell proliferation. These findings suggest that KURO3 could be involved in aggressive phenotype of prostate cancers, including hormone-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers.
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 1675. doi:10.1158/1538-7445.AM2011-1675
Abstract 1679: Increased expression of hCAS/CSE1L in colorectal cancer: Correlation with tumor progression
Authors: Henderson-Jackson Evita , Eschrich Steven A. , Chen Dung-Tsa , Yeatman Timothy J. , Coppola Domenico , Malafa Mokenge P. 
Published: June 2012

Abstract
Introduction. The human cellular apoptosis susceptibility (hCAS) gene product has been shown to be involved in cellular proliferation, apoptosis, invasion and metastasis. CSE1 is a yeast gene with high homology to hCAS (CSE1-like or CSE1L) which has been shown to be involved in chromosome segregation during mitosis. hCAS has also been shown to be a key player in cytoplasm-to-nuclear transport by shuttling importin-alpha from the nucleus back out into the cytoplasm. We hypothesized that the expression of hCAS may be altered during the progression of human colorectal cancer (CRC).
Methods. In order to examine hCAS at the gene expression level, we surveyed three different datasets from studies in which Affymetrix U133+gene chips had been performed on patients with CRC, as well as patients with adenomas and normal individuals. We examined relative gene expression levels for 3 probe sets on the U133+ gene chip that closely align to the refseq for the hCAS gene. hCAS protein expression level was semiquantitatively measured using immunohistochemistry (IHC) and the tissue microarray (TMA) technique. A CRC TMA had been previously created at the Moffitt Cancer Center using resection specimens of primary CRC of different stages, and inclusive of adenomas and normal tissues samples from the same patients.
Results. hCAS gene expression was increased in all adenoma and CRC samples tested by microarray, compared to histologically normal colonic mucosa. However, the difference in hCAS mRNA levels between adenoma and CRC samples was not statistically different. No correlation was found between hCAS and cancer stage, grade, vascular invasion, sex and/or age. Interestingly, in the invasive CRCs, intense hCAS proteins expression was localized to both nucleus and cytoplasm. Conversely, early stage lesions showed predominantly cytoplasmic hCAS staining.
Conclusions. Our results demonstrate that hCAS protein is expressed early and across all stages of CRC development. Because of its early expression hCAS may represent a marker for early detection of CRC. In addition, because of its involvement in a variety of important cellular processes, this gene product might represent a new potential target for prevention and treatment of CRC.
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 1679. doi:10.1158/1538-7445.AM2011-1679
Abstract 1684: 2-Methoxyestradiol reverses the epithelial-mesenchymal transition in Barrett's adenocarcinoma cells
Authors: Chattopadhyay Indranil , Majumder Monami , Haque Inamul , De Archana , Wickliffe Joi , Banerjee Snigdha , Van Veldhuizen Peter J. , Banerjee Sushanta K. , Kambhampati Suman 
Published: June 2012

Abstract
2-Methoxyestradiol (2-ME2) is a novel anti-cancer agent because of its ability to potentiate apoptotic cell death and inhibit cancer cell growth and angiogenesis. In our study, we have investigated whether 2-ME2 is able to modulate epithelial-mesenchymal transition (EMT) in Barrett's esophageal adenocarcinoma cell (OE33), which has been postulated as an absolute requirement for tumor invasion and metastasis. Expression of epithelial (E-cadherin, β-catenin, Keratin-19) and mesenchymal markers (Oct-4, Vimentin) and stem cell markers (CD44, CD24) were studied at mRNA and protein levels in OE33 cells that were treated with 5µmolar/L of 2-ME2 for 24 h and 48 h. Our results indicate expression of β-catenin and E-cadherin is activated in a 2-ME2 dependent fashion in OE33 cells. Expression of Vimentin and Oct-4 is significantly down-regulated in 2-ME2 treated OE33 cells. Altogether, these results provide new insights into the role of 2-ME2 in EMT modulation, which may facilitate development of new therapeutic strategies to prevent the tumor invasion and metastasis.
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 1684. doi:10.1158/1538-7445.AM2011-1684
Abstract 1716: Mechanisms of resistance in carboplatin, docetaxel and dual drug resistant ovarian cancer cell lines
Authors: Lannér Carita , Armstrong Stephen , Kalatskaya Irina , Guo Baoqing , Parissenti Amadeo 
Published: June 2012

Abstract
Carboplatin and docetaxel are two standard chemotherapeutics used to treat ovarian cancer. Patients often exhibit resistance to single agent therapy, and dual agent therapy was developed to overcome this resistance. However, resistance still commonly occurs in dual agent therapy. It is known that specific changes in gene expression occur in single agent resistance, but it is not known whether resistance to combined chemotherapy involves novel gene expression changes or if resistance is only the sum of changes seen in single agent resistant cells.
Using the chemotherapy-naïve A2780 ovarian cancer cell line, we have generated three resistant cell lines including carboplatin and docetaxel single agent resistant lines (A2780CBN, and A2780DXL respectively), and a carboplatin/docetaxel dual resistant line (A2780CBNDXL) by exposing A2780 cells to increasing concentrations of drug until a dose is reached where resistance could no longer be developed. The concentration of drug at which 50% of cells die (IC50) was measured for reach resistant cell line using a clonogenic assay. The IC50 of A2780CBN is 8×10−5 M, 13-fold more resistant than the parent line. The IC50 of A2780DXL is 3×10−7 M, 5000-fold more resistant than the parent line. The IC50 of A2780CBNDXL is 8×10−6 M for carboplatin and 8×10−9 M for docetaxel.
Changes in gene expression associated with the development of resistance in each cell line were identified by microarray analysis on Agilent 4×44k total human genome arrays. In the A2780CBN line there were a total of 1209 significant changes in gene expression, in the A2780DXL line there were 955 changes, and in the A2780CBNDXL line there were 1336 changes. The majority of changes in each cell line (70%) were unique, indicating that novel changes in gene expression occur in the dual line. A Functional Interaction Network-based analysis was conducted on the microarray data identify important gene clusters acting in the drug resistant A2780 ovarian cancer cell lines. Ten major clusters were found in the A2780CBN line, 8 clusters in the A2780DXL line and 10 clusters in the A2780CBNDXL line. Although similar clusters occurred among the lines, the genes in them were different and several unique clusters occurred in the dual line. Functional enrichment analysis will be done for every cluster and the most significant pathways will be taken into further consideration for validation.
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 1716. doi:10.1158/1538-7445.AM2011-1716
Abstract 1724: Inhibition of the PI3K and mTOR pathways reverses gemcitabine resistance in pancreatic cancer
Authors: Chung Vincent , Gaur Shikha , Ann David , Yen Yun 
Published: June 2012

Abstract
BACKGROUND: Despite chemotherapy, survival for most patients with pancreatic cancer is less than one year. These dismal statistics reflect the lack of effective therapy. Understanding the molecular pathways that drive cancer growth may help target our therapy. Over 90% of pancreatic cancers are K-ras mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. We explored the combination of gemcitabine and BEZ235, a novel dual PI3K/mTOR inhibitor, in pancreatic cancer cell lines.
METHODS: Cytotoxicity assays were performed utilizing the CellTiter-96-Aqueous-One-Solution-Cell-Proliferation-Assay-(MTS) from Promega in K-ras mutant MIA PaCa-2 pancreatic cancer cell lines. We generated gemcitabine resistant cell lines by serial passage of cells with increasing concentrations of drug. We utilized the CalcuSyn program by Biosoft to quantify synergism or antagonism with drug combinations. We also collected cells 6 hours after drug treatment for analysis of phosphorylated proteins.
RESULTS: MIA PaCa-2 wild-type and gemcitabine resistant cells were treated with 100, 50 and 25 nM of either gemcitabine, BEZ235 or the combination of both. At the 100 nM dose, cell viability of the wild-type cells was 66%, 55% and 39% respectively. In the gemcitabine resistant cells, cell viability was 84%, 63% and 44%. The combination index was 0.51 in the wild-type cells and 0.46 in the gemcitabine resistant cells indicating synergy in both cell lines. In both cell lines, p-S6K and p-AKT levels increased with gemcitabine treatment which was abrogated by treatment with BEZ-235. Interestingly, in the gemcitabine resistant cells, there appeared to be significantly increased levels of p-MEK1 compared to control.
CONCLUSION: Because pancreatic cancer remains resistant to current therapies despite recent advances in the development of molecular targeted therapies, there is an urgency to understand these pathways. We showed that the combination of gemcitabine and BEZ235 is synergistic in both cell lines but cell viability still remains high at 39% and 44% respectively. Combination with a MEK inhibitor may help to increase cell apoptosis and studies are on-going.
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 1724. doi:10.1158/1538-7445.AM2011-1724
Abstract 1725: Activation of the p53 pathway by the MDM2 antagonist nutlin-3 downregulates the DNA repair protein hABH2 and sensitizes glioma cells to chemotherapy
Authors: Johannessen Tor-Christian A. , Prestegarden Lars , Grudic Amra , Tysnes Berit B. , Bjerkvig Rolf 
Published: June 2012

Abstract
Glioblastoma is the most frequent and most malignant primary brain tumor in adults. Standard first line treatment for glioblastoma patients includes surgery followed by focal fractionated radiotherapy with concomitant and adjuvant administration of the alkylating agent temozolomide. During the course of therapy, however, radio- and chemoresistance typically become evident through local tumour recurrence, and median survival time for glioblastoma patients remains around 15 months. In order to improve this poor prognosis, there is a critical need to recognize the molecular basis for the low sensitivity of glioblastomas towards chemotherapeutic treatment. We have previously reported that elevated expression levels of the DNA repair protein hABH2 may provoke temozolomide resistance in glioma cells. In this work, we explored whether activation of the p53 (encoded by TP53) pathway by the MDM2 antagonist nutlin-3 would influence cellular levels of hABH2 and subsequently chemoresistance. Immunoblotting following nutlin-3 exposure for 24 hours showed increased protein levels of p53, MDM2, p21 and PUMA in glioma cell lines expressing wild type p53, but decreased hABH2 levels in a dose-dependent manner. Real-time quantitative PCR confirmed reduced hABH2 mRNA levels after nutlin-3 therapy, suggesting that hABH2 downregulation occurred at a transcriptional level. Combination therapy with nutlin-3 and temozolomide further enhanced activation of the p53 pathway, diminished levels of hABH2 protein and increased cellular cytotoxicity compared to either agent alone. Our results show that levels of hABH2 can be downregulated by activation of the p53 pathway in glioma cells. This suggests that p53 pathway activation may increase glioma sensitivity to chemotherapy not only by increased transcription of pro-apoptotic genes such as PUMA, but also by reducing levels of DNA repair proteins such as hABH2 that would otherwise promote drug resistance.
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 1725. doi:10.1158/1538-7445.AM2011-1725