bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3442: Overexpression of Kruppel-like factor 4 inhibits the growth and migration in human hepatoma cells
Authors: Sung Ming-Ta , Lee Hsin-Chen , Chi Chin-Wen 
Published: August 2012

Abstract
The zinc-finger transcriptional factor Kruppel-like factor 4 (KLF4), can inhibit cell proliferation and maintain the differentiation of epithelial cells by regulating the expression of genes with GC-rich promoters, plays important roles in development and tumorigenesis. Recently, reduction of KLF4 expression has been reported in multiple gastrointestinal cancers such as gastric cancer, colorectal cancer and hepatocellular carcinoma (HCC), and this observation was associated well with tumor progression and poor clinical outcome. However, the exact role of KLF4 in the progression of HCC is still unclear. In this study, we used lentiviral transduction method to overexpress KLF4 in a highly metastatic HA22T/VGH hepatoma cell line. Using MTT and sulforhodamine B assay, we found that cell growth was decreased in KLF4-overexpressing HA22T/VGH cells as compared to parental cells. Moreover, wound healing assay revealed the migration ability was significantly suppressed in KLF4-overexpressing HA22T/VGH cells. Consistent with these findings, KLF4 overexpression also resulted in the up-regulation of E-cadherin expression and concomitant down-regulation of vimentin expression in HA22T/VGH cells. Moreover, our preliminary finding showed that KLF4 knockdown by transfection of KLF4 shRNA caused the decrease in E-cadherin expression in HEK293T cells. E-cadherin, a key adhesion molecule in the process of epithelial-mesenchymal transition (EMT) and tumor metastasis, was regulated by many transcription factors such as Snail. Interestingly, in this study we have found that KLF4 overexpression led to an obvious reduction in the Snail expression in HA22T/VGH cells. Therefore, these results together suggest that KLF4-induced E-cadherin expression may result from regulation at E-cadherin transcription level or inhibition of the expression of Snail. Furthermore, our findings also suggested that the role of KLF4 may be associated with the cell growth, EMT process and metastasis in the tumor progression of 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 3442. doi:1538-7445.AM2012-3442
Abstract 3444: Exon 4 of osteopontin: A unique target to reduce malignant behavior in non-small cell lung cancer
Authors: Donington Jessica S. , Goparaju Chandra M. , Slomiany Mark , Hirsch Nathalie , Pass Harvey I. 
Published: August 2012

Abstract
INTRODUCTION: Osteopontin (OPN) is a ubiquitous protein associated with a wide range of normal and pathologic functions. It is a central regulator of malignant phenotype in non-small cell lung cancer (NSCLC). OPNa, the full length isoform, is disproportionately expressed in NSCLC tumors and cell lines, and increases malignant behavior when over expressed. OPNc, the shortest isoform, does not induce malignant properties when expressed in NSCLC. The only structural difference between OPNa and OPNc is the transcription of exon 4. The hypothesis of this project is that a small interfering peptide to OPN exon 4 will reduce in vitro malignant activity in NSCLC. METHODS: A 16-amino acid peptide which mimics the central sequence in OPN exon 4 and a scrambled sham were constructed and florescent labeled. Three NSCLC cell lines, H358 (low), A549 (moderate), and H460 (high endogenous OPN) were used in binding, proliferation, and invasion assays in presence of exon 4 mimic or sham. Cisplatin sensitivity was performed with peptides in A549. RESULTS: There was florescent evidence for cell surface binding of the exon 4 mimic in all of the NSCLC cell lines without binding of the sham. The exon 4 mimic significantly decreased in vitro invasion and proliferation in the A549 and H460 cell lines, with a lesser effect in H358 with low endogenous OPN. (Table) The exon 4 mimic increased cisplatin sensitivity, decreasing cell viability 2-fold compared to sham and control at cisplatin concentrations 0.1-0.8 uM/ml. CONCLUSIONS: Exon 4 of OPN has not previously been identified as a regulatory region essential for OPN's effect on malignant behavior. We have evidence for an un-described cell surface receptor to this region. A small mimicking peptide to OPN exon 4 significantly decreased in vitro malignant behavior, suggesting interference with important regulatory pathways. This novel binding site could serve as an ideal for target for antibody or small molecule therapies in NSCLC.

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 3444. doi:1538-7445.AM2012-3444
Abstract 3445: Targeting Thromboxane A2 receptor (TP) to block breast cancer metastasis
Authors: Zhang Xuejing , Nie Daotai 
Published: August 2012

Abstract
The thromboxane A2 (TXA2) receptor, TP, is a G-protein coupled receptor. Previous studies in our lab have shown that the TP pathway regulates tumor cell cytoskeleton and TP activation induces rapid tumor cell contractions through small GTPase RhoA activation. Conversely, TP depletion reduces the metastatic dissemination of breast cancer cells in vivo by blocking the extravasation of tumor cells. Humans express two TP isoforms, TPγ and TPα. We report here that elevated TPγ expression is associated with metastasis in patients with breast cancer. While TPγ is expressed in all breast cancer cell lines that we examined, TPγ is only expressed in malignant cell lines, indicates that TPγ plays a role in breast cancer progression. Treatment with a selective TPγ inhibitor (CAY10535) blocks TP agonist (U46619) induced cell body contraction and RhoA activation. Additionally, TPγ inhibitor reduces migratory capacity and invasiveness in human breast cancer cell lines. Our previous work has shown that active TP is required for efficient extravasation of tumor cells in vivo; in this study, we further demonstrate that mice treated with SQ29548 (a high affinity TP antagonist) prior to tumor cell injection developed fewer metastatic lesions than the mice treated with SQ29548 after tumor cell injection. In all, our study indicated that TPγ can be targeted to reduce the risk of breast cancer metastasis.
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 3445. doi:1538-7445.AM2012-3445
Abstract 3446: Stat3 is a potential molecular target for chemoradiosensitization of colorectal cancer cells
Authors: Spitzner Melanie , Roesler Birte , Bielfeld Christian , Gaedcke Jochen , Rave-Fränk Margret , Beißbarth Tim , Ried Thomas , Ghadimi B. Michael , Grade Marian 
Published: August 2012

Abstract
Introductory sentence: Resistance to preoperative chemoradiotherapy represents a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of novel molecular targets that are differently expressed in responsive and resistant tumors is exceedingly important. Furthermore, modulating target gene expression may sensitize a priori resistant tumors to multimodal therapy. Experimental procedures: Previously, we established an in vitro model for chemoradiotherapy in 12 colorectal cancer cell lines, and correlated differences in treatment sensitivity with pretherapeutic gene expression profiles. Within our signature we identified the signal transducer and activator of transcription 3 (STAT3), which was significantly correlated with treatment resistance. To test the functional relevance of the observed over-expression of STAT3, we first determined STAT3 mRNA and protein expression levels in all 12 cell lines. Subsequently, we established doxycycline-inducible stable shRNA single cell populations and a non-silencing shRNA (shNEG) in SW480. The induced single cell clones and shNEG were treated with 3µM 5-FU and exposed to 1, 2, 4, 6, and 8 Gy of X-rays. In addition, STAT3 was inhibited using two different siRNAs and a small-molecular inhibitor (STATTIC). Successful RNAi-mediated silencing of STAT3 and inhibitor treatment was detected by Western blot. Data: STAT3 was significantly overexpressed in resistant cells at mRNA and protein level. In stable STAT3 knockdown single cell clones and transiently siRNA transfected SW480 and SW837 cells, successful silencing of the STAT3 protein was detected after 72 hours, and STATTIC-induced inhibition of STAT3-phosphorylation after 1 hour. The silencing/inhibition resulted in a significantly increased chemoradiosensitivity with dose-reduction factors of 1.8 to 2. Conclusions: STAT3 is highly overexpressed in resistant colorectal cancer cells, and silencing of STAT3 leads to a significantly increased chemoradiosensitivity. This highlights the potential relevance of STAT3 as a novel molecular target in rectal cancer to sensitize a priori resistant colorectal tumor cells to chemoradiotherapy.
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 3446. doi:1538-7445.AM2012-3446
Abstract 3450: Functional characterization of a DNA damage response network in glioblastoma associated with long-term patient survival
Authors: Yoon Taewon , Loughlin Danielle , Yu Shuqian , Desai Brijal , Choe Kevin , Minn Andy J. 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer in humans with a median survival of less than 14 months. However, a small minority of GBM patients have a median survival of over three years. In an effort to identify genetic and epigenetic events that might explain this relative long-term survival, an integrative genomic approach was utilized. We show that in contrast to most GBM patients, relative long-term survivors have tumors that lack a biological network that responds to DNA damage. This network is comprised of pro-inflammatory genes and genes normally regulated through interferon signaling. By overlaying the network with phenotype information, key genes and gene-gene interactions that strongly associate with patient survival were identified to facilitate the discovery of important genes and genetic dependencies in the network. One such gene is Interferon-Stimulated Gene 15 (ISG15), which is part of the interferon subnetwork and encodes for an ubiquitin-like protein. Targeted disruption of ISG15 in various GBM cell lines unmasked a DNA damage response as characterized by delayed S-phase entry and G2/M accumulation, increased γH2AX, and senescence. Various genes that displayed a predicted interaction with ISG15 were tested for evidence for a biological interaction. Functional validation confirmed that these predicted interactions with ISG15 were mirrored by genetic and regulatory interactions that resulted in rescue of the effects of ISG15 knockdown. We also investigated genes that control the pro-inflammatory subnetwork. Targeted disruption of one such gene, MYD88, resulted in decreased invasion and increased sensitivity to DNA damage. In summary, we have identified a biological network that responds to and regulates DNA damage. The absence of network genes results in susceptibility to DNA damage, senescence, and decreased invasion. GBM patients with tumors lacking the network are rare long-term survivors of an otherwise uniformly and rapidly fatal tumor.
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 3450. doi:1538-7445.AM2012-3450
Abstract 3451: Lack of CD47 in the tumor microenvironment enhances anti-tumor adaptive immune responses when combined with ionizing radiation
Authors: Pantoja David R. Soto , Masaki Terabe , Ridnour Lisa A. , DeGraff William , Berzofsky Jay A. , Roberts David D. 
Published: August 2012

Abstract
Over half of the new cancer patients diagnosed this year in the United States will require ionizing radiation (IR) therapy as part of their course of treatment. Achieving a curative response, however, is limited by detrimental side effects and off-target toxicities of IR to normal cells. We previously demonstrated that CD47 null mice or blockade of CD47 confers radioprotection to normal tissues including radiosensitive hematopoietic progenitors. On the other hand, blockade of CD47 enhanced the radiation-induced tumor growth delay in two syngenic mouse models. One possible explanation for this observation is that, by protecting tumor-associated immune cells, CD47 suppression increases tumor immune surveillance. To examine the role of T cell immunity, we used the F15-12 RM mouse fibrosarcoma model in athymic mice. Blockade of CD47 in combination with IR did not alter tumor growth in these T-cell deficient mice versus IR alone. However, adoptive transfer of CD8+ T-cells in combination with CD47 blockade and IR significantly enhanced the reduction in tumor growth when compared to tumors of mice irradiated in combination with the T cell transfer alone (186 ± 50 vs. 370 ± 123 mm3 respectively, N=8). In vitro experiments showed that blockade of CD47 enhances antigen dependent CD8+ mediated cytotoxicity of tumor cells. Furthermore, in a syngeneic tumor model of B16 melanoma we observed over a 50% reduction in volume of irradiated tumors in a CD47-/- host versus a WT host. Immunohistochemical staining indicated an increase of intratumoral CD8+ cytotoxic T-cells. Further analysis indicated that lack or blockade of CD47 in combination with IR resulted in a significant increase in granzyme B expression, further indicating that the increased target cell death may be mediated by this pathway. CD47 suppression may also reduce tumor growth by altering the immunosuppressive factor VEGF. In both tumor models, either blockade of or lack of CD47 in combination with IR was associated with a reduction in VEGF. VEGF is a potent pro-angiogenic factor and a potent immunosuppressive factor that inhibits activation of cytotoxic T-cells. Our findings indicate that agents targeting CD47 enhance anti-tumor T cell immunity when combined with radiation. Combining CD47 suppression with IR and adoptive T cell transfer may increase the percentage of curative responses.
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 3451. doi:1538-7445.AM2012-3451
Abstract 3453: SPARC overexpression inhibits cell proliferation in neuroblastoma and is partly mediated by tumor suppressor protein PTEN and AKT
Authors: Bhoopathi Praveen , Gorantla Bharathi , Sailaja G.S. , Gondi Christopher S. , Gujrati Meena , Klopfenstein Jeffrey D. , Rao Jasti S. 
Published: August 2012

Abstract
Secreted protein acidic and rich in cysteine (SPARC) is also known as BM-40 or Osteonectin a multi-functional protein modulating cell-cell and cell-matrix interactions. In cancer, SPARC is not only linked with a highly aggressive phenotype, but it also acts as a tumor suppressor. In the present study, we sought to characterize the function of SPARC and its role in sensitizing neuroblastoma cells to radio-therapy. SPARC overexpression in neuroblastoma cells inhibited cell proliferation in vitro. Additionally, SPARC overexpression significantly suppressed the activity of AKT and this suppression was accompanied by an increase in the tumor suppressor protein PTEN both in vitro and in vivo. Restoration of neuroblastoma cell radio-sensitivity was achieved by overexpression of SPARC in neuroblastoma cells in vitro and in vivo. To confirm the role of the AKT in proliferation inhibited by SPARC overexpression, we transfected neuroblastoma cells with a plasmid vector carrying myr-AKT. AKT overexpression reversed SPARC-mediated PTEN and increased proliferation of neuroblastoma cells in vitro. PTEN overexpression in parallel with SPARC siRNA resulted in decreased AKT phosphorylation and proliferation in vitro. Taken together, these results establish SPARC as an effector of AKT-PTEN-mediated inhibition of proliferation in neuroblastoma in vitro and in vivo.
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 3453. doi:1538-7445.AM2012-3453
Abstract 3454: Establishing role of KRAS mutation on NSCLC radio-sensitivity
Authors: Bhardwaj Vikas , Likhacheva Anna , Byers Lauren A. Byers A. , Diao Lixia , Allen Pamela K. , Minna John D. , Ihle Nathan T. , Powis Garth , Das Amit K. , Girard Luc , Peyton Michael , Yordy John , Liao Zhongxing , Ang Kian K. , Story Michael , Kalhor Neda , Komaki Ritsuko , Kim Edward S. , Heymach John V. , Welsh James 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer related mortality in the US of which more than 75% cases are that of non-small cell lung carcinoma (NSCLC). Mutations in the proto-oncogene KRAS have been linked with poor prognosis for NSCLC patients. In this study, we aimed at analyzing the relationship between specific KRAS mutations and NSCLC cell radiosensitivity and protein expression patterns. We analyzed 22 NSCLC cell lines and stratified them according to their KRAS status. Our results show that NSCLC cells harbouring G12C mutations are more sensitive to radiation compared to cells with other KRAS status (SF2 = 0.35 ± 0.16 for G12C vs. 0.63 ± 0.17 for other KRAS mutants vs 0.54 ± 0.15 for wt KRAS). Our protein expression data suggests that G12C mutants have reduced expression of DNA-repair proteins such as ATM, Rad 50, Ku 80 and XRCC1 (p &lt; 0.05) which may be responsible for their radiosensitive nature. Further we found that G12C mutant NSCLC cell lines have reduced expression of pAkt compared to cells with other KRAS status (p =0.009). This suggests that NSCLC cells harboring G12C mutation would be less susceptible to PI3K inhibition induced radio-sensitization. Our clonogenic assay results confirm our finding when 1-hour pretreatment with 5 µM LY294002 (PI3K inhibitor) sensitized H460 and A549 (non-G12C mutated NSCLC cells) but not H1792 and H23 (G12C mutant NSCLC). Our results strongly suggests that G12C KRAS mutant cells are radio-sensitive compared to NSCLC cells of other KRAS status and PI3K inhibitor therapy along with radiation could be beneficial for patients harboring non-G12C mutational KRAS status.
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 3454. doi:1538-7445.AM2012-3454
Abstract 3457: Galectin-1 suppression enhances combined anti-EGFR and radiation-therapy of NSCLC
Authors: Siedow Michael , Chakravarti Arnab , Lautenschlaeger Tim 
Published: August 2012

Abstract
Lung cancer remains the leading cause of cancer related death worldwide and will account for nearly 160,000 deaths in the United States alone in 2010. Between 80-90% of all cases diagnosed are classified as non-small cell lung cancer (NSCLC). Recent studies have shown a significant subpopulation of patients diagnosed with NSCLC have an activation of the epidermal growth factor receptor (EGFR) domain resulting from gene amplification, overexpression, or kinse-domain activating mutations. EGFR inhibitors such as Erlotinib and Gefitnib have shown promising results in this subpopulation of patients however median overall survival remains poor. LSGAL1, Galectin-1 (GAL1), is a beta-galactoside-binding protein we recently identified to play an important role in the activation of the PI3-Kinase pathway located directly downstream of EGFR. Silencing Galectin-1 in combination with an EGFR-inhibitor and radiation therapy may be a promising therapeutic strategy for patients with NSCLC. Using a short-hairpin RNA strategy we silenced GAL1 expression in four different NCSLC cell lines and assessed their relative radioresistance via clonogenic survival assay in the presence and absence of an EGFR inhibitor. In order to elucidate the mechanism between GAL1 and EGFR, western blotting and QPRC analysis was performed on downstream pathway members, specifically the RAS/PI3-Kinase and RAS/ERK signaling cascades. Functional assays focusing on proliferation/survival were carried out to determine the effect silencing GAL1 had on the combination of EGFR inhibition and radiation therapy in our NSCLC cell lines. Our preliminary results suggest silencing GAL1 reduces the clonogenic survival of NSCLC cells when used in combination with an EGFR inhibitor following irradiation. In addition well known players within PI3-Kinase pathway such as pAKT S473 appear to be altered in the absence of GAL1. Our preliminary findings suggest GAL1 is a promising therapeutic target in NSCLC when used in combination with an EGFR inhibitor and radiation therapy and is worthy of further investigation.
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 3457. doi:1538-7445.AM2012-3457