bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-142: Induced expression and activation of oncogenes in NSCLC (non-small cell lung cancer) in the absence of activating mutations of EGFR and k-Ras
Authors: Gorgisen Gokhan , Ozes Derya , Pehlivanoglu Suray , Erdogan Abdullah , Dertsiz Levent , Ozbilim Gulay , Ozbudak Irem Hicran , Ozes Osman N. 
Published: August 2012

Abstract
Induced expression and activation of oncogenes in NSCLC (non-small cell lung cancer) in the absence of activating mutations of EGFR and k-Ras Background: Activating mutations in exon 18,19 and 21 of EGFR and changes in codons 12,13 and 61 of k-RAS are blamed for the development of NSCLC in 88% of patients. Therefore, it is suggested that the use of tyrosine kinase (TK) inhibitors, Erlotinib or Gefitinib, can be very useful to treat NSCLC patients. NSCLC patients harboring activating mutations of EGFR are very responsive to TK inhibitors; while, patients who do not have these mutations are unresponsive to these treatment. Therefore, it is recomended that before initiating therapy with these TK inhibitors, mutation status of EGFR must be determined. Methods: The protein lysates of tumor samples and DNA have been isolated from tumor and corresponding normal tissues of 16 NSCLC patients who underwent surgery. Genomic-DNA is used to sequence exons 18, 19 and 21 of EGFR1 as well as the second exon of k-RAS. Protein lysates have also been used to determine the expression or phosphorylation levels of EGFR and down-stream elements such as, STAT3, ERK and AKT. The expression levels of metastatic factors TWIST1 and GAPDH have also been determined. Results: Even though sequence analysis of indicated regions of EGFR and k-RAS reveal no mutation, the protein analysis of 16 tumor samples show remarkable changes in the activation or expression levels of above mentioned oncogenes. Among the patients different levels of induced phosphorylation have been found; these levels are, 2 to 23 fold induced phosphorylation of ERK, 1.5 to 20 in AKT, 2 to 10 in EGFR, and 2 to 24 in TWIST1 and 2-450 in GAPDH. These results indicate that even in the absence of any activating mutations of EGFR or k-Ras, the EGFR pathway is still very active in some NSCLC patients. Conclusion: If activating mutations of EGFR is considered the main reason for TK therapy, then TK use may not be the optimal decision to make. Results clearly indicate that NSCLC patients who do not show any activating mutations of EGFR may benefit from TK therapy. Even though, activating mutations of EGFR is the “gold standard” for TK therapy, surgery materials of NSCLC patients must be examined for oncogene activation. This is especially true for the EGFR pathway since, as shown in this work, the tumor micro-environment created by the tumor or surrounding cells can be as important as the activating mutations of EGFR.
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 LB-142. doi:1538-7445.AM2012-LB-142
Abstract LB-145: Folliculin interacts with p0071 (Plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis
Authors: Nahorski Mike S. , Seabra Laurence , Straatman-Iwanowska Ania , Wingenfeld Aileen , Reiman Anne , Lu Xiaohong , Gissen Paul , Hatzfeld Mechthild , Maher Eamonn 
Published: August 2012

Abstract
Inherited mutations in the folliculin gene (FLCN) cause the Birt-Hogg-Dubé syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterised. We identified plakophilin-4 (PKP4, p0071) as a potential novel folliculin interacting protein by yeast-2-hybrid analysis. We confirmed the interaction of folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell folliculin status on p0071-related functions. Folliculin and p0071 partially colocalised at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of folliculin deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in folliculin deficient cells. Deficiency of folliculin and of p0071 resulted in tight junction defects and mislocalisation of E-cadherin in IMCD-3 renal tubular cells. These findings suggest that aspects of folliculin tumour suppressor function are linked to interaction with p0071 and regulation of RhoA signalling.
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 LB-145. doi:1538-7445.AM2012-LB-145
Abstract LB-146: A study of p16 inactivation in lung cancer cell lines and tumor samples with a meta-analysis of the literature
Authors: Tam Kit W. , Zhang Wei , Soh Junichi , Chen Min , Sun Han , Stastny Victor , Thu Kelsie , Lam Wan , Gazdar Adi 
Published: August 2012

Abstract
Introduction: p16 inactivation is a common genetic alteration in lung adenocarcinoma and is often inactivated by homozygous deletion (HD) or methylation of promoter, or rarely by point mutation. While p16 methylation was reported to be linked to KRAS mutation and smoking, the association between specific p16 inactivation mechanism and other common genetic changes and smoking status remains controversial. In this study, we examined all of the three p16 inactivation mechanisms and correlated them with other common genetic chanes in lung adenocarcinoma: EGFR, KRAS, and LKB1, and smoking status. We also performed a meta-analysis to study the effect of smoking on p16 inactivation. Methods: We examined 40 cell lines and 45 tumor samples from patients with primary NSCLC, mostly adenocarcinoma. SNP and qPCR were used to detect HD. Methylation was determined by MSP analysis and mutation was identified by sequencing. We performed the meta-analysis by using Woolf's test to identify heterogeneity and followed by using a random-effect model. Results: The cell lines and tumor samples demonstrated similar results. No statistical differences were found between the two groups and the data were hence combined for analysis. p16 inactivation occurred at similar frequencies (54-57%) regardless of mutational status of EGFR, KRAS and LKB1 but the major mechanism of inactivation varied. Multivariate analysis showed that LKB1 inactivation was associated with p16 HD; p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. No significant association was established between any p16 inactivation mechanism and smoking status based on our data. HD was found to be the major mechanism of p16 inactivation among both smokers and never smokers although the rate of p16 methylation was higher in smokers. The result of our meta-analysis showed that p16 methylation was associated with smoking. The results from the literature were homogenous and the overall odds ratio from the meta-analysis was 2.01, which is significant at 0.05 level. Conclusions: p16 inactivation is a common event in lung adenocarcinoma and the inactivation mechanism of p16 is associated with other genetic changes and smoking status. Meta-analysis confirmed the association between p16 methylation and smoking. Our results indicate the presence of different pathways via p16 inactivation in the development of lung adenocarcinoma.
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 LB-146. doi:1538-7445.AM2012-LB-146
Abstract LB-148: The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells
Authors: Shin Yong Jae , Kim Jeong-Ho 
Published: August 2012

Abstract
Degradation of the extracellular matrix (ECM), a critical step in cancer metastasis, is determined by the balance between MMPs (matrix metalloproteinases) and their inhibitors TIMPs (tissue inhibitors of metalloproteinases). In cancer cells, this balance is shifted towards MMPs, promoting ECM degradation. Here, we show that EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells. The TIMP genes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. EZH2 catalyzes H3K27 trimethylation and subsequent DNA methylation of the TIMP gene promoters. Overexpression of EZH2 confers an invasive phenotype on benign prostate epithelial cells; however, this phenotype is suppressed by cooverexpression of TIMP3. EZH2 knockdown markedly reduces the proteolytic activity of MMP-9, thereby decreasing the invasive activity of prostate cancer cells. These results suggest that the transcriptional repression of the TIMP genes by EZH2 may be a major mechanism to shift the MMPs/TIMPs balance in favor of MMP activity and thus to promote ECM degradation and subsequent invasion of prostate cancer cells.
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 LB-148. doi:1538-7445.AM2012-LB-148
Abstract LB-149: The OPCML tumor suppressor binds and negatively regulates the Axl receptor tyrosine kinase, sensitizing cells to foretinib in epithelial ovarian cancer (EOC)
Authors: Nawathe Sushmita Roy , Zanini Elisa , Hayward Giles , McKie Arthur B. , Gabra Hani 
Published: August 2012

Abstract
OPCML (opioid binding protein/cell adhesion like molecule) is a tumour suppressor gene that is silenced almost by somatic methylation in more than 80% of EOC cases, with loss of heterozygosity (LOH) occurring in 49% of cases [1,2]. OPCML binds a specific repertoire of receptor tyrosine kinases (RTKs) consisting of HER2, HER4 EphA2, FGFR1 and FGFR3. OPCML switches RTKs from clathrin to non clathrin dependent endocytosis, resulting in polyubiquitination of the RTK and targeting to the proteasome for destruction with associated signalling and growth inhibition [3]. We show that Axl, a TAM family RTK that is frequently activated in ovarian cancer [4], also interacts with and is downregulated by OPCML. Axl is downregulated following transient and stable OPCML expression in ovarian cancer lines SKOV3 and PEO1, with reciprocally increased Axl expression following stable knockdown of physiological OPCML in normal ovarian surface epithelial line OSE-C2. We performed co-IP and mammalian 2-hybrid (M 2-H) analysis between Axl and OPCML and determined that the Ig and FNIII domains are crucial to this interaction. We previously reported a complete loss of function proline 95 to arginine mutation [2]. Transfection of OPCMLWT protein in OPCML deficient cells promotes intercellular adhesion and adhesion to Collagen I and Fibronectin matrix, in association with Axl downregulation, In contrast OPCMLP95R transfection did not repress Axl and did not promote intercellular or cell to matrix adhesion. M 2-H data demonstrated that OPCMLP95R expression abolishes the interaction seen between OPCMLWT and Axl. We explored the impact of OPCML expression on cell signalling response to Foretinib (GSK1363089), a potent inhibitor of Axl [5]; OPCML led to a 3-fold sensitization to the tyrosine kinase inhibitor. The finding that OPCML, a frequently inactivated ovarian cancer tumor suppressor negatively regulates Axl, a frequently activated RTK in ovarian cancer and sensitises Axl positive OPCML deficient cells to Foretinib defines a promising predictive and therapeutic role for OPCML in ovarian cancer. References 1. Gabra et al (1996) Cancer Res 56: 950-954. 2. Sellar et al (2003) Nat Genet 34: 337-343. 3. McKie et al (Feb2012) Cancer Discovery (in press). 4. Rankin et al (2010) Cancer Res 70: 7570-7578 5. Liu et al. (2009) Cancer Res 69: 6871-6878.
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 LB-149. doi:1538-7445.AM2012-LB-149
Abstract LB-15: Alpha-2 Heremans Schmid glycoprotein (AHSG) promotes growth in head and neck squamous cell carcinoma
Authors: Thompson Pamela D. , Marshall Dana , Sawke Amos , Koumangoye Rainelli 
Published: August 2012

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the eighth most common tumor in the world. In the United States, approximately 30,000 new cases of HNSCC are reported each year and 8,000 related deaths. HNSCC of the oral cavity is highly metastatic and has a recurrence rate of 20%-50%, with a dismal 5-year survival rate of ∼50%. There continues to be no consistent means for early detection or a reliable biomarker for the disease. This has contributed to the lack of improvement in the mortality rates of the disease, despite advances in delivery of treatment and surgical reconstruction. In a proteomic study seeking possible biomarkers for HNSCC, AHSG was detected at elevated serum levels. AHSG is a cell surface glycoprotein that is known to be synthesized by hepatocytes and found in most body fluids including serum. AHSG is also a negative acute phase function protein, which makes the results from the proteomic study, elevated levels of AHSG, intriguing. Our lab has recently shown that the lack of AHSG reduces tumor incidence and prolongs tumor latency. We now show that some HNSCC cell lines synthesize and secrete AHSG at both the message and protein levels. This is important as most cells acquire AHSG through uptake from serum. To our knowledge, this is the first report of AHSG synthesis and expression in HNSCC cell lines. We are currently depleting AHSG expression in these HNSCC cell lines in order to evaluate the effects of AHSG on the growth and metastatic properties (invasiveness and motility) in vitro and in vivo. &lt;br
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 LB-15. doi:1538-7445.AM2012-LB-15
Abstract LB-150: Binding selectivity of RNAs by eukaryotic initiation factor 3f in pancreatic cells
Authors: Uribe Diana J. , Wen Fushi , Shen Alex , Choi Andrw , Shi Jiaqi 
Published: August 2012

Abstract
Deregulation of translation is necessary for an increase in protein production that benefits cancer cells to increase proliferation and tumor growth. Eukaryotic initiation factor 3f (eIF3f), a subunit in the eIF3 protein complex, has been shown to be a regulator for translation initiation. Our group was the first to describe eIF3f as a tumor suppressor, where we show its expression is lost in melanoma and pancreatic tumor tissues. In this study, we show that eIF3f binds to various RNAs for genes involved in GTP-binding, RNA binding, RNA capping and other cellular processes, through the use of RNA-Immunoprecipitation assay followed by a microarray analysis, coined RIP-Chip in normal human pancreatic ductal epithelial (HPDE) cells. We confirmed the binding of eIF3f to these RNAs through RNA-Immunoprecipitation (RIP) assay using an antibody against eIF3f to pulldown of our sample RNA and visualized by RT-PCR analysis. To determine the role of this selective binding of eIF3f to these particular RNAs, we observed their expression in the HPDE cells, were eIF3f was stably knocked-down with lentivirus containing eIF3f-siRNA. Preliminary results demonstrate some correlation between the absence of eIF3f and the protein levels of the genes encoding for the eIF3f pulled-down RNA. Our results demonstrate that eIF3f may be involved in directly targeting specific oncogenic RNA sequences for degradation. Further investigations will be needed to elucidate the role of these genes and eIF3f expression in the transformation of pancreatic tissues to the aggressive phenotype of pancreatic 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 LB-150. doi:1538-7445.AM2012-LB-150
Abstract LB-20: mTOR kinase inhibition relieves feedback suppression of receptor tyrosine kinase leading to a biphasic regulation of AKT signaling in breast cancer cells
Authors: Rodrik-Outmezguine Vanessa S. , Chandarlapaty Sarat , Pagano Nen C. , Poulikakos Poulikos I. , Scaltriti Maurizio , Baselga José , Guichard Sylvie , Rosen Neal 
Published: August 2012

Abstract
Activation of mitogenic signaling by receptor tyrosine kinases (RTKs) is regulated by negative feedback. Feedback is in part mediated by mTORC1/S6K dependent downregulation of IRS proteins which downregulate IGF/insulin receptor signaling. We have found that mTORC1 inhibitors or rapalogs relieve feedback inhibition of receptor tyrosine kinases and cause mTORC2-dependent phosphorylation of AKT S473 leading to activation of AKT kinase and signaling. This relief of feedback inhibition of mTORC2/AKT signaling has been associated with the limited clinical efficacy of these compounds. mTOR kinase inhibitors have now been developed to circumvent these problems; they block mTORC1 and mTORC2 and thus do not cause the mTORC2-dependent activation of AKT observed with the mTORC1 inhibitors. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473 dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. Inhibition of mTOR kinase also relieves feedback suppression of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound inhibition of mTORC1 and accumulation of activated AKT phosphorylated on T308 but not S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regressions in vivo. These results highlight the possible need for combinatorial approaches to block feedback-regulated pathways.
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 LB-20. doi:1538-7445.AM2012-LB-20
Abstract LB-203: Mathematical modeling of the dynamic interaction between cancers stem cells and non-stem cancer cells and its potential clinical implication
Authors: Liu Xinfeng , Kanojia Deepak , Lo Pang-Kuo , Chen Hexin 
Published: August 2012

Abstract
Cancer stem cells (CSCs) have been identified in primary breast cancer tissues and cell lines. The size of CSC population varies a lot among cancer tissues and cell lines but is associated with aggressiveness of breast cancer. Despite of the high tumor heterogeneity among different samples, CSCs isolated from either primary tissues or cell lines can rapidly regenerate the original heterogeneity and maintain a relatively constant proportion of CSCs. It remains largely unknown how the CSC population is maintained within a tumor. In this study, we develop a mathematical model to explore the key factors which control the size of CSC population during tumor cell growth both in vitro and in vivo. Our mathematic modeling and experimental data suggest that there is a negative feedback mechanism to control the balance between CSC and non-stem cancer cells. We further calculated how feedback sensitivities and robustness can be regulated by different intrinsic and extrinsic factors. As an example, our mathematical model predicts that overexpression of oncogeneHER2 leads to increase in the proportion of CSC via regulating the division mode or proliferation rate of CSCs. The prediction is supported by both in vitro cell culture results and the clinical data. We also show that enrichment of CSCs in suspension culture is due to both depletion of differentiated cancer cells and partial relieve of negative feedback. Mathematical modeling this culture condition reveals that the majority of tumporspheres are derived from progenitor cancer cells but not CSCs. Overall, these findings contribute to our understanding of cancer heterogeneity and may have significant implications in development and selection of anti-cancer therapies.
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 LB-203. doi:1538-7445.AM2012-LB-203