bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4155: Comprehensive glucan profile exploration of mutated K-ras knockdown in colorectal cancer
Authors: Kawamata Hiroshi , Yamashita Keishi , Kuno Atsushi , Shirasawa Seiji , Narimatsu Hisashi , Watanabe Masahiko 
Published: August 2012

Abstract
(Background) In colorectal cancer (CRC), K-ras mutation is found in nearly 40% of the patients, and it is of prognostic significance (Onozato W et al, J Surg Oncol, 2010). Moreover, its knockdown in CRC cell lines with mutated K-ras gene results in robust reduction of ability of cell proliferation and anchorage independent growth (Shirasawa S, Science, 1993), both of which reflect metastatic ability. On the other hand, robust alterations of glycan structures have been reported in CRC promotion steps, accompanied by remarkable phenotypic changes, however there is no report that mentions the relationship of K-ras mutation and glycan change. (Materials and Methods) We examined glycan change of CRC cell lines (DLD1 and HCT116) somatically knocked out for K-ras gene by lectin array including 41 lectins to elucidate whether K-ras mutation-induced glycan changes play a critical role in CRC promotion. (Result) (1) In DLD1, we compared DLD1 wild type genotype cells (DLD1, DKS-5) with those that were knocked out for mutated K-ras gene (DKO-3, DKS-8), and the signals of MAL, MPA, UEA-I, and TJA-II were remarkably decreased in the knockdown cells. (2) In HCT116, we compared HCT116 wild type genotypic cells (HCT116, Hk2-10) with those that were knocked out for the mutated K-ras gene (Hke-3), and both MAL and MPA were remarkably declined. (3) In both cell lines, expression changes of glycans which can bind with MAL and MPA were consistent with the results of the lectin blotting, and both lectin signals were confirmed to be commonly altered by removing the mutated K-ras gene. (Conclusion) Mutated K-ras may be involved in critical phenotype change of CRC, accompanied by abnormal sialic acid recognition.
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 4155. doi:1538-7445.AM2012-4155
Abstract 4157: DACH1 Inhibited proliferation and tumor growth of lung adenocarcinoma cells
Authors: Li Zhaoming , Cai Shaoxin , Hu Junbo , Pestell Richard G. , Wu Kongming 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer death worldwide. A key driver to the proliferation of lung cancer includes increased activity of the gene encoding the epidermal growth factor receptor (EGFR) and mutation of K-ras oncogene. Target therapies through small molecules to inhibit the tyrosine kinase domain of EGFR (Gefitinib) or monoclonal antibody to EGFR (Cetuximab) have demonstrated clinical benefit. Unfortunately, development of resistance to those treatments occurs in most patients within one year. Studies of the hyperactive EGFR in drosophila identified a genetic inhibitor of EGFR signaling, known as dachshund (dac). Activate ras inhibits DACH1 expression in malignant peripheral nerve sheath tumor. Dachshund can activate or represses transcription, and regulates cell proliferation and differentiation in multiple context-dependent manners. Our studies have proved that DACH1, human homolog of dac, functions as a potential tumor suppressor of breast and prostate cancer. Expression of DACH1 is lost during cancer progression and re-expression of DACH1 gene inhibited cellular proliferation, migration and tumor formation. The expression levels and the role of DACH1 in lung cancer are largely unknown. As both EGFR and Ras signaling interact with DACH1, we hypotheses that loss of endogenous DACH1 may contribute to the lung tumorigenesis. The mRNA expression of DACH1 was decreased in lung adenocarcinoma compared with normal lung tissues. Ectopic expression of DACH1 by stably transduction inhibited cellular proliferation of lung cancer cell lines A549 and SKLU, cell cycle progression and clone formation rate in contact-dependent and -independent growth. ELISA using conditional medium from A549 cells expressing vector control or DACH1 demonstrated remarkable inhibition of secreting factors, such as CXCL1, CXCL2, CXCL5 and CXCL8. Those chemokines have already been proved to positively regulating angiogenesis and proliferation. To test in vivo tumorigenesis, 2x106 A549 cells expressing DACH1 or vector control were injected subcutaneously into nude mouse and tumor size was monitored weekly. Tumor growth was dramatically blocked by DACH1. Tumor weight was 297.8 ± 38.6mg for vector control and 31 ± 6.1mg for cells expressing DACH1(p value &lt;0.001). Importantly, over-expression of CXCL5 can partly rescue tumor growth inhibition by DACH1 in A549 cells. Together, our study demonstrated that DACH1 is a potentially tumor suppressor of lung cancer though repression of chemokines secretion.
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 4157. doi:1538-7445.AM2012-4157
Abstract 4160: DEPTOR, an mTOR inhibitor, is a novel substrate of SCFαTrCP E3 ubiquitin ligase upon S6K1/RSK1 phosphorylation and regulates survival and autophagy
Authors: Zhao Yongchao , Xiong Xiufang , Sun Yi 
Published: August 2012

Abstract
DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFαTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, αTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by αTrCP; being decreased or increased upon αTrCP overexpression or knockdown, respectively. DEPTOR half-life is shortened by αTrCP but extended by its dominant negative mutant, by RSK1/S6K1 inhibition, or upon αTrCP degron site mutations. Biologically, DEPTOR, accumulated upon αTrCP knockdown, inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR, accumulated upon glucose deprivation and mTOR inhibition, induces autophagy. Thus, αTrCP-DEPTOR-mTOR intertwines to regulate cell survival and autophagy.
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 4160. doi:1538-7445.AM2012-4160
Abstract 4162: PTPRO silencing by MAPK pathway in colorectal cancer
Authors: Vecchione Loredana , Narzo Antonio Fabio di , Asbagh Layka Abbasi , Tejpar Sabine 
Published: August 2012

Abstract
Background The analysis of gene expression profile of a total of 688 primary colorectal (CRC) cancers revealed PTPRO to have an intriguing bimodal distribution. When looking for variables associated to it, such as clinical variables, mutation status, gene copy number variation and methylation pattern, a significant association was found with the BRAF mutated (BRAF mut) tumors and a not perfect association with the CIMP high methylation subtype. Based on these findings, we postulated that the Ras/Raf mitogen activated protein kinase (MAPK) pathway and the methylation could concomitantly or independently be involved in the downregulation of the gene. Material and methods Basal PTPRO mRNA was evaluated in a total of 13 CRC cell lines (7 wild type for BRAF and KRAS, 2 BRAF mut and 4 KRAS mut) by RT-qPCR. PTPRO promoter region (366bp, 15475534 - 15475900 - Human Genome browser gateway NCBI36/hg18) was studied by sequencing analysis after bisulfite conversion of DNA extracted from these cells. Treatments with 10 microM of 5-azacytidine (5-AZA), 1 microM of Mek inhibitor (AS703026) and the combination of 10 microM of 5-AZA with 1 microM of Meki were performed in SW480 and Lim1215. After 72 hrs of treatment samples were profiled for gene expression and methylation. Results 10 out of 13 cell lines showed low PTPRO expression at mRNA level independently from the methylation status. The expression of the gene was induced after treatment with 5-AZA in SW480 and Lim1215. PTPRO expression was also induced after Mek inhibition of 5,6 fold and 44 fold in SW480 and Lim1215, respectively, without any modifications of the methylation pattern. Moreover, Mek inhibitor could further increase the expression of the gene in cells treated with 5-AZA Conclusion Our clinical and preclinical data confirm the MAPK pathway to be involved in PTPRO silencing independently from its methylation status. PTPRO loss might play a role in mediating the oncogenic function of the MAPK activation in CRC cells either by deregulating receptor type kinanses (RTKs) or by directly modulating Erk activity. On going experiments will answer to this question
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 4162. doi:1538-7445.AM2012-4162
Abstract 4163: Determination of synthetic lethal interactions in KRAS oncogene dependent cancer cells reveals novel therapeutic targeting strategies
Authors: Molina-Arcas Miriam , Hancock David , Steckel Michael , Downward Julian 
Published: August 2012

Abstract
Oncogenic mutations in RAS genes are very common in many human cancers, including those affecting the lung and the gastro-intestinal tract. RAS mutant cancers tend to be resistant to most targeted therapies, emphasising a clear need for the development of more effective treatments. Oncogenic KRAS deregulates numerous downstream pathways, resulting in cells with well-characterised selective advantages, but also less well understood vulnerabilities. In a panel of twenty-six non-small cell lung cancer (NSCLC) cell lines, half of which carry an activating KRAS mutation, knock-down of KRAS using siRNA indicates that KRAS mutant cells require KRAS expression to maintain viability. Moreover, KRAS depletion produces a clear inhibition of ERK and AKT signaling. As RAS proteins cannot be inhibited directly at present, we tested small molecule inhibitors targeting pathways directly controlled by RAS, such as RAS/RAF/MEK or PI3K/AKT/mTOR, as well as drugs directed against other targets (such as HSP90, topoisomerases or the proteasome) in order to affect tumour-specific vulnerabilities associated with the oncogenic state. Viability assays showed that cells harbouring an activated KRAS oncogene were more sensitive to MEK, RAF and IGF-1R inhibitors than cells carrying only wild-type KRAS alleles. In contrast, no differential loss of cell viability was observed when cells were treated with either PI3K or AKT inhibitors. Combinations of IGF-1R inhibitors with MEK or RAF inhibitors resulted in a synergistic anti-proliferative effect in KRAS mutant cell lines. Similar effects were observed upon simultaneous treatment with PI3K and MEK inhibitors. However, in this case, wild-type KRAS cells were also affected by PI3K inhibition, resulting in a less-pronounced differential effect. Pathway inhibition analysis showed that, whereas MEK and PI3K inhibitors respectively decreased ERK and AKT phosphorylation in all cell lines, IGF1R inhibitors decreased AKT phosphorylation only in KRAS mutant cell lines. Inhibition of AKT phosphorylation correlates with effectiveness of IGF-1R inhibitor in blocking cell proliferation. Mechanistically, it appears that mutant KRAS activation of PI3K requires coordinate input from IGF-1R. These findings suggest potential therapeutic strategies for NSCLC tumours harbouring KRAS mutations.
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 4163. doi:1538-7445.AM2012-4163
Abstract 4164: Regulatory mechanism for Ras degradation and its role in the suppression of cellular transformation and tumorigenesis
Authors: Jeong Woo-Jeong , Choi Kang-Yell 
Published: August 2012

Abstract
Ras is a well-characterized proto-oncogene, and its various mutations contribute to transformation and tumorigenesis in a wide variety of human cancers. Although the GTP/GDP loading switch is known as a major regulatory mechanism of Ras, other mechanisms affecting Ras activity, especially those related to cancer, are poorly understood. Here, we report a novel regulatory mechanism for Ras degradation and its role in suppression of cellular transformation and tumors induced by Ras mutations. We show that the negative regulators of Wnt/β-catenin signaling are associated with polyubiquitin-dependent degradation of Ras following phosphorylation and subsequent recruitment of α-TrCP-E3 ligase. The interaction of Ras with the WD40 domain of α-TrCP targeted Ras for polyubiquitination and degradation. This process stimulated by Axin or adenomatous polyposis coli (Apc) and was inhibited by Wnt3a via modulating the phosphorylation status of Ras. Ras-mediated cellular transformation was also inhibited by the expression of α-TrCP and/or Axin. In vivo regulation of Ras stability by Wnt/β-catenin signaling was indicated via measurements of the status of Ras in the intestines of mice stimulated with recombinant Wnt3a by intravenous tail vein injection. The Ras deregulation by negative Wnt/β-catenin signaling was also revealed in human cancers such as colorectal cancer and HCCs etc. Together, our results indicate an essential role for phosphorylation and degradation of Ras and suppression of Ras-induced transformation via the Wnt/β-catenin pathway and provide insight into the role of this novel regulatory mechanism for Ras in colorectal tumorigenesis.
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 4164. doi:1538-7445.AM2012-4164
Abstract 4168: Akt pathway in human breast cancer: A comparison between estrogen positive and estrogen negative tumors using reverse phase protein array
Authors: Carniello Jose Victor Scarpa , Assadi Maziar , Mello Fernanda M. , Rocha Rafael M. , Nogoceke Everton , Soares Fernando A. , Andrade Victor P. 
Published: August 2012

Abstract
INTRODUCTION: Estrogen receptor status is crucial for breast cancer treatment planning. Some estrogen receptor (ER) negative tumors carry a worse prognosis and lack more specific therapies. The AKT pathway is a promising target in breast cancer and was reported hyper activated in ER- tumors cells using in vitro models. We aimed to compare the level of Akt pathway activation between ER+ and ER- tumors using frozen human breast tumor samples. METHODS: 40 cases of breast cancer (20 ER+, 20 ER-) were identified from the frozen tumor bank. Patients were between 40 and 70 years old, with Stage I or II, node negative disease. About 20.000 cells from each tumor cells were purified by laser capture microdissection (LCM) and the protein lysate applied to the Reverse Phase Protein Array (RPPA). Antibodies tested by RPPA included Src, p-Src, Akt, p-Akt Thr308, p-Akt Ser473, mTOR, p-mTOR, PDGFRα, p-PDGFRα Tyr751. We also compared these results to patient matched non-microdissected samples and to immunohistochemistry (IHQ) using digital quantification. RESULTS: 6 out of 9 antibodies showed higher mean expression in ER- negative tumors but only p-Src had statistically significant different levels (0.043). The coordinated high levels (above median) of p-Src/p-Akt/p-mTOR was observed in 1 (5%) of ER+ and in 8 (40%) of ER- tumors. All 8 cases from the ER- group were triple negative (ER-/PR-/Her2-). Correlation coeficients of LCM-RPPA samples and non-microdissected/RPPA samples varied from 0.02 to 0.47. Only p-Akt Ser473 showed a significant correlation (r=0.47, p=0.003). Correlation coeficients between LCM-RPPA and IHQ for antibodies Akt, p-Akt and mTOR were 0.03, –0.22 and 0.05, respectively. CONCLUSION: Protein quantification using LCM-RPPA in human breast tumors is feasible and can detect significant differences between ER+ and ER- tumors. Triple negative tumors showed a high Akt pathway activation profile compared to ER+ tumors. Triple negative tumors are more likely to benefit from targeted therapies directed against the Akt pathway. LCMed and non-LCMed matching samples analyzed by RPPA showed discrepant results. The same happened to the comparison between LCM-RPPA and IHQ with digital quantification.
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 4168. doi:1538-7445.AM2012-4168
Abstract 417: Inflammation initiates OCT4/NANOG expression through IL-6-IGF-1R signaling activation and is associated with early recurrence of HBV-related HCC
Authors: Chang Te-Sheng , Lee Kam-Fai , Chi Ching-Chi , Yang Ya-Ting , Lin Hsin-Yi , Chang Pey-Jium , Tung Shui-Yi , Kuo Liang-Mou , Ling Thai-Yen , Huang Yen-Hua 
Published: August 2012

Abstract
Inflammatory microenvironment is a well-known promoter of hepatocellular carcinoma (HCC), a cancer with high rates of postoperative recurrence and poor prognosis. However, mechanisms underlying the inflammation-induced HCC promotion remain largely unknown. Here we demonstrate the effect of proinflammatory cytokine IL6 on IGF-1R signaling activation which initiates OCT4/NANOG expression and is associated with HBV-related HCC (HBV-HCC) recurrence. In this study, real-time quantitative PCR analysis demonstrated a high correlation between IGF-1R and OCT4/NANOG transcriptional expression in human HCC frozen tissues (N=119, R=0.8097 for OCT4; R= 0.8375 for NANOG). Interestingly, the OCT4, NANOG, or IGF-1R level in HBV-HCC was significantly higher than that in non HBV-HCC. Cultivation of cells in inflammation condition medium (Inflam-CM) increased OCT4/NANOG level in HBV+HBsAg+ cells (HepG2.2.15 and Hep3B), but not in HBV+HBsAg− (HA22T) or HBV−HBsAg− cells (HepG2 and Huh7). Epifluorescence/luciferase assay further demonstrated that Inflam-CM increased the GFP+ cell population as well as the luciferase activity of OCT4 promoter-GFP/luciferase-HepG2.2.15 cells. Besides, Inflam-CM significantly increased the IGF-1/IGF-1R transcriptional level and activated the IGF-1R signaling (phospho-IGF-1R and phospho-Akt) in HepG2.2.15 and Hep3B. Blockage of IGF-1R phosphorylation by picropodophyllin (PPP) dramatically decreased the OCT4/NANOG transcriptional activity. IL-6 stimulated the autocrinal IGF-I and IL-6 expression whereas AG490 (a phospho-STAT inhibitor) decreased the IGF-1R phosphorylation. The significant clinical association between early and overall postoperative recurrence and IGF-1R/OCT4/NANOG expression in both gene (real time RT-PCR) and protein (immunohistochemical staining) levels were demonstrated. When etiologic differences were considered, HBV-positive patients have the trend towards early HCC recurrence. Conclusion: Niche inflammatory stress might activate an autocrinal IL-6-IGF-I/IGF-1R-Akt signaling and OCT4/NANOG expression which is associated with early HBV-HCC recurrence. These results provide potential targets for individualized adjuvant therapy for HBV-HCC.
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 417. doi:1538-7445.AM2012-417
Abstract 4174: Identification of PRPF4 as a novel cancer promoter through AKT signaling in lung cancer
Authors: Choi So-Young 
Published: August 2012

Abstract
We recently constructed a large-scale gene expression database containing more than 33,000 tumors samples by applying cancer outlier profile analysis, and identified many candidate genes as therapeutic targets (Shin G et al., 2011). One of potential target candidates is PRPF4, which is over-expressed in a variety of human cancer, particularly in the breast, colon, ovary, skin and lung cancer patients. PRPF4 (PRP4 pre-mRNA processing factor 4 homolog), also called PRP4, HPRP4, Prp4p, or HPRP4P, is involved in pre-mRNA splicing and interacts with U4/U6-U5 tri-snRNP complex. Moreover, there have been a few studies on the roles of PRPF4 in diseases including cancer. In one study, PRPF4, along with MDR1 (ABCB1) and survivins, was involved in drug resistance in ovarian cancer patients (Duan Z et al., 2008), but its role in cancer is mostly unknown. In this study, we found that PRPF4 was over-expressed in breast, colon, and lung cancers, and involved in cancer progression, invasion, and migration, and interacted with AKT. Knock-down of PRPF4 by small interfering RNA in both lung and breast cancer cell lines dramatically reduced invasion, migration, and cell proliferation in vitro. We confirmed the up-regulation of PRPF4 in about 30% of lung and breast cancer specimens by RT-PCR. We also found that PRPF4 interacts with AKT and thus activates PI3K/AKT signaling pathway and increases proliferation, invasion, and migration of lung cancer cells. Collectively, we suggest PRPF4 is a novel up-regulated gene involved in various cancer progression and propose it as a novel cancer biomarker for targeted therapeutics.
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 4174. doi:1538-7445.AM2012-4174