bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 166: MicroRNA profiling analysis identify new signature of tumor-promoting M2-type macrophages
Authors: Ng Yee Seng , Roca Hernan , Sud Sudha , Pienta Kenneth J. , Chinnaiyan Arul M. , Keller Evan T. , Varsos Zachary S. , Maher Christopher A. , Cao Xuhong 
Published: June 2012

Abstract
M2-type macrophages are a major inflammatory component in prostate cancer and are associated with cancer cell growth, survival, and metastasis. Since recent findings have demonstrated the importance of microRNAs in the differentiation of human cells, we hypothesize that microRNAs are involved in regulating monocytic differentiation into M2-type macrophages and we aim to identify the microRNAs involved. Methods: Human CD14+ PBMCs were isolated from healthy donors and stimulated with cytokines known to promote differentiation into the M2-type macrophages (IL4, IL13, IL6, and MCSF). As controls, we also treated cells with media only and with INFγ, a cytokine known to promote M1-type polarization. Cells were collected at 48 hours post-stimulation and sent for microRNA profiling by microarray. Microarray findings were then confirmed by qRT-PCR. Results: Microarray profiling of cytokine-stimulated M2-type macrophages demonstrated an altered miRNA expression compared to M1-type macrophages and untreated monocytic cells. Specifically, of the 858 microRNAs that were profiled, miR-135a, miR-193b, miR-203, miR-302, miR-375, miR-452, miR-511, miR-603, miR-622, miR-654, miR-938 and miR-1238 were found to be up-regulated by greater than 2 folds. Furthermore, qRT-PCR analysis confirmed the microarray results. When the qRT-PCR analysis was repeated for cells treated with cytokines for 6 hours, 18 hours and 24 hours, we noticed that the overexpression in these microRNAs could already be observed at 6 hours post-treatment, although the expression levels were noticeably greater at later timepoints. Flow cytometric analysis showed the surface expression of CD206 (mannose receptor: the well characterized surface marker of M2-type macrophages) in both MCSF and IL-4-treated cells but only after at least 18 hours of stimulation. Conclusions: MicroRNA expression in PBMCs is altered when they are stimulated by M2-type promoting cytokines and the change in microRNA expression preceded the expression of the M2-specific CD206 surface marker. This change in microRNA expression can therefore be used as a marker for M2-polarized macrophages and may play critical roles in the regulation of macrophage differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 166. doi:10.1158/1538-7445.AM2011-166
Abstract 1666: Targeting tumor-initiating cells for the treatment of hepatocellular carcinoma
Authors: Zhang Zhiqian , Zhao Wei , Wang Limin , Han Haibo , Xing Baocai , Li Jiyou , Wang Yu 
Published: June 2012

Abstract
Tumor-initiating cells (TICs) or so-called cancer stem cells (CSCs) are a minor subpopulation of poor differentiated cells that are responsible for tumor initiation, maintenance, and spreading. Hence, eliminating these cells is supposed to be an effective way of the treatment of cancer. By immunizing mice with TIC-enriched hepatocellular carcinoma (HCC) cells (Xu XL, et al. The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor. Carcinogensis. 2010; 31:167-74.) and by subsequent hybridoma technique, we have obtained an antibody 1B50-1, which recognizes the antigen of a 150 KD ion channel-composing protein. Despite the percentage of 1B50-1 positive cells varies from &lt;1% to ∼90% in established hepatocellular carcinoma cell lines, the administration of this antibody by i.p. injection at a dose of 40mg/kg could suppress the growth of HCC cell lines’ engraftments in NOD/SCID mice with an inhibition rate that could be as high as 87%, comparing with control groups. Furthermore, 100 of 1B50-1 positive cells, but not the negative compartments, from several HCC cell lines were sufficient to initiate tumor growth in NOD/SCID mice, and displayed self-renewal ability as demonstrated by serial transplantation assay in mice. The 1B50-1 positive cells also expressed higher levels of Nanog, Sox-2, and Oct 4 than the negative ones. Immunohistochemical staining of 29 HCC specimen with 1B50-1 has revealed that only a small population of positive cells were scattered in 16 HCC tissues, and that these cells with similar distribution pattern were only found in 4 out of 12 paracancerous tissues. These data suggest that the antigen for 1B50-1 is a new marker for HCC tumor-initiating cells, and that it is a promising target for HCC molecular therapy. 1B50-1 is worthy of further developing into drug for the treatment of HCC.
Funding: This study was supported by the National Basic Research Program of China (973 Program, No 2010CB529402), National Natural Science Foundation of China, and “863” Program (2008AA02Z108).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1666. doi:10.1158/1538-7445.AM2011-1666
Abstract 1691: Niche inflammation strengthens the IGF-1R-Akt signaling and results in poor prognosis of HBV-HCCs
Authors: Lin Hsin-Yi , Chang Te-Sheng , Jen Hsin-Wei , Yang Ya-Ting , Lin Ya-Ping , Lee Kam-Fai , Tung Shui-Yi , Kuo Liang-Mou , Huang Yen-Hua 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Inflammation of various etiologies has been documented to highly associate with the development of HCC. However, the role of inflammation in virus-induced hepatocarcinogenesis still remains largely unknown. Here we demonstrate that the potential synergistic effect of HBV and proinflammatory cytokines might associate with the poor prognosis of HBV-related HCC (HBV-HCC) via IGF-1R signaling activation. In this study, human HCC frozen tissues and tissue blocks were collected for clinical analysis under IRB approval. Real-time quantitative PCR analysis of HCC frozen tissues revealed a reciprocal correlation between the transcriptional levels of IGF-1R and disease-free interval (DFI) in HBV-HCC tissues (N=117). Immunohistochemical staining of HCC tissue blocks also showed a strong correlation between IGF-1R signaling activation (IGF-1R/phospho-IGF-1R) and short DFI. To test the collaborative effect of HBV and inflammation, human HCC cell lines including HBV-related cells (HepG2.2.15, PLC5, Hep3B, and HA22T) and non-HBV-related cells (HepG2 and Huh 7) were cultivated with inflammation condition medium (inflam-CM). We found that inflam-CM treatment significantly increased the levels of pluripotent regulator IGF-1/IGF-1R and IGF-1R signaling (phospho-IGF-1R and phospho-Akt) in HBV- HCC cells (HepG2.2.15 and Hep3B). Additionally, inflam-CM also markedly increased the drug resistance capacity of HepG2.2.15 and Hep3B cells. Blockage of IGF-1R phosphorylation by picropodophyllin (PPP) or down-regulation of IGF-1R by siRNA dramatically increased the drug sensitivity of HBV-HCC cells. Further analysis using neutralizing antibodies against potential proinflamatory cytokines is ongoing to identify the cross-talk between inflammation and IGF-1R signaling in HBV- HCCs. In summary, our works demonstrate that niche inflammation may activate the IGF-1R-Akt signaling and result in poor prognosis of HBV-HCC. This finding may provide a potential therapeutic target for HBV-HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1691. doi:10.1158/1538-7445.AM2011-1691
Abstract 1697: Gene signature, histopathological classification, and cisplatin-activated expression profiles in human epithelial ovarian cancer
Authors: Guo Yi , Zhu Honglan , Liang Xiaobing , Mueller Michael D. , Yu Jing Jie 
Published: June 2012

Abstract
PURPOSES: To identify biomarkers in epithelial ovarian cancer (EOC) and investigate mechanism of cisplatin-induced activation and expression, 50 genes were screened from 131 ovarian cancer patient samples. Twenty expressed genes were assessed in 30 samples by qPCR. Ovarian cancer cells were treated with cisplatin and studied for expression of cisplatin-activated genes.
RESULTS: Studies of gene signature of histopathological classification TAL2, EGF, ILF3 and UBE21 shown unique expression patterns in EOC histological types. The expression of ILF3 in tumor tissues was significantly higher than normal samples, and especially high in serous carcinomas, compared to mucinous, endometrial and clear cell carcinomas. ILF3 and UBE21 showed overexpression in advanced stage and poorly differentiated patient samples. Investigation of cisplatin-activated signaling indicated increased mRNA expression of ILF3, UBE21 and other kinases involved in cell cycle checkpoint, DNA repair, and apoptosis such as p53, Chk2, c-jun, and hMLH1.
CONCLUSIONS: Overexpression of ILF3 and UBE21 in advanced stage and advanced grade of EOC specimens suggests that these two genes may play important roles in tumorgenesis, tumor progression and pathological differentiation of the disease. Results from in vitro studies demonstrate that activated genes p53, Chk2, c-jun and hMLH1 play a role in chemo-resistance to cisplatin therapy. Further investigation of the molecular mechanisms of the identified genes is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1697. doi:10.1158/1538-7445.AM2011-1697
Abstract 1699: Thymidylate synthase and thymidine phosphorylase expression contributes to cisplatin resistance
Authors: Lin Yun-Wei , Tsai Min-Shao , Chiu Yu-Fan , Weng Shao-Hsing , Kuo Ya-Hsun , Chuang Show-Mei 
Published: June 2012

Abstract
Chemotherapy for advanced human non-small cell lung cancer (NSCLC) includes platinum-containing compound such as cisplatin in combination with a second- or third-generation cytotoxic agents. 5-Fluorouracil (5-FU) belongs to anti-metabolite chemotherapeutics, and its mechanism of cytotoxicity is involved in inhibition of thymidylate synthase (TS). TS and thymidine phosphorylase (TP) were key enzymes of the pyrimidine salvage pathway. In this study, we have examined the molecular mechanism of TS and TP in regulating the drug sensitivity to cisplatin in NSCLC cell lines. Cisplatin could increase the phosphorylation of MKK1/2-ERK1/2 and the protein levels of TS and TP through enhancing the protein stability in A549 and H1975 cells. Blocking ERK1/2 activation by MKK1/2 inhibitor (U0126) decreases TS and TP protein levels in both cell lines treated with cisplatin. Depletion of endogenous TS or TP expression by specific small interfering RNA transfection significantly increases cisplatin-induced cell death and growth inhibition. Moreover, pemetrexed (TS inhibitor) enhances cisplatin-induced cytotoxic effects. Combined treatment with 5-FU can decrease cisplatin-induced ERK1/2 activation and the induction of TS and TP, which can subsequently result in synergistic cytotoxic effects. Enforced expression of constitutive active MKK1/2 vectors rescue the protein levels of phospho-ERK1/2, TS and TP, and the cell viability which were decreased by cisplatin and 5-FU combination. In contrast, U0126 enhances the drug sensitivity to cisplatin and/or 5-FU in lung cancer cells. We conclude that the up-regulation of ERK1/2-dependent TS and TP can protect human lung cancer cells from cisplatin-induced cytotoxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1699. doi:10.1158/1538-7445.AM2011-1699
Abstract 170: Combined mRNA and miRNA profiles in lung cancer cell lines as a tool to screen the targets contributes to cisplatin resistance
Authors: Sun Yunguang , Zheng Siyuan , Zhao Zhongming , Lu Bo 
Published: June 2012

Abstract
microRNAs (miRNAs) are small RNAs average only 22 nucleotides long. miRNA signatures have been associated with histopathological and clinical features, suggesting a potential role of these molecules as prognostic and predictive markers. In this study, we generated a cisplatin resistance cell line. We profiled miRNA and mRNA expression in this cisplatin resistant cells and its parental cells using Exqon miRNA array platform and Affymetrix 1.0 ST array respectively. In order to identify functional regulatory gene-miRNA pairs in cisplatin resistance, we constructed a deregulated miRNA-gene network by incorporating miRNA-target genes information from TargetScan.
The resulting miRNA-gene deregulation network consists of 72 genes and 27 miRNAs. 30 genes were up regulated and 42 were down regulated. Of the miRNAs, 26 were down regulated and 1 was up regulated. The network was further refined by retaining the negative correlated pairs considering that miRNAs predominantly decrease their target mRNA levels. We found several members of has-let-7 family were present in the network. IGF pathway gene, IGF2BP1, was also an important node. In our previous work, this pathway was identified as a promising target for cisplatin resistance treatment.
Our results show that the has-let-7 miRNA family and IGF pathway genes may play important roles in cisplatin resistance. Exploration of the deregulation network can potentially provide more insights to the identification of candidate targets. Our approach also demonstrates the value of systems biology in the analysis of genomic data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 170. doi:10.1158/1538-7445.AM2011-170
Abstract 1719: Integrative genomic analysis of ovarian cancer cell lines points to EMT involvement in the development of cisplatin resistance
Authors: Haslehurst Alexandria , Koti Madhuri , Vidal Ricardo , Park Paul , Jiang Wenyu , Squire Jeremy , Feilotter Harriet 
Published: June 2012

Abstract
Ovarian cancer is the 5th leading cause of cancer related death in women, and has the highest associated mortality rate of any of the gynecological cancers. Approximately 75-80% of women diagnosed will succumb to the disease. The high mortality rate associated with ovarian cancer is due to poor screening and detection methods, resulting in late stage diagnosis, and also to resistance of the tumours to chemotherapeutic drugs. Primary drug resistance occurs in about 20% of patients during their treatment phase while approximately 70-80% of women that initially respond to chemotherapy will develop drug resistance over the course of treatment or at the time of relapse. Being able to accurately predict which patients will not successfully respond to drugs is the first step in developing personalized medicine and preventing useless chemotherapy treatments. In order to discover biomarkers of cisplatin resistance, a multi-platform integrative approach was taken utilizing data from aCGH as well as miRNA and mRNA microarrays. Data were collected from a drug sensitive and drug resistant ovarian cancer cell line pair (A2780 and A2780cis). Working with the paired cell lines provided a homogeneous population with which to build an integration algorithm. Data analysis using GeneSpring and Nexus software showed an enrichment of genes involved in TGFβ and EGF signaling. These signaling pathways lead us to investigate the involvement of the epithelial to mesenchymal transition (EMT) in drug resistance. Interestingly, many of the key genes involved in the regulation of the EMT process were found to be upregulated in our mRNA expression data. Observations from cell culture work support EMT involvement. We have noted a slower growth rate and a change to a fibroblastic appearance in the resistant cells relative to their drug sensitive parents. Immunohistochemistry has also been utilized to show an increase in mesenchymal markers in the resistant cell line. In order to determine if these findings were representative of drug resistance in human ovarian cancer, expression data from cisplatin sensitive and resistant ovarian cancer tumours were mined specifically for these and other EMT genes. A large number of the same EMT genes were consistently shown to be upregulated in the drug resistant tumour tissues relative to the sensitive tumours. Together, these data suggest the potential involvement of the epithelial to mesenchymal transition in the development of cisplatin resistance in ovarian cancer. Further validation of these results in vitro is currently in progress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1719. doi:10.1158/1538-7445.AM2011-1719
Abstract 1732: Synthesis and evaluation of NSC23925 isomers to reverse multidrug resistance in cancer
Authors: Duan Zhenfeng , Choy Edwin , Harmon David , Liu Xianzhe , Mankin Henry , Hornicek Francis 
Published: June 2012

Abstract
The eventual development of multidrug resistance (MDR) during the course of chemotherapy treatment is a fundamental obstacle associated with cancer care. Prior studies have identified NSC23925 ((2-(4-methoxyphenyl)-4-quinolinyl) (2-piperidinyl) methanol)) to be a small molecule agent that reverses MDR in cancer cells. Analysis of the structure of NSC23925 indicates that NSC23925 has two chiral centers which lead to 4 different stereo-isomers (erythro-7a, threo-7b, threo-9a and erythro-9b). Each isomer may or may not have distinct bio-activity from the others. In this study, we synthesized all four isomers of NSC23925 and analyzed by liquid chromatography-mass spectrometry (LCMS, HPLC-MS). Structure and activity relationships for reversing MDR in several MDR human cancer cell lines were evaluated by MTT assay. We observed that compound erythro-9b (NSC23925-9b) is the most potent isomer on reversing drug resistance, threo-7b and threo-9a also showed modest but lesser activity, and Erythro-7a showed the least potency. NSC23925-9b is able to reverse MDR in several drug resistant cell lines expressing Pgp in vitro, including ovarian, breast, colon, and sarcoma cancer cell lines. NSC23925-9b was able to re-sensitize these cell lines to paclitaxel, doxorubicin, vincristine and ET-743 with no effect on cell sensitivity to cisplatin, topotecan and methotrexate. NSC23925-9b was unable to reverse drug resistance in non-Pgp expressing drug resistant cell lines. Furthermore, NSC23925-9b significantly enhanced in vivo antitumor activity of paclitaxel in MDR ovarian cancer cell line SKOV-3TR xenograft models, without significant increasing the level of paclitaxel toxicity. In conclusion, these results demonstrated that NSC23925-9b and derivatives of this compound may hold therapeutic value in the treatment of MDR dependent cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1732. doi:10.1158/1538-7445.AM2011-1732
Abstract 1736: Src inhibitor dasatinib enhances anti-tumor activity of irreversible or T790M-selective epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer cells with T790M gate-keeper mutation
Authors: Yoshida Takeshi , Zhang Guolin , Bai Yun , Edwards Arthur , Fang Bin , Rawal Bhupendra , Okabe Takafumi , Okamoto Isamu , Nakagawa Kazuhiko , Haura Eric B. 
Published: June 2012

Abstract
Despite the therapeutic benefit of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutation, most if not all eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) accounts for 50% of all cases of acquired resistance to EGFR-TKIs. Although irreversible EGFR-TKIs are thought to be one of the strategies to overcome T790M, the efficacy of these drugs appears limited. To investigate how signal transduction is altered in NSCLC cells with T790M, we generated PC9GR cells with T790M by long term gefitinib exposure of PC9 cells with exon 19 deletion. Global phospho-proteomics approach revealed that Src family kinases were phosphorylated by erlotinib treatment in PC9GR cells, suggesting that Src family kinases compensate EGFR inhibition in NSCLC cells with T790M. Western blot assays demonstrated that BIBW2992, an irreversible EGFR-TKI currently in several clinical trials, also activated Src family kinases in PC9GR and H1975 NSCLC cells with T790M. The Src inhibitor dasatinib combined with BIBW2992 abolished this Src phosphorylation along with complete suppression of phospho Akt and Erk. In addition, significant PARP cleavage was observed in these cells suggesting apoptotic cell death. Consistent with the effects on cell signaling and apoptosis, dasatinib enhances anti-tumor activity of BIBW2992 in both GLO cell proliferation assay and caspase-3 apoptosis assay in PC9GR and H1975 cells. Additional experiments also demonstrated that dasatinib enhanced the effects of T790M selective EGFR-TKI WZ4002, which was recently reported to be another possible strategy to overcome T790M, in PC9GR and H1975 cells. Finally, the combination of BIBW2992 and dasatinib showed significant in vivo tumor suppression (including tumor regression) in PC9GR xenograft studies. These results suggest a role for Src in maintaining downstream signaling despite irreversible EGFR inhibitors and support further studies of irreversible EGFR combined with dasatinib in NSCLC patients who acquired resistance to EGFR-TKI by T790M.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1736. doi:10.1158/1538-7445.AM2011-1736