bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5075: PI3K activation restores KrasG12D oncogenic ability in a mouse model of follicular thyroid cancer by directly opposing multiple Kras-initiated negative feedback signals
Authors: Dima Mariavittoria , Baker Kristen , Cristofano Antonio Di 
Published: February 2011

Abstract
Activating mutations of Ras family members and aberrant activation of the PI3K/AKT pathway are quite common in thyroid cancer originating from the follicular epithelium.
We have recently shown in a relevant in vivo model that, contrary to many other cell types, Kras activation is unable to induce oncogenic transformation of the thyroid follicular cells. However, PI3K activation is able to potently cooperate with Kras oncogenic mutation, thus inducing aggressive and metastatic thyroid follicular carcinomas. We now show that one key event mediated by PI3K in this cross-talk is the inhibition of multiple Kras-initiated negative feedback signals shutting down MAPK signaling and the induction of proliferation. Through these mechanisms, PI3K signaling restores Kras-initiated MAPK activation, induction of proliferation, and oncogenic transformation.
In particular, our data reveal that activation of p38α MAPK, as well as up-regulation of MKP2 and MKP3 phosphatases, play a pivotal role in mediating the growth-suppressive negative feedback initiated by Kras oncogenic activation.
Activation of p38α MAPK acts by inducing cell cycle arrest and the establishment of cellular senescence, while MKP2 and MKP3 stunt ERK1/2 activation through direct dephosphorylation of these kinases.
Strikingly, we have found that PI3K acts through Akt1 (but not Akt2) to potently suppress p38 phosphorylation and activation. Furthermore, PI3K activation results in the transcriptional repression of MKP2 and MKP3 promoters. Through these two molecular mechanisms, PI3K activation contributes to unleashing to its full extent Kras oncogenic ability.
These data not only uncover novel oncogenic pathways controlled by PI3K signaling, but also further strengthen the rationale for the dual targeting of PI3K and MAPK pathways in thyroid cancer.
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 5075.
Abstract 5078: FGFR2 gene amplification status in gastric carcinoma and clinicopathologic significance
Authors: Jung Eun-Jung , Kim Woo Ho , Jung Eun-Ji , Kim Min A. 
Published: February 2011

Abstract
Background: Fibroblast growth factor receptor 2 (FRFG2) is a member of FGFR receptor tyrosine kinase family. FGFR2 gene amplification or missense mutation has been observed in various human cancers, including gastric carcinoma. Recent studies showed that, anti FGFR2 agents inhibit tumor progression in other tumors. Gastric carcinoma is one of the most frequent causes of cancer-related death worldwide. Evaluate the status of FGFR2 gene amplification in gastric carcinoma is beneficial in targeted cancer therapy.
Methods: We evaluated FGFR2 amplification status in the surgically resected 312 gastric carcinoma cases, using fluorescence in situ hybridization (FISH) and real-time quantitative-polymerase chain reaction (q-PCR), and compared the results. We compared clinicopathologic parameters with the presence of FGFR2 amplification, and performed survival analysis.
Results: Among 312cases, 14 cases (4.5%) showed FGFR2 amplification by FISH. FGFR2 amplification was associated to higher pT stage (p=0.015), pN stage (p=0.031) and distant metastasis (p=0.023). In survival analysis, FGFR2 amplification was significantly associated with lower cancer-specific survival in univariate analysis (p=0.012). The Real-time q-PCR results were concord with the FISH result.
Conclusions: Gastric carcinoma with FGFR2 amplification showed more advanced disease and poor survival. Evaluate the FGFR2 amplification status may identify a subset of cancers that are sensitive to targeted therapy using FGFR2 inhibitors.
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 5078.
Abstract 5079: Gadd45a differentially modulates breast tumorigenesis by promoting or suppressing tumor growth in response to distinct oncogenic stress
Authors: Tront Jennifer S. , Haung Yajue , Hoffman Barbara , Liebermann Dan 
Published: February 2011

Abstract
Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli, including oncogenic stress. Generating novel MMTV-ras and MMTV-myc mouse models which are either wildtype or null for Gadd45a, we identified Gadd45a as a tumor suppressor in ras-mediated breast tumorigenesis. In sharp contrast, recent findings have shown that Gadd45a promotes myc-driven breast cancer. Furthermore, the function of Gadd45a as either a tumor promoter or suppressor was observed to be mediated through distinct, mutually exclusive, signaling pathways. Whereas Gadd45a tumor suppressor function is mediated via activation of JNK and p38 stress kinases promoting ras-induced apoptosis and senescence, Gadd45a function as a tumor promoter is exerted by negatively regulating MMP10 expression via the GSK3b/Beta-catenin signaling cascade, resulting in increased tumor vascularization. Analyzing specimens obtained from human breast cancer patients has shown relatively high levels of Gadd45a expression in low to moderate grade tumors compared to normal breast tissue, and no Gadd45a expression in high grade tumors. Correlating the status of Gadd45a expression in human breast cancer to activated oncogenes and Gadd45a signaling, as well as to patient survival following treatment is in progress. Collectively, these observations highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis.
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 5079.
Abstract 508: Synergistic effect of β-catenin knockdown and radiation combination toward AMC-HN9 head and neck cancer cells is associated with down-regulation of Ku expression.
Authors: Chang Hyo Won , Kim Hyo Jung , Moon So Young , Kim Mi Ra , Kim Seong Who , Kim Sang Yoon 
Published: February 2011

Abstract
Based on our previous report showing that up-regulation of Ku70/Ku80 in AMC-HN9 (HN9) cells is required for cell-cycle re-entry and cell proliferation following irradiation, further study to investigate the mechanism by which β-catenin knockdown sensitizes the cells to irradiation have been conducted. β-Catenin, as a multifunctional protein involved in cadherin-mediated cell-cell adhesion and Wnt signaling transduction, have been well known to regulates cell growth and survival following radiation in various types of cancer cells. However, the molecular mechanisms by which β-catenin affects radiation sensitivity are still not fully understood, which led us to explore, with regard to regulation of Ku70/Ku80 expression, the molecular mechanism of the synergistic effects of β-catenin silencing and radiation combination in radio-resistant head and neck cancer cells.
β-Catenin silencing using small interfering RNA(siRNA) down-regulated β-catenin expression up to 72 h both in membranous and nuclear fraction of HN9 cells. β-Catenin knockdown induced cell cycle arrest on G1 phase and thus decreased cell proliferation, but didn't cause any DNA damage response and cell death. Whereas expression of Ku70/Ku80 was up-regulated in HN9 cell following irradiation (4Gy), in the cells treated with combination of radiation and β-catenin siRNA, Ku70/Ku80 expression were dramatically decreased. In addition, when β-catenin silenced cells were exposed to single dose of radiation, irradiation-induced cell death was much more increased from 3.1% to 13% and accompanied with caspase-3 activation and PARP cleavage.
Taken together, these results suggest that inhibition of Ku expression through β-catenin silencing is associated with its radio-sentitizing effect in HN9 cells and further studies to clarify the pathway linking β-catenin signaling and regulation of Ku70/Ku80 expression are warranted.
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 508.
Abstract 5095: Differential sensitivity to dietary restriction in xenograft models harboring PI3K pathway mutations in nude mice
Authors: Gulledge Travis , Blackwell Amber R. , Mullin Robert J. , Hollister Beth A. , Cheatham Lynn A. 
Published: February 2011

Abstract
The inhibitory effect of dietary restriction on the growth of human tumors has been well established. Recent evidence exploring the molecular mechanisms underlying this observation has been accumulating and supports a strong link with the PI3K/PTEN signaling pathway. Despite these recent advances, there remains a significant gap in our understanding of this observation. We have investigated the effects of dietary restriction on tumor growth in nude mouse xenografts of human tumor cell lines containing mutations in either PI3K or PTEN. In these experiments, dietary restriction was started after mean tumor size had reached between 60-100mg and continued until control groups reached endpoint (1000-2000mg). Diet restriction was achieved by feeding the experimental group a vitamin and nutrient enriched chow at a 20-40% reduction in overall amount relative to control groups. Our findings suggest that while activation of the PI3K/PTEN pathway may afford some resistance to dietary restriction, there may be other underlying mechanisms involved.
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 5095.
Abstract 5097: ITCH E3 ubiquitin ligase regulates LATS1 tumor suppressor stability
Authors: Ho King Ching , Yang Xiaolong 
Published: February 2011

Abstract
The Large Tumour Suppressor 1 (LATS1) is a serine/threonine kinase and tumour suppressor found downregulated in many human tumour types. Our lab and others previously revealed that LATS1 plays critical regulatory roles in various cancer development events, including cell proliferation, cell migration and apoptosis. However, despite such biological importance, relatively little is known regarding to how LATS1 is regulated at the molecular level. Through a recent binidng screen, we identified a HECT class E3 ubiqitin ligase ITCH (or API4) as a novel binding partner of LATS1. Further mapping showed that this interaction is particularly mediated through the PPxY (P, proline; x, any amino acids; Y, tyrosine) motifs of LATS1 and the WW domains of ITCH. Significantly, we found that ectopic expression of ITCH readily promotes downregulation of LATS1 proteins in a dose dependent manner and that this effect requries an intact ligase activity of ITCH. Further experiments also revealed that ITCH can promote in vivo polyubiquitination and subsequent degradation of LATS1 through the 26S proteasome pathway. Consistent with these results, stable shRNA knockdown of endogenous ITCH also causes upregulation of endogenous LATS1 in the MDA-MB-231 breast cancer cells, suggesting ITCH is a direct regulator of LATS1's protein stability. Together, our study provided convincing evidences demonstrating ITCH as the first negative regulator of the LATS1 tumour suppressor. Further elucidation of the effect of ITCH on LATS1's tumour suppressive activity may therefore shed light on our understanding of their roles in cancer development and 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 5097.
Abstract 5098: Targeting the cholesterol pathway gene SC4MOL sensitizes cancer to EGFR inhibitors
Authors: Sukhanova Anna L. , Bagnyukova Tetyana , Kratz Lisa E. , Kelley Richard I. , Serebriiskii Ilya G. , Weiner Louis M. , Golemis Erica A. , Astsaturov Igor A. 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) has been exploited as a target for blockade in cancer therapy, based on the known central role of EGFR signaling in promoting cancer cell growth. We have identified a novel mechanism for influencing EGFR activity that involves the sterol biosynthesis pathway enzyme sterol C4-methyl oxidase-like (SC4MOL). SC4MOL, in conjunction with other members of the ergosome complex (erg26/NSDHL; erg27/HSD17B7), catalyzes a non-redundant, irreversible step of demethylation at C4 of 14-demethylated lanosterol and dihydrolanosterol to produce zymosterol and 8(9)-cholestenol, respectively. Depletion of SC4MOL with siRNA caused accumulation of methylsterol intermediaries; inhibition of the key EGFR effectors, ERK and AKT; and a 3-fold increase in apoptosis specifically in the presence of EGFR antagonists. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA eliminated methylsterols and completely reversed the effect of SC4MOL depletion, while added cholesterol did not rescue cancer cells from accelerated apoptosis upon concurrent SC4MOL and EGFR blockade. These results indicate that accumulation of specific cholesterol precursors enhances efficacy of anti-EGFR drugs. Further, we found that SC4MOL and the other ergosome components are transcriptionally regulated by EGFR signaling, suggesting involvement of C4 methylsterols in physiological activation of the EGFR signaling pathway.
A metabolic effect of sterol intermediaries on EGFR signaling has not been previously characterized. Such an effect could be exploited in cancer therapeutically by employing already existing drugs such as synthetic 4,4-dimethylsterols currently in use for in vitro fertilization.
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 5098.
Abstract 51: Blood pressure lowering medications disrupt fatty acid metabolism in pancreatic cancer
Authors: Sivarajah Maheshwaran , Lim SuhYueh , Chipitsyna Galina , Gong Qiaoke , Aziz Tamer , Witkiewicz Agnes , Yeo Charles J. , Arafat Hwyda A. 
Published: February 2011

Abstract
Despite the routine use of chemotherapy and radiotherapy, survival has not significantly improved in patients with pancreatic ductal adenocarcinoma (PDA), a situation that signifies the urgent need for novel therapeutic approaches. Angiotensin II (AngII), the principal hormone of the renin angiotensin system, is actively generated in the pancreas and has been suggested as a key mediator of PDA cell survival. Fatty acid synthase (FAS) is a key enzyme involved in synthesis of fatty acids and its high levels have been correlated with poor prognosis in many cancers. In this study, we investigated the potential molecular basis for the role of AngII in pancreatic carcinogenesis through studying its effect on FAS. AngII significantly increased the expression of FAS mRNA and protein in Panc-1 and PK9 PDA cells lines and induced FAS promoter activity. AngII-FAS mRNA induction was inhibited by an AngII type 1 receptor (AT1R) antagonist, losartan, and to a lesser extent by an AT2R antagonist. AngII activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced FAS synthesis. AngII activated the phosphorylation of AKT. Inhibition of AKT activation prevented the AngII-mediated increase of FAS. In human premalignant (n=6) and invasive PDA lesions (n=25), high expression levels of FAS correlated well with tumor stage and invasion status, and with high expression levels of angiotensin converting enzyme (ACE). Immunohistochemical staining of PDA serial sections show co localization of ACE with FAS in the malignant ducts and stromal cells. Oral administration of losartan significantly (p&lt; 0.05) decreased the growth of PANC-1 and PK-9 cells xenografted on the flank of nude mice and significantly (p&lt;0.05) reduced the expression of FAS mRNA and protein in the xenografts. Our data suggest a positive autocrine/paracrine action for the local pancreatic AngII generating system during pancreatic carcinogenesis, and provide the first insight into an AngII-initiated signal transduction pathway that regulates fatty acid metabolism and modulate lipogenesis in PDA. These results raise the possibility that AngII blockade therapies could be potential candidates in novel treatment strategies of PDA.
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 51.
Abstract 510: Intermittent hypoxia confers resistance to radiation in human neuroblastoma cells
Authors: Ezhilarasan Rave Sanker , Mohanam Indra , Rao Jasti S. , Mohanam Sanjeeva 
Published: February 2011

Abstract
Neuroblastoma, the most common extracranial solid tumor of children, arises from the sympathetic nervous system, is characterized by extensive genetic, morphologic, and clinical heterogeneity and presents as benign to highly aggressive forms in various stages. Hypoxia has been linked to tumor progression and increased malignancy. Like the most common malignant solid tumors, neuroblastomas contain zones of chronic or acute hypoxia reflecting poor oxygenation. Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of therapies. Radiotherapy is commonly applied in higher stage neuroblastoma patients with MYCN oncogene amplification and metastases. The present study focuses how intermittent hypoxia modulates the effects of radiation treatment in human neuroblastoma cells. Intermittent hypoxia-conditioned cells were derived from human neuroblastoma cells that were exposed to 10 cycles of hypoxia and reoxygenation. Intermittent hypoxia stabilized the expression of HIF-l α in neuroblastoma cells. Cell survival to radiation treatment was assessed by the colony formation assay. The hypoxia-conditioned neuroblastoma cells exhibit increased survival to irradiation treatment compared with parental cells suggesting alterations in apoptotic pathways. The expression of selected genes associated with DNA damage as well as genes of BCL-2 family and caspase family were studied in parental and hypoxia-conditioned neuroblastoma cells in response to radiation treatment. Radiation caused an increase in the levels of proapoptotic proteins Bax, Bad, Bid and cleaved products of caspase-3 and −9 in parental tumor cells. Similar observations were not obtained in hypoxia-conditioned neuroblastoma cells upon radiation treatment demonstrating their increased radioresistance characteristics. We also assessed how hypoxia modulates radiation-induced in vitro angiogenesis. Human microvascular endothelial cells were exposed to conditioned medium from irradiated parental and irradiated hypoxia-conditioned tumor cells and capillary-like structure formation was studied. Further, tumor cell conditioned medium was also evaluated in chorioallantoic membrane assay for its angiogenic capabilities. These results suggest that intermittent hypoxia-conditioned neuroblastoma cells demonstrate increased survival, resistance to induction of apoptosis and angiogenic capabilities to radiation treatment.
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 510.
Abstract 5100: Expression of the insulin signaling related genes by infection of hepatitis C virus
Authors: Matsumura Takuya , Makino Reiko , Ito Kazuo , Imawari Michio , Kato Takanobu 
Published: February 2011

Abstract
BACKGROUND: Hepatitis C virus (HCV) induces chronic liver diseases such as chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Either molecular or clinical studies support a correlation between HCV infection and insulin resistance. Patients with chronic HCV infection have a significantly increased prevalence of type 2 diabetes mellitus compared to controls or HBV-infected patients. The HCV core protein is known to contribute to insulin resistance related steatosis, fibrosis, and carcinogenesis of the liver. Although several hypotheses have been demonstrated, a mechanism of insulin resistance by HCV infection is complex and still unclear. AIM: The aim of this study is to investigate the molecular mechanisms of liver injury by HCV through insulin signaling pathway. MATERIALS AND METHODS: HCV infected cultured cells and transgenic mice expressing HCV core gene were used for this study. A HCV strain JFH-1 replicates efficiently in cultured cells with production of infectious HCV. A transgenic mouse was established by introducing the core gene derived from the HCV genome of genotype 1b. Total RNA was extracted from the cells with and without HCV infection, and the livers of transgenic mice and their littermate wild type mice. The cDNA was synthesized from the RNA then applied to the real-time PCR. The relative amount of the mRNAs of 84 genes related to the insulin receptor and target genes for insulin signaling were compared between the cells or tissues with or without HCV. RESULTS and DISCUSSION: The expression of one of the insulin receptor substrate (IRS) family mRNA was increased in cells infecting HCV, compared to uninfected cells. On the other hand, the Akt mRNA expressed at higher level in the liver of transgenic mouse than that of normal littermate. The IRS family proteins are key mediators in insulin signaling and have been reported to associate with glucose metabolism. The Akt protein kinase is a critical regulator of human physiology that controls an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation and metabolism. The activation of Akt signaling may induce not only the insulin resistance but also the development of HCCs in the patients with HCV chronic infection. CONCLUSIONS: Our results indicates that the alteration of IRS family and Akt expression by HCV could be predictive for insulin resistance. Since the insulin resistance promotes inflammation and fibrogenesis in the liver, HCV infection leads to the development of liver cirrhosis and HCC by activation of insulin signaling.
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 5100.