bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2958: Knockdown of Src expression dissolves resistance to TRAIL-induced apoptosis in oral cancer cells.
Authors: Hamakawa Tomohiro , Hino Satoshi , Nakashiro Koh-ichi , Hamakawa Hiroyuki 
Published: August 2014

Abstract
A radical operation for advanced oral cancer results in malfunction of chewing, swallowing, and pronouncing etc. Nevertheless, the most standard therapy for oral cancer is a surgical resection because of its good outcome compared to radiation and chemotherapy. It is expected that treatment is less-invasive and effective against not only primary lesion but also metastatic sites or cells with metastatic potential. Because the acquisition of resistance to anoikis and apoptosis is considered as an essential event to successfully metastasize, we focused on the apoptotic signaling pathways mediated by natural death ligands. In this study, we have used oral squamous cell carcinoma (OSCC) cell lines with distinct metastatic potential and attempted to disclose their apoptosis sensitivity. More than half of the cells died under the low attachment culture condition in all OSCC cell lines with no relation between their metastatic potential, while other kind of cancer cell lines showed anoikis resistance. SAS cells established from human tongue squamous cell carcinoma showed modest sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), whereas SAS-T5 and SAS-L1 cells, a clone with high metastatic potential showed robust resistance. Fas ligand (Anti-Fas/CD95 monoclonal antibody) showed the similar trend of apoptosis induction as well as TRAIL, but TNF-α had no effect in these cells. We confirmed that the expression levels and the localization of TRAIL receptors were not correlated with TRAIL sensitivity. One of the mechanisms underlying the differences in resistance between these cell lines was an activity of Src kinase. Phosphorylated Src (Tyr 416), the active form, was upregulated in SAS-T5 and SAS-L1 cells compared to parental SAS cells. Src inhibitor PP2 suppressed cell proliferation in response to dependence on Src signaling. Downregulation of Src with siRNA made metastatic cells dissolve the resistance to TRAIL-induced apoptosis. These results suggest that combination therapy with TRAIL plus medicine inhibiting Src kinase may be a treatment strategy for oral squamous cell carcinoma.
Citation Format: Tomohiro Hamakawa, Satoshi Hino, Koh-ichi Nakashiro, Hiroyuki Hamakawa. Knockdown of Src expression dissolves resistance to TRAIL-induced apoptosis in oral cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2958. doi:10.1158/1538-7445.AM2013-2958
Abstract 2972: Pharmacological reactivation of epigenetically regulated genes in prostate cancer.
Authors: Krause Hans , Ikromov Odiljon , Al Kamal Imad , Magheli Ahmed , Kempkensteffen Carsten , Miller Kurt 
Published: August 2014

Abstract
Transcriptional silencing caused by promoter hypermethylation is a widespread mechanism for inactivation of known and putative tumor suppressor genes in many types of cancers. GSTP1, CDKN2A, CDH1, APC, and RASSF1A among others are known to be downregulated in prostate cancer. The aim of this study was to search for hitherto unknown genes that are upregulated after treatment by demethylating agents (i.e. DMNT inhibitors) thereby marking them as potential new therapeutic targets and putative biomarkers in prostate carcinogenesis.
Prostate cancer cell lines DU-145 and LNCaP were treated in three independent biological experiments with 100μM zebularine for ten days and monitored for cytotoxic and apoptotic side effects. Efficacy of the treatment was verified on the RNA expression level of known epigenetically regulated genes. Expression changes of total RNA from treated and untreated cells were compared using whole genome expression microarrays (Affymetrix Human Gene 1.0 ST). A number of conspicuously upregulated genes (&gt;15.0-fold, presence of CpG islands, higher expression in normal prostate) were further evaluated by Q-PCR in 50 cases of paired normal and tumor tissue samples of prostate cancer patients who underwent radical prostatectomy in our clinic between 2002 and 2004.
The seryl-tRNA synthetase gene SARS was discovered by us for the first time to be downregulated in 34/50 cases (66%; p = 0,04) in prostate cancer. The DNA-damage-inducible transcript 1 (DDIT1), also known as GADD45A and was downregulated in 42/50 cases (84%; p = 0,0004). The discovery of a downregulated GADD45A in our independent experiments supports the already known fact of a methylation-mediated repression of GADD45A in prostate cancer (Ramachandran et al., 2009) and its suitability as a potential therapeutic target. In addition, we found a statistically significant inverse correlation of SARS expression and raising patient Gleason scores.
Based on our estimated “upregulation-rate” of the promoter hypermethylation gold standard gene for prostate cancer GSTP1 in 98% of our patient samples (48/50; p = 0,0001) we present a robust workflow for the discovery of methylation-mediated transcriptionally inactivated genes.
Citation Format: Hans Krause, Odiljon Ikromov, Imad Al Kamal, Ahmed Magheli, Carsten Kempkensteffen, Kurt Miller. Pharmacological reactivation of epigenetically regulated genes in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2972. doi:10.1158/1538-7445.AM2013-2972
Abstract 2999: Targeted depletion of all somatically mutated genes in lung cancer cells facilitates identification of mutationally activated novel drivers of lung cancer.
Authors: Fawdar Shameem , Trotter Eleanor W. , Li Yaoyong , Ientile Sara , Miller Crispin , Brognard John 
Published: August 2014

Abstract
Approximately 70% of all NSCLC patients present with late stage disease (stage III-IV) and there is a pressing need to develop better therapies for these patients. This remains a major challenge as the underlying genetic causes of nearly half of all NSCLCs remain unknown. Recent success with therapies targeting mutationally activated EGFR and constitutively active EML4-ALK serve as proof of principle that drugs targeting genetically activated drivers of lung cancer result in better, more durable therapeutic responses in patients. In an effort to identify novel mutationally activated drivers of lung cancer, we performed a targeted siRNA screen to knockdown all somatically mutated genes in a panel of six NSCLC cell lines. Using this approach we have identified three mutationally activated drivers that include MLK1, PAK7 and FGFR4. We demonstrate that mutations in these genes are activating, that the cancer cells that harbour the genetically activated oncogenes rely on these drivers to maintain cell proliferation and survival and inhibition of these activated kinases results in specific killing of the lung cancer cells. As cancer genomic data accumulates at an unprecedented rate, approaches must be developed to filter through this data to identify druggable drivers that could lead to better therapeutic options for patients in the clinic. Our studies demonstrate that combining targeted siRNA screens with cancer genomics will be a successful approach to identify novel drivers of cancer.
Citation Format: Shameem Fawdar, Eleanor W. Trotter, Yaoyong Li, Sara Ientile, Crispin Miller, John Brognard. Targeted depletion of all somatically mutated genes in lung cancer cells facilitates identification of mutationally activated novel drivers of lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2999. doi:10.1158/1538-7445.AM2013-2999
Abstract 301: Microenvironmental regulation of epithelial-mesenchymal transitions in breast cancer metastasis.
Authors: Gao Dingcheng , Fisher Kari , Choi Hyejin , Dannenberg Andrew J. , Vahdat Linda , Altorki Nasser , Mittal Vivek 
Published: August 2014

Abstract
Metastatic spread is the main cause of death in breast cancer patients. To successfully develop metastatic lesions, tumor cells exhibit plasticity to adapt to the changing microenvironment that they encounter at both the primary and distant sites. Notably, tumor cells undergo epithelial-mesenchymal transition (EMT) to acquire metastatic potential. In the metastatic organ, the disseminated tumor cells are thought to undergo mesenchymal to epithelial transition (MET) to form lethal macrometastatic lesions. However, while EMT/MET has been well demonstrated in cancer cell lines in vitro, whether such transitions occur in vivo is debated.
Our study is based on an emerging paradigm that microenvironmental regulation of epithelial-mesenchymal transitions contributes to tumor growth and metastasis. To evaluate this, we have devised a lineage tracing approach where a unique EMT-induced Cre-mediated fluorescence switch system monitors epithhelial-mesenchymal transitions in physiologically relevant orthotopic and spontaneous breast cancer metastasis in vivo. Using this system, we found that the CD11b+F4/80+ tumor-associated macrophages promote EMT in the primary tumor by secreting TGFβ1 and PDGFA, while the CD11b+Gr1+ myeloid progenitors facilitate MET of disseminated tumor cells in metastatic lungs by secreting proteoglycan versican thereby providing novel mechanistic insights into how the tumor-stroma cross talk confers prometastatic properties.
Our finding that different subsets of inflammatory cells are associated with EMT in the primary tumor and MET in the metastatic organ has provided clinical translation opportunities. Previously, the therapeutic targeting of EMT (i.e. TGFβ1 blockade) has been associated with the caveat that it may actually promote the formation of fatal macrometastases. Here, the identification of unique cellular EMT and MET regulators provides an opportunity for inhibiting one process without promoting the other, or inhibiting both EMT and MET simultaneously. Importantly, administration of non-steroidal anti-inflammatory drugs impaired metastases by targeting specific inflammatory populations that contribute to the EMT/MET-promoting microenvironment in preclinical mouse models of breast cancer.
Citation Format: Dingcheng Gao, Kari Fisher, Hyejin Choi, Andrew J. Dannenberg, Linda Vahdat, Nasser Altorki, Vivek Mittal. Microenvironmental regulation of epithelial-mesenchymal transitions in breast cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2013-301
Abstract 3015: Identification of a novel gene target involved in tumor growth and metastasis of non-small cell lung cancer.
Authors: Chen Honglin , Lee James , Kljavin Noelyn M. , Johnson Leisa , Liang Yuxin 
Published: August 2014

Abstract
We have discovered a potential oncogenic role of a gene in non-small cell lung cancer (NSCLC) using RNAi technology. Silencing of the gene significantly inhibits soft agar colony formation of NSCLC cell lines, whereas its inhibition on cell proliferation in liquid culture is modest. This effect was observed in multiple murine and human NSCLC cell lines with varied Kras and p53 status. The inhibition on soft agar colony formation is reversed with ectopic overexpression of a cDNA encoding the full-length gene. Knocking down the expression of the gene also significantly impairs migration and enhances detachment-induced anoikis of NSCLC cells. An investigation of the molecular mechanisms reveals that silencing of the gene cytoskeleton signaling network. In xenograft studies using stable luciferase-expressing inducible shRNA cell lines, silencing of the gene upon doxycycline treatment leads to a modest reduction in tumor volumes while significantly decreases bioluminescent signals at metastatic sites including lung and lymph nodes. Furthermore, gene expression analyses in KrasG12D/p53 deletion-driven mouse tumors and clinical tumor samples show significantly increased expression of the gene in lung cancer as well as multiple other cancer types. Taken together, we have uncovered a novel oncogenic function of a gene in NSCLC, which could provide a potential new therapeutic target for cancer intervention.
Citation Format: Honglin Chen, James Lee, Noelyn M. Kljavin, Leisa Johnson, Yuxin Liang. Identification of a novel gene target involved in tumor growth and metastasis of non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3015. doi:10.1158/1538-7445.AM2013-3015
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3016: Implication of delta-catenin-promoted E-cadherin processing on human prostate cancer progression.
Authors: Kim Hangun , Yoon Somy , Park So-Yeon , Hwang Jun Eul , Kim Kwonseop , Kim Kyung Keun 
Published: August 2014

Abstract
Although δ-catenin overexpression is frequently observed in some human cancers, the mechanistic implications of δ-catenin expression in epithelial cells and carcinomas remain elusive. In this study, we found that prostate cancer cells overexpressing δ-catenin show an increase in multi-layer growth in culture. In these cells, δ-catenin colocalizes with E-cadherin at the plasma membrane, and the E-cadherin processing is noticeably elevated. A deletion mutant of δ-catenin totally abolishes the δ-catenin-induced E-cadherin processing and the multi-layer growth of the cells. In addition, prostate cancer cells overexpressing δ-catenin display an elevated total β-catenin level and increase nuclear distribution, resulting in the activation of β-catenin/LEF-1-mediated transcription. Indeed, human prostate tumor xenograft in nude mice, which is derived from cells overexpressing δ-catenin, shows increased β-catenin nuclear localization and more rapid growth rates. Moreover, the metastatic xenograft tumor weights positively correlate with the level of 29 kD E-cadherin fragment, and primary human prostate tumor tissues also show elevated levels of δ-catenin expression and the E-cadherin processing. Taken together, these results suggest that δ-catenin plays an important role in prostate cancer progression through inducing E-cadherin processing and thereby activating β-catenin-mediated oncogenic signals.
Citation Format: Hangun Kim, Somy Yoon, So-Yeon Park, Jun Eul Hwang, Kwonseop Kim, Kyung Keun Kim. Implication of delta-catenin-promoted E-cadherin processing on human prostate cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3016. doi:10.1158/1538-7445.AM2013-3016
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3036: The dependence receptor TrkC is a putative colon cancer tumor suppressor.
Authors: Genevois Anne-Laure , Ichim Gabriel , Coissieux Marie-May , Lambert Marie-Pierre , Lepinasse Florian , Herceg Zdenko , Scoazec Jean-Yves , Tauszig-Delamasure Servane , Mehlen Patrick 
Published: August 2014

Abstract
Backgrounds & Aims: The TrkC neurotrophin receptor belongs to the functional dependence receptors family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is yet a relatively classic tyrosine kinase receptor and therefore generally rather considered as a proto-oncogene. We investigated here whether, because of its dependence receptor activity, TrkC is a putative tumor suppressor in colorectal malignancies.
Methods: The level of TrkC was analyzed in a panel of 45 primary sporadic colorectal carcinomas. Loss of heterozygosity and epigenetic alterations in the TrkC promoter were also analyzed. The level of TrkC was also analyzed in a panel of colorectal cancer cell lines. The TrkC tumor suppressive activity was investigated by expressing TrkC and related TrkC variants in colorectal cancer cell lines and by measuring apoptosis, anchorage-independent growth, migration and tumor growth in a chicken model.
Results: We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Consequently, we show that reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation and in vivo tumor growth.
Conclusions: The loss of TrkC expression observed in human colorectal cancer is a selective advantage for tumor cell survival. Thus, TrkC appears to be a putative new colon cancer tumor suppressor.
Citation Format: Anne-Laure Genevois, Gabriel Ichim, Marie-May Coissieux, Marie-Pierre Lambert, Florian Lepinasse, Zdenko Herceg, Jean-Yves Scoazec, Servane Tauszig-Delamasure, Patrick Mehlen. The dependence receptor TrkC is a putative colon cancer tumor suppressor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3036. doi:10.1158/1538-7445.AM2013-3036
Abstract 3043: Akt-mTorc2 signaling underlies cellular addiction to HER3 signaling in HER2-amplified cancers.
Authors: Amin Dhara N. , Ahuja Deepika , Ducker Gregory S. , Yaswen Paul , Shokat Kevan , Moasser Mark 
Published: August 2014

Abstract
HER2 amplified breast cancers are characterized by constitutive HER3 phosphorylation. Efforts to target the functionally relevant HER2-HER3 signaling complex in these tumor cells has proven difficult due to robust feedback signaling mechanisms that restore its signaling in the face of anything short of the complete inactivation of HER2 kinase activity. To study this in more depth, we used a combination of genetic and chemical genetic approaches designed to study the cellular adaptational responses to network perturbation. We find that positive or negative perturbation of any signaling node from upstream HER2 or HER3 down to the two mTor complexes results in compensatory responses that function to maintain homeostasis. The responses to various perturbations are mechanistically distinct, but taken together reveal an uncompromising core topology driven by a concentric Akt-mTorc2 positive-feedback loop buffered by HER3 and PHLPP nodes. While mTorc1 signaling is also subject to feedback regulation, it is not involved in the core topology and its output is not always protected in these tumors. The central role of mTor is consistent with its known functions as a master regulator of cellular homeostasis highly conserved across eukaryotes. But the inclusion of HER3 in this central homeostatic network is a tumor cell anomaly. To better delineate how this homeostatic network is altered in tumor cells, we compared and contrasted the network topology in a panel of HER2-amplified cancer cells with a panel of immortalized breast epithelial cells. Much of the feedback circuitries are preserved across tumor and untransformed cells. But the driving Akt-mTorc2 positive-feedback loop is lacking in untransformed cells. This is due to the fact that Akt drives mTorc2 signaling in tumor cells but not in untransformed cells. Consistent with a central role of mTorc2 in these tumors, knockdown of Rictor, but not Raptor, is lethal in HER2-amplified SkBr3 tumor cells. These studies reveal a key alteration of Akt-mTor signaling in HER2 driven tumors that underlies the pathological incorporation of HER3 into an mTor-driven network, thus putting the HER2-HER3 tumor driver under the protection of this evolutionarily ancient pathway, highly competent at homeostasis.
Citation Format: Dhara N. Amin, Deepika Ahuja, Gregory S. Ducker, Paul Yaswen, Kevan Shokat, Mark Moasser. Akt-mTorc2 signaling underlies cellular addiction to HER3 signaling in HER2-amplified cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3043. doi:10.1158/1538-7445.AM2013-3043
Abstract 3057: miR-211 is contributive to the progression of oral carcinoma through modulating transcription factor 12 (Tcf12).
Authors: Chen Yi-Fen , Lin Shu-Chun , Chang Kuo-Wei 
Published: August 2014

Abstract
Oral squamous cell carcinoma (OSCC) is one of the prevalent neoplasms worldwide. MicroRNAs (miRNAs) are short RNA molecules that regulate pathogenesis, including OSCC carcinogenesis, by post-transcriptional down-regulation of target genes. Our previous study has identified a relationship between high miR-211 expression and the invasiveness of OSCC. This study further dissects the molecular mechanisms underlying the progression of OSCC as affected by miR-211. miR-211 is predicted to target the 3’UTR of transcription factor 12 (Tcf12). Reporter assays confirmed the direct targeting of miR-211 on Tcf12. Tcf12 is a helix-loop-helix transcription factor with obscure functions in malignancies. miR-211 expression decreased both endogenous and exogenous Tcf12. Exogenous Tcf12 expression suppressed oncogenic phenotypes of OECM-1 OSCC cells. On the contrary, knockdown of endogenous Tcf12 expression enhanced the oncogenic phenotypes of OSCC cells. Tcf12 expression was highly associated with EZH2 activity, and the expression levels of HOX family members in OSCC cells. To elucidate the in vivo oncogenic roles of miR-211 in OSCC carcinogenesis, K14 promoter driven miR-211 transgenic mouse lines (K14-GFP- miR-211) were established. The increased miR-211 expression was found to be associated with Tcf12 down-regulation in the squamous epithelium of transgenic mice. After tumor induction by 4-nitroquinoline 1-oxide, the transgenic mice exhibited more and bigger tumors comparing to wild type mice. The incidence of epithelial dysplasia on the tongue was also higher in the transgenic mice than that in control mice. In summary, this study reveals that miR-211 is a regulator of OSCC progression by targeting Tcf12. The in vivo model based on the K14-GFP-miR-211 transgenic mice will help further studies of the pathogenic mechanisms underlying OSCC progression and development of therapeutic strategy.
Citation Format: Yi-Fen Chen, Shu-Chun Lin, Kuo-Wei Chang. miR-211 is contributive to the progression of oral carcinoma through modulating transcription factor 12 (Tcf12). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3057. doi:10.1158/1538-7445.AM2013-3057