bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1185: Classification of lung carcinoma cell lines by integrated information of epidermal growth factor receptor and MET abnormalities and gene expression pattern correlates with response to chemotherapy and molecular targeted therapy
Authors: Matsubara Daisuke , Ishikawa Shumpei , Oguni Sachiko , Aburatani Hiroyuki , Fukayama Masashi , Niki Toshiro 
Published: February 2011

Abstract
Purpose: We have previously reported that lung adenocarcinoma cell lines could be classified into two groups based on the integrated information of epidermal growth factor receptor and MET abnormalities and gene expression pattern (2009 AACR annual meeting). In this study we sought to validate this classification by analyzing gene expression data set of primary lung adenocarcinomas. Also, we investigated whether this classification is clinically relevant to therapeutic outcomes.
Experimental Design: A panel of 40 lung carcinoma cell lines was analyzed. The activation levels of EGFR and MET were determined by Western blotting and gene expression data was obtained by Affymetrix Microarray. We retrieved gene expression data of 442 lung adenocarcinomas (Nature medicine, 2008, http://www.nature.com/nm/journal/v14/n8/abs/nm.1790.html?lang=en) and used them to validate our classification.
Results: Forty lung carcinoma cell lines could be classified into two distinctive groups. Group I (n=26) was characterized by high levels of TTF-1, MUC1, CK7, MET, HER3, E-cadherin, Cox-2, and lamininC2. In contrast, Group II (n=14) showed high levels of vimentin, FGFR1, and TCF8. Group I was characterized by high phosphorylation levels of MET and EGFR, and frequent mutation and amplification of EGFR and MET. In contrast, Group II exhibited low activation levels of EGFR and MET, and no mutation or amplification of EGFR and MET. We validated this classification by analyzing gene expression data of 442 lung adenocarcinomas. By hierarchical clustering we identified two clusters (Cluster A and B) that corresponded to Group I and II, respectively. Cluster A and B were similar in prognosis but among patients who received adjuvant chemo- or radiotherapy, Cluster B showed better survival than Cluster A. This finding was corroborated by analyzing in vitro sensitivities to chemotherapeutic and molecular-targeted agents: Group II cell lines showed a tendency to be sensitive to paclitaxel and cisplatin while they showed resistance to EGFR inhibitor gefitinib.
Conclusions: Lung adenocarcinoma cell lines can be classified into two groups with distinct gene expression patterns, genetic abnormalities and activation status of EGFR and MET. This classification will be clinically relevant with regard to clinical response to chemotherapy and molecular targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1185.
Abstract 1188: Cell-of-origin determines genetic selection and defines T-cell acute lymphocytic leukemia sub-types in mouse models
Authors: Berquam-Vrieze Katherine E. , Nannapaneni Kishore , Zagorodna Oksana , Mullighan Charles , Meyerholz David K. , Copeland Neal , Jenkins Nancy , Knudson C. Michael , Scheetz Todd , Dupuy Adam J. 
Published: February 2011

Abstract
The cell-of-origin has yet to be identified for most forms of cancer. However, such knowledge would provide insight into the earliest events that initially distinguish a tumor cell from its normal cell-of-origin. Understanding and identifying these events are critical, as these early genetic changes may create targets that can be exploited therapeutically. Unfortunately, the tools to address this question have only recently become available.
We have recently completed a forward genetic screen to examine how altering the cell-of-origin affects genetic selection in cancer. To accomplish this we made use of a Cre-inducible Sleeping Beauty (SB) system to initiate transposon mutagenesis in hematopoietic stem cells (HSCs), thymic progenitor cells (TP) or late stage CD4+/CD8+ thymocytes (DP). Each of these approaches produced predominantly T-cell lymphomas with different characteristics. Analysis of transposon-induced mutations in each of the three lymphoma models revealed clear differences in their genetic profiles. For instance, the HSC model was defined by frequent mutations in Notch1 (∼58%). By contrast, lymphomas in the DP model did not have Notch1 mutations, but instead had frequent mutations in Myc, Gfi1, Whsc1 and Akt2. Interestingly, tumors that were initiated in thymic progenitor cells had a genetic profile similar to that seen in the HSC or the DP model.
Recently, a sub-type of T-cell acute lymphoblastic leukemia (T-ALL), called early thymic progenitor ALL (ETP-ALL) was described in which the tumor cells resembled ETPs in both surface marker and mRNA expression. In addition, ETP-ALL patients have a much worse prognosis than typical T-ALL patients. We compared gene expression signatures from a subset of HSC and DP lymphomas to that of ETP-ALL and typical T-ALL. Interestingly, tumors from the DP model have a similar gene expression to human ETP-ALL, while HSC tumors show a greater resemblence to typical T-ALL.
Our data indicate that ETP-ALL may not arise from an early thymic progenitor, but from a differentiated T-cell that has undergone anaplastic transformation. The implications of this study are that cell-of-origin cannot be inferred from analysis of protein or gene expression patterns in tumors. Our findings also suggest that differentiation state of the cell-of-origin plays a critical role in determining what types of mutations will be selected during transformation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1188.
Abstract 119: Stabilization of hypoxia-inducible factor-1α by the human rhomboid family-1 gene product RHBDF1
Authors: Zhou Zhuan , Li Luyuan 
Published: February 2011

Abstract
Hypoxia inducible factor 1α (HIF1α) is a key transcription factor in the maintenance of oxygen and energy homoeostasis. Increased levels of HIF1α in cancer cells are often associated with increased tumor angiogenesis, metastasis, drug resistance, and poor prognosis. We reported recently that the human rhomboid family-1 gene (RHBDF1) plays a critical role in facilitating tumor growth. Here, we show that RHBDF1 interacts with and stabilizes HIF1α. RHBDF1 gene-silencing with siRNA leads to markedly decreased HIF1α protein stability and down-regulation of HIF1α-targeted genes. However, HIF1α gene transcription and translation is unaffected. RACK1 and HSP90 are protein factors that compete for binding to HIF1α, causing either oxygen-independent degradation or stabilization of the latter. Protection of HIF1α from degradation by RHBDF1 is the result of a switch of HIF1α binding from RACK1 to HSP90. Stabilization of HIF1a can be abolished by using 17-allylaminogeldanamycin, an inhibitor of HSP90. Moreover, engineered over-expression of RHBDF1 leads to hypoxia-induced resistance of cancer cells to apoptosis-inducing agent Etoposide, an anticancer drug, apparently due to high HIF1α levels. These findings are consistent with the view that RHBDF1 may function as a chaperone to maintain HIF-1α stability.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 119.
Abstract 1194: The splicing isoform osteopontin-c contributes to ovarian cancer progression
Authors: Tilli Tatiana M. , Franco Vanessa , Robbs Bruno , Wanderley João , Borges Fabrício , Viola João , Weber Georg , Gimba Etel 
Published: February 2011

Abstract
Introduction: Osteopontin (OPN) is a secreted glycophosphoprotein that is involved in tumorigenesis and metastasis in many solid tumors. Alternative splicing of OPN mRNA generates 3 known species and proteins, OPNa, OPNb and OPNc. Objective and Methodology: The aim of the present work was to investigate the expression profiling and the functional roles of OPN isoforms in ovarian carcinoma. Here we investigate the expression of each OPN isoform in ovarian cell lines and ovarian tissues, by quantitative real-time PCR using OPN splice variants specific primer pairs. We then investigated the roles of each one of these isoforms by using in vitro and in vivo models. Cell proliferation, migration and anchorage independent cell growth analysis were performed using OvCAr-3 cells overexpressing OPNa, OPNb or OPNc isoforms. Tumor formation was evaluated in athymic nude mice inoculated with OvCar3 cells overexpressing each oisoform as compared to empty vector controls. Results: We show that OPNa and OPNb are expressed in all ovarian tissues analyzed. However, the isoform OPNc is selectively present in malignant and borderline ovarian tumors and malignant tumor cell lines, but not in benign and normal ovarian tissues. Cell proliferation, migration, anchorage-independent growth and tumor growth in vivo are dramatically increased in OvCar-3 cells overexpressing OPNc. In contrast, OPNa and OPNb do not present these same pro-tumorigenic properties. Conclusions: These results together provide compelling evidence that OPNc plays important roles in ovarian cancer progression. Firstly, OPNc is specifically expressed in borderline and malignant ovarian tumors. Secondly, OPNc expression facilitates tumor progression towards an aggressive phenotype. Targeting OPNc in ovarian cancer has potential as a novel therapeutic strategy.
Financial Support: CNPq, CAPES, FAPERJ, Swiss Bridge Foundation, FAF/MS
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1194.
Abstract 1197: The role of mitochondrial permeability transition pore complex proteins VDAC1, ANT, and cyclophilin D in prednisolone-induced apoptosis in B-Lineage acute lymphoblastic leukemia (ALL)
Authors: Jiang Nan , Koh Grace Shi Min , Kham Shirley Kow Yin , Chew Fook Tim , Yeoh Allen Eng Juh 
Published: February 2011

Abstract
The loss of mitochondrial membrane permeability is central to apoptosis. The mitochondrial permeability transition pore (PTP) complex, comprising of at least voltage-dependent anion channel 1 (VDAC1), adenine nucleotide transporter (ANT) and cyclophilin D (CyD), mediates the permeability of the mitochondrial membranes. We investigated the involvement of VDAC1, ANT and CyD in prednisolone (PRED)-induced apoptosis in 2 ALL cell lines: Sup-B15 (sensitive) and REH (resistant). After 24h exposure to PRED (10.0µg/ml), VDAC1 protein was consistently upregulated only in PRED-sensitive cell line, but remained unchanged in the resistant one. Co-administration of non-specific VDAC1 inhibitor, 4, 4′-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) with PRED, blocked PRED-induced apoptosis and caspase-3 activity only in sensitive cell line. Surprisingly, complete VDAC1 silencing using siRNA (Dharmacon) failed to abrogate PRED-induced apoptosis, suggesting that VDAC1 is not critical. We next investigated the other members of the PTP complex i.e., ANT and CyD. Co-administration of PRED and bongkrekic acid (BA) a specific inhibitor of ANT, also resulted in a dose-dependent inhibition of apoptosis and the caspase-3 activity. The combination of DIDS and BA, even at reduced doses by 60% and 96% respectively, is highly synergistic in inhibiting PRED-induced apoptosis and surprisingly reduced VDAC1 upregulation in PRED-induced apoptosis, unlike each agent alone. PRED did not alter the level of CyD protein and administration of specific CyD inhibitor, cyclosporine A (CsA), did not affect PRED-induced apoptosis. We conclude that ANT protein is central in the mitochondrial PTP mediated apoptosis during PRED treatment of ALL; VDAC1 and CyD are dispensable. ANT is upstream to VDAC1 and it upregulates VDAC1 during PTP activation in PRED-induced apoptosis. Our investigation provides the basis for looking at the role of mitochondrial PTP complex proteins especially ANT in PRED treatment in childhood ALL. This may provide new avenues to reverse resistance to therapy in patients with relapsed ALL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1197.
Abstract 1200: Oncogenic KRAS sensitizes colorectal tumor cells to chemotherapy via p53-dependent induction of Noxa
Authors: de Bruijn Menno T. , Raats Daniëlle A. , Hoogwater Frederik J. , van Houdt Winan J. , Cameron Kate , Medema Jan-Paul , Rinkes Inne H. Borel , Kranenburg Onno 
Published: February 2011

Abstract
Oxaliplatin and 5-fluorouracil currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumor responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that the presence of oncogenic KRAS in colorectal tumor cells sensitizes these cells to chemotherapy. In the present manuscript we show that the sensitization of colorectal tumor cells to oxaliplatin and 5-FU by oncogenic KRAS is critically dependent on the presence of wild type p53. KRAS status did not influence p53 stabilization, p21 induction, or cell cycle arrest. A screen for induction of apoptosis regulators revealed that KRAS selectively promoted expression of the pro-apoptotic p53 target gene Noxa. Suppression of Noxa by RNA interference strongly reduced KRAS/p53-dependent apoptosis following exposure to chemotherapy, both in vitro and in tumor xenografts in mice. Noxa knockdown did not affect p53-dependent p21 induction or cell cycle arrest. Our results identify oncogenic KRAS as an important determinant of the cellular response to p53 activation following exposure to oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1200.
Abstract 1201: Inhibition of ASK1 through phosphorylation of serine 967 by PI3K/Akt-mediated pathways
Authors: Puckett Mary C. , Goldman Erinn , Cockrell Lisa , Khuri Fadlo , Fu Haian 
Published: February 2011

Abstract
Cancer is characterized in part by dysregulation of cell survival and cell death signals. In particular, many tumors show upregulated PI3K/Akt activity, leading to sustained cell survival and suppressed cell death. Here we report the identification of the apoptosis signal-regulating kinase 1 (ASK1) as a downstream effector of the PI3K/Akt survival signaling pathway. ASK1 can be suppressed by PI3K/Akt signaling, leading to inhibition of apoptotic signaling. ASK1 normally functions as a mitogen activated protein kinase kinase kinase (MAP3K) that, when activated by stress signals, can evoke a signaling cascade leading to activation of the MAPKs JNK and p38. This activation can result in many cellular responses, but ASK1 is most notably known for its role as a critical regulator of apoptosis. Because of its crucial role in the balance between survival and death, ASK1 activity is tightly controlled. In particular, 14-3-3 can bind ASK1 and inhibit its activity when the kinase is phosphorylated at serine 967. However, the signals that regulate this phosphorylation event are currently unknown. Recent evidence suggests that PI3K/Akt mediated pathways may be involved in phosphorylation of serine 967 and, subsequently, inhibition of ASK1. Specifically, treatment of cells with growth factors including IGF-1 and PDGF increased phosphorylation of serine 967, as did overexpression of a constitutively active Akt mutant. In addition, expression of a kinase dead Akt mutant blocked growth factor induced serine 967 phosphorylation, indicating that Akt plays a role in mediating survival signals leading to inhibition of ASK1. In support of this notion, treatment with the inhibitors of Akt and PI3K also reduced serine 967 phosphorylation. Interestingly, treatment of cells with IGF-1 or overexpression of Akt was also able to protect serine 967 from H2O2 induced dephosphorylation. Taken together, our study reveals a novel effector site in ASK1 for the action of PI3K/Akt, which may offer a potential target for cancer therapeutic development. This work was supported by the NIH Pharmacological Sciences Training Grant T32 GM008602 and NIH/NCI Grant PO1CA116676 and USAMRMC05075002 to FRK and HF.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1201.
Abstract 1203: Coordinated regulation of intestinal radio-sensitivity by PUMA and p21
Authors: Leibowitz Brian J. , Zhang Lin , Yu Jian 
Published: February 2011

Abstract
p53-upregulated modulator of apoptosis (PUMA) has been shown to be vital for radio-sensitivity in the small intestine. PUMA ablation results in drastic radio-resistance, lengthening the survival of mice exposed to 15 Gy whole body irradiation and blocking apoptosis in the crypts. In contrast, we and others have found that p21 ablation leads to slightly increased radio-sensitivity. To better elucidate the relative and perhaps linked roles of PUMA and p21 in the intestinal responses to irradiation, we produced PUMA/p21 double knockout (DKO) mice. Initial experiments revealed that DKO mice responded similarly to PUMA KO mice within the first 24 hours after 15 Gy ionizing radiation as measured by the DNA damage response and apoptosis in the crypts. Both groups showed more rapid, though less sustained, phosphorylation of H2AX than wild-type (WT) mice, while displaying significantly less apoptosis in the crypts. However, DKO mice were found to have similarly enhanced overall radio-sensitivity as p21 KO mice. Further studies revealed that DKO and PUMA KO mice may not be equally effective at repair despite their similar kinetics in the initial DNA damage response. At 48 and 72 hours post-irradiation, the crypts in DKO mice had a substantial number of TUNEL+ cells, while those in PUMA KO or WT mice had almost none. At 48 hours after irradiation, the crypts in p21 KO mice also had a large number of TUNEL+ cells, which declined by 72 hours. Additionally, the crypt cells in DKO and p21 KO mice, but not in WT or PUMA KO mice, were found to be positive for both γ-H2AX and the mitosis marker phospo-H3, indicating abrogated cell cycle control likely due to a futile attempt at proliferation. These data further suggest that the protection of intestinal epithelium against radiation injury through ablation of PUMA requires a functional p21 checkpoint in addition to inhibition of crypt apoptosis. Additional studies are underway in our laboratory to further elucidate how these two proteins might coordinately regulate intestinal injury and regeneration by modulating the survival and proliferation of intestinal stem cells and progenitors following irradiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1203.
Abstract 1208: Suppressor of cytokine signaling 6 (SOCS6) is targeted to mitochondria and regulates mitochondrial morphology and function
Authors: Lin Huan-Yu , Lai Rai-Hua , Lee Hsin-Chen , Wang Fung-Fang , Chen Jeou-Yuan 
Published: February 2011

Abstract
Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that loss-of-function of suppressor of cytokine signaling (SOCS) 6 is a frequent event in human gastric cancer and ectopic expression of SOCS6 sensitized cells to UV-induced apoptosis. In this study, we have identified SOCS6 as a novel mitochondrial protein that regulates mitochondrial dynamics. By confocal microscopy, we showed that ectopically expressed SOCS6 is predominantly localized in mitochondria, and that the carboxyl-terminal SOCS box is important for its mitochondrial localization. We further showed that localization of SOCS6 in mitochondria is accompanied with increased mitochondrial fragmentation with attenuated membrane potential, both of which can be reversed by coexpression of mitochondrial fusion proteins Mfn1 or Mfn2. Our data further suggested that SOCS6 interferes with mitochondrial dynamics by interrupting the fusion process. Firstly, SOCS6 expression severely impaired the dynamics and mobility of mitochondria in live cells as demonstrated by fluorescence recovery after photobleaching (FRAP) experiments. Secondly, SOCS6 expression significantly hampered intermitochondrial transfer and fusion in the somatic hybrid produced by PEG-induced fusion. Furthermore, elimination of the expression of endogenous SOCS6 by RNA interference technique led to elongated mitochondria, and conferred cells increased resistance to UV-induced apoptosis. Taken together, our data suggest that SOCS6 is a mitochondrial targeting protein involved in the regulation of mitochondrial dynamics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1208.