bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1619: Discovering a new physiological substrate of Aurora-A kinase
Authors: Toughiri Raheleh , Padmanabhan Achuth , Li Xiang , Bieberich Charles 
Published: June 2012

Abstract
Aurora-A is a serine/threonine kinase that has oncogenic properties in vivo. The expression and kinase activity of Aurora-A are up-regulated in many cancers including prostate cancer, which is the most frequently diagnosed malignancy in men and second leading cause of cancer death in the United States. Aurora-A is one of the key regulators of mitosis that localizes to the centrosome from G2 phase through mitotic exit, where it regulates mitotic spindle formation and centrosome separation. Although Aurora-A is known to be an oncogene, few Aurora-A substrates have been identified. It is essential to elucidate Aurora-A substrates to develop biomarkers for Aurora-A inhibitors, and to identify new targets downstream of Aurora-A for cancer therapy.
To identify new Aurora-A substrates, an Aurora-A Reverse In-gel Kinase Assay was developed. The basis of this method is co-polymerization of a denatured protein kinase throughout a polyacrylamide gel followed by protein refolding. Subsequently, an in-gel kinase reaction in the presence of γ-32P-ATP allows phosphorylation of potential kinase substrates that can be located by autoradiography. Phosphorylated proteins can be extracted from the gel and identified by liquid chromatography mass spectrometry. Using this method, we were able to identify Nuclear Mitotic Apparatus (NuMA) as an Aurora-A kinase substrate. Preliminary in vitro kinase experiments verify phosphorylation of recombinant NuMA C-terminus by Aurora-A. The identification of Aurora-A phosphorylation site/s will permit a better understanding of Aurora-A function in normal and cancer cells. The location of Aurora-A phosphorylation of NuMA and consequences of their mutation will be discussed.
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 1619. doi:10.1158/1538-7445.AM2011-1619
Abstract 1629: A protein-protein interaction network for RalB-TBK1 signaling pathway in KRAS mutant non small cell lung cancer
Authors: Kim Jae-Young , Fang Bin , Koomen John , Zhang Guolin , Haura Eric B. 
Published: June 2012

Abstract
KRAS mutation accounts for development of approximately 30% of Non Small Cell Lung Cancer (NSCLC) however therapeutic targets for KRAS mutant NSCLC have poorly been identified. A better understanding of the KRAS signaling network could uncover novel therapeutic targets or therapeutic strategies. RalB and TBK1 are important proteins used by KRAS to maintain tumor cell survival. To better understand oncogenic properties of RalB-TBK1 signaling for KRAS mutant lung cancer development, we are currently developing a protein-protein interaction network for RalB and TBK1 using Tandem Affinity Purification (TAP) coupled with Liquid Chromatography-Mass Spectrometry (LC-MS/MS). By interrelating protein-protein interactions and data from a RNA interference screen, a map of signaling will be constructed to highlight important components vulnerable to attack. Data from this mapping will be used to interrogate novel targets in a larger collection of lung cancer cell lines. We have expressed Strep-HA tagged versions of both RalB and TBK1 in KRAS mutant lung cancer cells using retroviruses. A two step purification coupled to LC-MS/MS is used to purify and identify protein complexes. Preliminary studies have identified the bait (TBK1) in the MS results along with HSP90 isoforms. Based on these results, we determined if HSP90 inhibition can modulate TBK1 levels. We found that 17-DMAG and AUY922, two HSP90 inhibitors, lead to reduced levels of TBK1 proteins. AUY922 also had potent effects on cell viability in vitro. Suppression of TBK1 expression using shRNA significantly induced cell death in KRAS mutant NSCLC cells, confirming that TBK1 signaling is essential for survival of those cancer cells, and loss of TBK1 by HSP90 inhibitors could in part lead to their cytotoxic effect. Collectively, we expect this network approach to KRAS-RalB-TBK1 signaling pathways will provide better insight into molecular mechanism by which TBK1 mediates KRAS mutant lung cancer cell survival and novel therapeutic targets for this cancer subtype. Updated work will be presented. Supported by the SPORE in Lung Cancer (P50-CA119997).
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 1629. doi:10.1158/1538-7445.AM2011-1629
Abstract 1634: Targeting L1 cell adhesion molecule using lentivirus-mediated short hairpin RNA interference reverses aggressiveness of oral squamous cell carcinoma
Authors: I-Hui Wu , Hung Shiao-Chen , Hsue Shui-Sang , Liao Chia-Hui , Wang Hsien-Chi , Chuang Pei-Hsin , Sung Shian-Ying , Hsieh Chia-Ling 
Published: June 2012

Abstract
Oral cancer consistently ranks as one of the ten most frequently diagnosed cancers in the world. Despite multidisciplinary treatment with surgery, chemotherapy, and radiation, more than 50% of patients with oral squamous cell carcinoma (OSCC) receiving therapy will eventually develop recurrent and metastatic disease, which carries a particularly poor prognosis. Characterization of the specific molecular alternations associated with OSCC cell growth, invasion, and metastasis can advance our understanding of the molecular mechanisms underlying cancer induction and progression as well provide a basis for the development of new and effective therapeutic treatments for cancer patients. The L1 cell adhesion molecule (L1CAM) has been implicated in tumor progression of many types of cancers, but its role in OSCC has not been investigated. In the present study, we demonstrated overexpression of L1CAM in OSCC cells, but not in normal keratinocytes, using both clinical specimens and cell lines. This overexpression demonstrated a strong correlation with less differentiation and a higher invasion potential of cancer cells, supporting the significance of L1CAM in human OSCC tumor progression. Targeting L1CAM gene expression in SCC4 cells overexpressing L1CAM using a lentivirusmediated small hairpin RNA (shRNA) led to a significant reduction in cell proliferation in vitro via retardation of cell cycle at the G1 phase. In addition, shRNA knockdown of L1CAM strongly attenuated the migration and invasion of SCC4 cells, and this was also observed to parallel increased E-cadherin levels and decreased levels vimentin, fibronectin, and Snail-family transcription factors, indicating that L1CAM expression was related to the epithelial-mesenchymal transition. Furthermore, while mice receiving orthotopically placed control SCC4 cells died within 40 days due to invasive tumor growth and regional lymph node metastasis, prolonged animal survival and complete suppression of tumor progression was observed in mice implanted with L1CAM-deficent SCC4 cells, further substantiating the fundamental importance of L1CAM in OSCC pathophysiology. Our findings suggested that L1CAM is a critical mediator of tumor progression in OSCC, and targeting L1CAM using lentivirus-mediated shRNA may be a useful molecular pharmaceutical approach for the treatment of advanced OSCC.
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 1634. doi:10.1158/1538-7445.AM2011-1634
Abstract 1639: Targeting the p38 MAPK pathway inhibits irinotecan resistance in colon adenocarcinoma
Authors: Paillas Salomé , Boissiere Florence , Bibeau Frederic , Mollevi Caroline , Causse Annick , Denis Vincent , Vezzio-Vié Nadia , Ait-Arsa Imade , Pourquier Philippe , Martineau Pierre , Del Rio Maguy , Gongora Céline 
Published: June 2012

Abstract
Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from the colon adenocarcinoma HCT-116 and SW48 cell lines. These clones show various levels (6 to 60 fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared to the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both alpha and beta isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which specifically inhibits p38 alpha and beta, enhanced the cytotoxic activity of SN38, but not of 5-FU or oxaliplatin. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared to non-responder patients. This indicates that enhanced level of expression of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show for the first time that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal 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 1639. doi:10.1158/1538-7445.AM2011-1639
Abstract 1646: In vivo target validation in orthotopic hepatocellular carcinoma model using formulated siRNA
Authors: Liao Baisong , Kellner Debra , Wang Chunrong , Wu Shilu , Molina Marion , Zhu De-Min , Gollerkeri Ashwin , Pachuk Catherine 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence continues to increase. Although there are approved therapies for HCC, the prognosis remains poor. The 5-year survival rate is &lt; 5%. Nucleic acid-based therapeutics such as RNAi may improve patient outcome. Nevertheless, target identification/validation for HCC and delivery of siRNA are major challenges facing the development of HCC-specific RNAi based therapeutics. To enable target validation in vivo using RNAi, we have developed nanolipid siRNA formulations for the in vivo delivery of siRNA to orthotopic tumors. PK/PD studies in model systems demonstrate that up to 80% knockdown of target protein is achievable within tumors and that significant knockdown persists for at least 10 days following a single dose of formulated siRNA. Efficacy studies using similar formulations of siRNAs against potential HCC tumor targets, including mTOR, will be presented.
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 1646. doi:10.1158/1538-7445.AM2011-1646
Abstract 165: MicroRNA-29c expression as a new prognostic marker for esophageal squamous cell carcinoma
Authors: Kinoshita Koichi , Watanabe Masayuki , Kamohara Hidenobu , Tanaka Yohei , Kurashige Junji , Saito Seiya , Karashima Ryuichi , Hirashima Kotaro , Imamura Yu , Nagai Yohei , Iwagami Shiro , Iwatsuki Masaaki , Hayashi Naoko , Baba Hideo 
Published: June 2012

Abstract
Introduction and Objective: MicroRNAs (miRNAs) are small non-cording RNAs that act at the posttranscriptional level to control gene expression in virtually every biological process, including oncogenesis. Lately, the discovery of miRNAs in cancer patients opened up the exciting prospective of using miRNAs as powerful cancer biomarkers. We screened miRNAs which would become the prognostic factor in esophageal squamous cell carcinoma (ESCC) patients and performed validation about miRNAs identified by screening.
Matherial and Method: Tissues of ESCC and the matched normal counterparts were obtained from surgical specimens after resection from patients undergoing primary surgical treatment of ESCC. Total RNAs were obtained from the archive of formalin-fixed paraffin-embedded (FFPE) tissues using the RecoverAll Total Nucleic Acid Isolation kit for FFPE (Ambion) according to the manufacturer's instructions. Here, we investigated 45 miRNAs expression levels and prognosis in 20 patients with ESCC and assessed by reverse transcription-PCR analysis of the endogenous control RNU6B. About miRNAs which was significant difference for prognosis, we examined a correlation with the clinicopathologic factors including gender, age, TNM stage, vessel invasion and presence of recurrence with 65 ESCC patients.
Result: MiR-29c was identified to have an influence on prognosis. We re-analyzed the miR-29c expression level in 65 ESCC samples and investigated the various clinicopathological factors associated with miR-29c expression. The venous invasion and presence of recurrence were significantly correlated with high expression of miR-29c(p&lt;0.05). The Kaplan-Meier analyze showed that, high expression level of miR-29c was found to be correlated with a low overall survival rate(p&lt;0.001).
Conclusion: Our results suggest that the miR-29c overexpression might be a poor prognotic factor and miR-29c acts as an oncomir associated with the development and progression of ESCC.
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 165. doi:10.1158/1538-7445.AM2011-165
Abstract 1652: MRGBP (C20orf20) contributes to development of colorectal cancer
Authors: Yamaguchi Kiyoshi , Sakai Michihiro , Kim JooHun , Yamada Yoshinao , Akiyama Yoshiyuki , Nakamura Yusuke , Furukawa Yoichi 
Published: June 2012

Abstract
MRGBP (MRG-binding protein, also known as C20orf20) encodes a subunit of TRRAP/TIP60-containing histone acetyltransferase complex. In our earlier study, a genome-wide expression analysis found that MRGBP was up-regulated in the majority of colorectal tumors. Importantly, the enhanced expression was associated with cell proliferation. In the present study, we extensively investigated MRGBP expression in 22 adenomas and 47 carcinomas of the colon and rectum by immunohistochemical analysis. Each stain result was sub-divided into three groups according to the percentage of positive stains in tumor cells (negative, &lt;10%; low, 10 – 50%; high, &gt;50%). As a result, carcinomas with negative, low, and high expression were comprised of 15, 11, and 21 tumors, respectively. On the other hand, adenomas with negative, low, and high expression were 12, 9, and 1, respectively. Statistical analysis has revealed that MRGBP expression in carcinomas was significantly increased compared with that in adenomas. No clinicopathological factors were associated with the expression of MRGBP in colorectal cancer. We further investigated genes regulated by MRGBP using DNA microarray. Comparison of gene expression profiles between MRGBP-knocked down cells and control cells identified a total of 41 genes whose expressions were clearly suppressed. The 41 genes included MCM2, MCM5, CDT1, and CDCA7, implying that MRGBP plays a role in DNA replication, minichromosome maintenance, and cell division. These data suggest that MRGBP may contribute to the development of colorectal cancer through rendering advantages in cell proliferation to cancer cells. Our findings may be helpful for the identification of biomarker and development of therapeutic approach to colorectal tumors.
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 1652. doi:10.1158/1538-7445.AM2011-1652
Abstract 1664: Maternal embryonic leucine aipper kinase (MELK) is a critical regulator of proliferation and is independently prognostic in estrogen receptor-negative breast cancer
Authors: Wheatley Karrie , Speers Corey , Tsimelzon Anna , Sexton Krystal , Hilsenbeck Susan , Chang Jenny , Brown Powel 
Published: June 2012

Abstract
Background: Molecularly targeted therapies such as tamoxifen, aromatase inhibitors, and trastuzumab are useful for the treatment of breast cancer. However, these targeted therapies do not treat all breast cancers, especially estrogen receptor alpha (ER)-negative, progesterone receptor (PR)-negative, HER2-negative (“triple-negative”) breast cancer. Our lab previously used gene expression profiling of human breast cancers to identify kinases overexpressed in ER-negative breast cancers. One of the kinases highly expressed in a poor prognosis group of triple negative breast cancers is maternal embryonic leucine-zipper kinase (MELK). The purpose of this study was to demonstrate that MELK expression is upregulated in ER-negative breast cancers, and to test the hypothesis that MELK is a critical regulator of ER-negative breast cancer cell growth.
Methods: RNA from breast cancer cell lines and 60 human breast tumors was isolated for Q-PCR analysis of MELK. To determine if MELK regulates cell proliferation, ER-positive and ER-negative breast cancer cell lines were transfected with siRNA targeting MELK. Cells were replated 36 hours after transfection in 96-well plates at a density of 2,000/well. Cell number was measured by the MTS assay every day for 6 days. To determine if MELK levels are independently prognostic, we performed uni- and multivariate Cox regression analysis, including all available biological characteristics of the tumor in the model.
Results: MELK mRNA levels were significantly higher (p&lt;0.02) in ER-negative breast cancers (20.2 ± 7 fold) compared to ER-positive breast cancers (5.0 ± 2 fold). In 6 of 7 ER-negative cell lines, MELK knockdown suppressed growth (≥50% growth inhibition) compared to cells transfected with control siRNA. MELK knockdown had little to no effect on growth of the 3 ER-positive cell lines tested. Importantly, in a multivariate Cox proportional hazards model, high MELK expression was shown to be independently associated with a poor prognosis, [HR=1.19 95% CI: (1.05, 1.36) p=0.007]. Current studies are focused on understanding how MELK regulates ER-negative cell growth, using ER-negative cell lines stably expressing an inducible dominant negative MELK protein.
Conclusions: MELK is highly expressed in ER-negative breast cancer, essential for ER-negative breast cancer cell growth, and is independently prognostic. These findings suggest that MELK is a promising target for the treatment of ER-negative breast cancer.
Supported by a Susan G. Komen for the Cure Promise Grant. (KG081694).
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 1664. doi:10.1158/1538-7445.AM2011-1664
Abstract 1669: Expression of a novel zinc-finger transcription factor ZKSCAN3 in human tumors and its potential as a therapeutic target
Authors: Yang Lin , Orlowski Robert Z. 
Published: June 2012

Abstract
Previous studies from our group demonstrated that zinc finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel zinc-finger transcription factor, coordinated a gene expression program targeting Cyclin D1, Cyclin D2, NF- κB, Integrin β4, as well as VEGF and IGF-2, among others, in which these genes have been suggested to play critical roles in tumor progression. To examine if ZKSCAN3 represents a potential cancer therapeutic target, expression of ZKSCAN3 was investigated in multiple tumor types. By immunohistochemistry (IHC), we observed that ZKSCAN3 protein greatly expressed in majority tumor tissues and cells, including solid tumors (colorectal carcinoma, prostate cancer, bladder cancer, and breast cancer) and liquid malignancies (multiple myeloma, non-Hodgkin B cell lymphoma, mantle cell lymphoma, MALT, diffuse large B cell lymphoma), but not non-malignant adjacent tissues. ZKSCAN3 expression was also associated with tumor progression, evidenced by IHC staining in different stages of colorectal carcinoma and prostate cancer samples. Very interestingly, lack of ZKSCAN3 expression was observed in Hodgkin lymphoma and angioimmunoblastic T cell lymphoma, suggesting that ZKSCAN3 selectively expressed in certain tumor types. Moreover, quantitative real-time polymerase chain reaction (qPCR) was performed to verify ZKSCAN3 mRNA expression in multiple myeloma. Consistent with the IHC data, CD19+ normal B cells and CD138+ plasma cells have little expression of ZKSCAN3, meanwhile malignant plasma cells greatly expressed ZKSCAN3 gene. The differential expression pattern of ZKSCAN3 between tumor cells and non-malignant cells strongly suggests that ZKSCAN3 may play an important role in tumor pathogenesis. Indeed, in addition to the identified gene expression program that was regulated by ZKSCAN3, targeting ZKSCAN3 by its small interfering (si) RNA led to slowed tumor growth and decreased chemosensitivity, and overexpression of ZKSCAN3 greatly promoted tumor growth and enhanced chemosensitivity in the models of multiple myeloma and colon cancer, indicating that ZKSCAN3 may represent a promising cancer therapeutic target.
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 1669. doi:10.1158/1538-7445.AM2011-1669