bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 16: Downregulation of CYLD leads to acquisition of mesenchymal state and increased migration via ligand-independent TGFβR1 activation in human oral squamous cell carcinoma cells
Authors: Shinriki Satoru , Nakamura Takuya , Hayashi Mitsuhiro , Guo Jianying , Atsuyama Eri , Nishimura Yasuharu , Yamamoto Yutaka , Sueyoshi Takanao , Ota Tomoko , Shinohara Masanori , Ando Yukio 
Published: August 2012

Abstract
The 5-year survival of patients with oral squamous cell carcinoma (OSCC) has not changed apparently for the past 30 years. Although cylindromatosis (CYLD) is thought as a potent tumor suppressor, its biological significances in malignancies are largely unknown. The aim of this study was to clarify the role of CYLD in OSCC progression. We investigated expression of CYLD in OSCC including intraepithelial neoplasia (IEN; n = 48) and invasive carcinomas (n = 133) tissues and normal oral mucosal tissues (n = 35) by immunohistochemistry. In addition, effects of CYLD knockdown by siRNA transfection on OSCC progression using 5 OSCC cell lines (SAS, Tu4, HSC3, Ca9-22, and SCC-NA) and HaCaT keratinocytes. Our immunohistochemical analyses revealed that CYLD expression was significantly reduced at invasive lesions in OSCC tissues whereas it was conserved in normal epithelium and IEN. In addition, lower CYLD expression was associated with the correlation with the increased tumor size, advanced clinical stage, and poor overall survival in invasive OSCC. Accordingly, CYLD knockdown led to acquisition of mesenchymal state and increased migratory activity in all the OSCC cell lines as well as HaCaT keratinocytes. Notably, such EMT-like changes were completely blocked by a TGFβR1 inhibitor in all the OSCC cell lines, but not in HaCaT keratinocytes. Furthermore, treatment with excess amount of anti-TGFβ antibody (1D11) did not inhibit the EMT-like changes induced by CYLD repression. These findings suggest that downregulation of CYLD promotes invasion through EMT-like changes via ligand-independent TGFβR1 activation in OSCC cells in mechanisms distinct from normal epithelium. Further studies for these mechanisms probably provide new insights into the biology including “TGFβ switch” and development of a novel therapy in OSCC.
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 16. doi:1538-7445.AM2012-16
Abstract 160: Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells
Authors: Raina Deepak , Ahmad Rehan , Rajabi Hasan , Panchamoorthy Govind , Kufe Donald W. , Kharbanda Surender 
Published: August 2012

Abstract
The MUC1 heterodimeric protein is aberrantly overexpressed in diverse human carcinomas and contributes to the malignant phenotype. The MUC1-C transmembrane subunit contains a CQC motif in the cytoplasmic domain that has been implicated in the formation of dimers and in its oncogenic function. The present studies demonstrate that MUC1-C forms dimers in human breast and lung cancer cells. MUC1-C dimerization was detectable in the cytoplasm and was independent of MUC1-N, the N-terminal mucin subunit that extends outside the cell. We show that the MUC1-C cytoplasmic domain forms dimers in vitro that are disrupted by reducing agents. Moreover, dimerization of the MUC1-C subunit in cancer cells was blocked by reducing agents and increased by oxidative stress, supporting involvement of the CQC motif in forming disulfide bonds. In support of these observations, mutation of the MUC1-C CQC motif to AQA completely blocked MUC1-C dimerization. Importantly, these studies were performed with MUC1-C devoid of fluorescent proteins, such as GFP, CFP and YFP. In this regard, we show that GFP, CFP and YFP themselves form dimers that are readily detectable with cross-linking agents. The present results further demonstrate that a cell-penetrating peptide that targets the MUC1-C CQC cysteines blocks MUC1-C dimerization in cancer cells. These findings provide definitive evidence that (i) the MUC1-C cytoplasmic domain cysteines are necessary and sufficient for MUC1-C dimerization and (ii) these CQC motif cysteine represent an Achilles’ heel for targeting MUC1-C function.
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 160. doi:1538-7445.AM2012-160
Abstract 1601: Ethanol promotes chemically induced oral cancer in mice through activation of the 5-lipoxygenase pathway of arachidonic acid metabolism
Authors: Guo Yizhu , Wang Xin , Zhang Xinyan , Sun Zheng , Chen Xiaoxin Luke 
Published: August 2012

Abstract
Alcohol drinking is a known risk factor for oral cancer in humans. However, previous animal studies on the promoting effect of ethanol on oral carcinogenesis were inconclusive. It is necessary to develop an animal model with which the molecular mechanism of ethanol-related oral carcinogenesis may be elucidated in order to develop effective prevention strategies. In this study, mice were first treated with 4-nitroquinoline-1-oxide (4NQO, 100μg/ml in drinking water) for 8 weeks, and then given water or ethanol (8%) as the sole drink for another 16 weeks. During the experiment, 8% ethanol was well tolerated by mice. The incidence of squamous cell carcinoma (SCC) increased from 20% (8/41) to 43% (17/40; p&lt;0.05). Expression of 5-lipoxygenase (5-Lox) and cyclooxygenase 2 (Cox-2) was increased in dysplasia and SCC of 4NQO-treated tongues, and further enhanced by ethanol. Using this mouse model, we further demonstrated that fewer cancers were induced in Alox5-/- mice, as were cell proliferation, inflammation, and angiogenesis in the tongue, as compared with Alox5+/+ mice. Interestingly, Cox-2 expression was induced by ethanol in knockout mice, while 5-Lox and leukotriene A4 hydrolase (LTA4H) expression and leukotriene B4 (LTB4) biosynthesis were dramatically reduced. Moreover, ethanol enhanced expression and nuclear localization of 5-Lox and stimulated LTB4 biosynthesis in human tongue SCC cells (SCC-15 and SCC-4) in vitro. In conclusion, this study clearly demonstrated that ethanol promoted 4NQO-induced oral carcinogenesis, at least in part, through further activation of the 5-Lox pathway of arachidonic acid metabolism.
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 1601. doi:1538-7445.AM2012-1601
Abstract 1604: Treatment with Pequi (Caryocar brasiliense Camb) fruit pulp oil decrease the DNA damage caused by chemical carcinogenesis in experimental model of lung cancer.
Authors: Colombo Natália B. , Parra Edwin Roger , koppe Grisolia César , Hage Marcia , Rangel Maristela P. , Capelozzi Vera Luíza 
Published: August 2012

Abstract
Background: It is well known that a daily consumption of foods that are rich in antioxidants prevents the oxidative damage caused by reactive species (ROS), including DNA damage, and can reduce the risk of cancer, atherosclerosis and other degenerative diseases. The pulp of Caryocar brasiliense Camb, most known as pequi, is a Brazilian fruit that has high levels of antoxidants properties, such as vitamin C, carotenoids, phenolic compounds like flavonoids, saponins and tannins, and essential oils. The aim of this study was to evaluate the action of the pequi oil in the DNA damage in experimental model of lung cancer induced by the urethane. Material and Methods: Male BALB/c mice (n=14) received by gavage 0,5μL/mg/day of pequi oil (CBC oil) during 75 days. After 15 days of the beginning of the gavage, 10 of these animals received two doses of 1,5g/kg intraperitoneal of urethane (Urethane + CBC oil). Urethane animals (n=4) were only submitted to two doses of 1,5g/kg intraperitoneal of urethane (urethane group). After these 75 days, lung tissues were submitted to histological and biochemical analysis by comet assay method to evaluated the DNA damage. The DNA damage was quantificate by image analysis. Results: The lung parenchyma from the urethane groups without oil and with oil showed neoplasic formations induced by the chemical carcinogenesis in contrast with oil control group. The image analysis of the comet assay showed a statistical significant diminish of the DNA damage cells in the urethane oil group when compared with urethane control group (p=0.001). The decreased DNA damage was very similar that we obtained in the oil control group. Conclusion: We conclude that the different antioxidant components found in the pequi oil diminish the DNA damage in the mouse lung after chemical carcinogenesis, suggesting that this type of strategies may have a greater impact in lung cancer treatment. Financial Support: FAPESP, CNPq
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 1604. doi:1538-7445.AM2012-1604
Abstract 1605: α-cryptoxanthin supplementation inhibits the carcinogen-initiated and nicotine-promoted lung carcinogenesis in AJ mice by suppression of AKT activation
Authors: Iskandar Anita R. , Liu Chun , Ernst Hansgeorg , Choi Sang-Woon , Ausman Lynne , Wang Xiang-Dong 
Published: August 2012

Abstract
A pooled analysis from well-implemented cohort studies reported that increased dietary α-cryptoxanthin (BCX) intake, rather than α-carotene used in earlier human trials, is associated with reduced risk of lung cancer. Nonetheless, BCX efficacy on lung carcinogenesis has not been reported. In these studies, we examined the protective effects of BCX at different doses against lung carcinogenesis at the initiation and the promotion stages of the cancer development in male AJ mice. In the tobacco carcinogen 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone [NNK]-initiated lung carcinogenesis model, we found a 52-63% reduction of lung tumor multiplicity in mice pre-treated with BCX at 0.2 and 2 mg kg BW-1 d-1, as compared to the NNK group (P&lt;0.01). In contrast, BCX did not significantly alter the spontaneous lung tumor multiplcitiy in mice without the NNK treatment. Furthermore, in the NNK-initiated and nicotine-promoted lung cancer model, we found that nicotine treatment by intraperitoneal injections not only significantly induced emphysema, a risk for lung cancer, but also greatly increased lung tumor multiplicity of the NNK-treated mice. Remarkably, BCX at 2 and 4 mg kg BW-1 d-1 prevented the nicotine-induced pulmonary emphysema and decreased tumor multiplicity by 86-91% (P&lt;0.01). BCX protective effect on carcinogenesis was associated with significant suppression of lung AKT activation measured by immunoblotting. BCX also reduced the emphysema-related IL-6 and early growth response-1 induction of mRNA levels measured by real-time PCR. Contrary to α-carotene reported in prior animal studies, BCX also induced the retinoic acid receptor-α mRNA. As measured by HPLC analysis, the concentrations of liver BCX were higher in the BCX supplemented mice, without alteration of the retinol concentrations. Our data suggest that BCX is a unique chemopreventive agent for lung cancer prevention, which is likely to be independent of its provitamin A activity.
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 1605. doi:1538-7445.AM2012-1605
Abstract 1606: Antitumor effects of vitamin D in a carcinogen-induced mouse model of lung cancer
Authors: Mazzilli Sarah A. , Reid Mary E. , Seshadri Mukund , Bogner Paul N. , Foster Barbara A. , Johnson Candace S. , Trump Donald L. 
Published: August 2012

Abstract
Lung cancer accounts for the majority of cancer mortality in both men and women. It is critical to better understand the biology of lung cancer development as no preventive agents and few effective treatment options exist for lung cancer. Epidemiological studies indicate that low serum levels of 25(OH)D3 are associated with increased risk and poor prognosis of lung cancer. Calcitriol, the active metabolite of vitamin D, induces cell cycle arrest, apoptosis and differentiation in preclinical and clinical studies, has limited toxicity, and hence, is an attractive agent for chemoprevention. To investigate the preventive effects of vitamin D on lung squamous cell carcinoma (SCC), pre-clinical studies were conducted using a carcinogen-induced (CI) mouse model of lung SCC which uses N-nitroso-tris-chloroethylurea (NTCU) applied topically to the back of a SWR/J mouse twice weekly. Following ∼15 weeks of NTCU treatment, mice begin to develop bronchial epithelial hyperplasia and in time, progress through metaplasia, carcinoma in situ, and ultimately form lung SCC by approximately 35 to 40 weeks. We conducted a preliminary study investigating the effects of vitamin D on cancer progression in the CI model where animals received NTCU (80 mM/week). 12 week old female mice were randomized into one of three treatment groups: 1) vitamin D deficient diet (DD) (0IU D3 in the diet), 2) sufficient diet (SD) (2000IU/day D3 in the diet) and 3) SD with weekly intraperitoneal (IP) injections of calcitriol (80 ug/kg) (SD+D). Animals treated with NTCU on a DD, SD and SD+D had average serum 25(OH)D3 levels of 15, 70 and 75 nmol/L, respectively (normal range in mice is 70- 90 nmol/L). Preliminary histological evaluation at 12 weeks revealed bronchial epithelial hyperplasia in both the SD and SD+D groups. There were more advanced changes including hyperplasia, metaplasia and dysplasia in the DD mice. The histological evaluation of the DD mice at 24 weeks revealed even more advanced disease, in that most mice had developed lung SCC. The histological evaluation of the SD and SD+D groups at 24 weeks indicated the presence of bronchial epithelial hyperplasia, squamous metaplasia and dysplasia in all mice with some low level of carcinoma in situ. This study indicates that mice deficient in vitamin D develop disease at a more rapid rate suggesting that vitamin D status may play an important role in progression of lung SCC. Supported by NCCAM F31 AT006487 & R01-CA-067267.
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 1606. doi:1538-7445.AM2012-1606
Abstract 1608: Silibinin synergizes with histone deacetylase (HDAC) inhibitors in upregulating E-cadherin expression in non-small lung cancer (NSCLC) cells
Authors: Mateen Samiha , Raina Komal , Agarwal Chapla , Chan Daniel , Agarwal Rajesh 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer-related mortalities, and the 5-year survival rate of this malignancy remains at 15%. This feature is attributed primarily to the early metastasis of the disease within the organ and to distant sites that involves the epithelial-to-mesenchymal transition (EMT) of lung cancer cells. Aggressive cancer cells with EMT are characterized by loss of cell adhesion, repression of E-cadherin expression and increased cell mobility. NSCLC cells widely differ in their basal level of E-cadherin expression, which is epigenetically silenced in most of them due to deacetylation by histone deactylases. This suggests that inhibitors of HDACs would be useful in NSCLC control. Several HDAC inhibitors (HDACi) have shown potential in this regard, and are in clinical trials; however, their toxicity and cancer cell resistance are the limiting factors. Silibinin (Sb), a non-toxic chemopreventive agent, has shown strong efficacy against epithelial cancers including NSCLC, and previously, we have demonstrated that Sb alters HDAC enzymatic activity and protein levels in a total cellular extract of H1299 cells. Herein, we sought to determine the putative role of Silibinin, either alone or in combination with other HDACi in modulating E-cadherin levels in NSCLC cell lines including H1299 cells (epigenetically silent E-cadherin levels). Treatment with HDAC inhibitors, Trichostatin A [TSA] (0.33-1 µM) or SAHA (0.5-5 µM) led to a dose-dependent induction of E-cadherin expression levels. Furthermore, the combinations of TSA (0.5 µM) with low doses of Sb (3.75-25 µM) in H1299 cells, significantly increased E-cadherin protein levels (24h), which remained sustained at later time points (48-72h) longer than with TSA alone treatments. Also, at these time points, Zeb1, a major transcriptional repressor of E-cadherin, was inversely down-modulated with the combination treatments. Substantial inhibition of invasion/migration of H1299 cells with similar treatment conditions further emphasized the biological significance of E-cadherin restoration. Unlike H1299 cells, treatment of H322 and H358 cells (with detectable E-cadherin level) with Sb (3.75-25 µM) alone was sufficient to consistently increase the basal levels of E-cadherin, with concomitant reduction of Zeb1 levels, which also led to inhibition of migratory potential of these cells. Overall these findings demonstrate that Sb alone or in combination with HDAC inhibitors upregulates E-cadherin expression levels in NSCLC cell lines, and this consequently leads to inhibition of invasion/migratory phenotype of these 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 1608. doi:1538-7445.AM2012-1608
Abstract 161: The role of mTOR in the cisplatin resistant phenotype in ovarian cancer lineage
Authors: Ladislau Taciane , Silva Débora , Madeira Klesia Pirola , Daltoé Renata Dalmaschio , Paes Marcela Ferreira , Herlinger Alice Laschuck , Junior Paulo Cilas Morais Lyra , Silva Ian Victor , Rangel Leticia Batista Azevedo 
Published: August 2012

Abstract
Background Ovarian cancer (OVCA) is the second cause of gynecological-cancer deaths in Brazil, being frequently associated to chemotherapy resistance, a characteristic usually associated to PI3K/Akt/mTOR. We herein present data concerning the role of mTORC2 in cisplatin-resistant phenotype acquisition by OVCA cells. Methods Antineoplastic efficacy of cisplatin, doxorubicin, paclitaxel, and rapamycin was accessed, in different combinations, in the OVCA lineage OVCAR3 (cisplatin-resistant, advanced serous OVCA), through cellular metabolic viability (CMV) (MTT method). Cells were cultured in RPMI media supplemented with 10% (v/v) FBS and antibiotics until subconfluence. To characterize the role of mTORC1 or mTORC2 in OVCAR3 MCV, 1.5x105 cells/well were treated according to: EA1) Inhibition of mTORC1: Drugs at IC50 for 24h; EA2) Inhibition of mTORC1 and mTORC2: Rapamycin 100nM for 72h, followed by drugs at IC50 for 24h. Modulation of MTOR expression by PKA, PKC, and PI3K was investigated by real time RT-PCR. Statistical analysis was performed using PrismaGraphPad version 5.1. Findings OVCAR3 CMV was not significantly changed by cisplatin (IC50 0,08mM) nor paclitaxel (IC50 0,06nM) or rapamycin (IC50 0,02nM) (CMV 95%, 100%, 100%, respectively), but by doxorubicin (IC50 0,02nM) (CMV 60%), especially in combination with cisplatin (CMV 31%), following EA1. Considering the irreversible doxorubicin-induced cardiotoxicity, we pursued with EA2. Intriguingly, OVCAR3 cisplatin sensitivity was, at least partially, recovered (CMV 65%). No addictive effect was observed with cisplatin/doxorubicin following EA2 (CMV 60%), suggesting that OVCA-resistant patient might benefit from less toxic rapamycin-based chemotherapy, leaving doxorubicin for palliative final-staged disease management. Finally, neither PKA nor PI3K modulate MTOR expression; however, PKC suppresses its transcription by 4.42-fold. Interpretation Altogether, our data suggest that mTORC2, but not mTORC1, might influence cisplatin sensitivity in OVCA. Moreover, PKC inhibits the expression of MTORC in cisplatin-resistant OVCA. We propose that the inhibition of mTORC2 followed by cisplatin treatment might lead to a conjunction of autophagic cell death and apoptosis in OVCA. Of remarkable clinical interest, we point to the urge of better design clinical trials, in which not only novel drugs are tested, but also the chronological order of drugs administration to the patient is seen as crucial for treatment efficacy.
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 161. doi:1538-7445.AM2012-161
Abstract 1610: Curcumin inhibition of the functional interaction between integrin α6β4 and the epidermal growth factor receptor
Authors: Soung Young Hwa , Chung Jun 
Published: August 2012

Abstract
The functional interaction between integrin α6β4 and growth factor receptors has been implicated in key signaling pathways important for cancer cell function. However, few attempts have been made to selectively target this interaction for therapeutic intervention. Previous studies showed that curcumin, a yellow pigment isolated from tumeric, inhibits integrin α6β4 signaling important for breast carcinoma cell motility and invasion, but the mechanism is not currently known. To address this issue, we tested the hypothesis that curcumin inhibits the functional interaction between α6β4 and the epidermal growth factor receptor (EGFR). In this study, we found that curcumin disrupts functional and physical interactions between α6β4 and EGFR, and blocks α6β4/EGFR dependent functions of carcinoma cells expressing the signaling competent form of α6β4. We further demonstrated that curcumin inhibits EGF dependent mobilization of α6β4 from hemidesmosomes to the leading edges of migrating cells such as lammelipodia and filopodia, and thereby prevents α6β4 distribution to lipid rafts where functional interactions between α6β4 and EGFR occur. These data suggest a novel paradigm in which curcumin inhibits α6β4 signaling and functions by altering intracellular localization of α6β4, thus preventing its association with signaling receptors such as 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 1610. doi:1538-7445.AM2012-1610