bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3972: MicroRNAs as potential therapeutic agents for AML: Targeting the AML1-ETO Oncogene by pre-miR-520 and -373
Authors: Toniolo Patricia A. , Pilarski Patrick M. , Bach Christian , Griffin James D. , Adamia Sophia 
Published: August 2015

Abstract
Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of poorly differentiated myeloid cells in the bone marrow and blood of patients. Differentiation therapy is an attractive therapeutic approach for treating patients with AML. All-Trans Retionic Acid, induces differentiation of patients with the PML/RARa oncogene, but is ineffective in treating other more frequent types of AML. Here we describe the use of microRNAs to target the oncogene formed as a result of the (8;21) translocation, The goals was to identify miRNAs that could target the breakpoint region of the fusion protein, and determine if this would reduce expression of AML1-ETO and promote differentiation and/or apoptosis. Bioinformatics analysis was used to identify 28 different miRNAs that could potentially target AML1-ETO transcripts. Among those, miRNA-520 and -373 showed the highest degree of complimentary to AML1-ETO transcripts at the braikpoint. To look for miR-520 and -373 efficacy, we transfected two AML cell lines, Kasumi 1 and SKNO1, which have AML1-ETO translocation, with pre-miR-520 and -373 LNA probes, as well as HL60 cells which lack AML1-ETO. Expression of the LNA pre-miR-520/373 in Kasumi-1 and SKNO-1 cell lines decreased AML1-ETO transcripts and led to a significant reduction of AML1-ETO protein levels. The inhibition of AML1-ETO fusion protein also induced apoptosis of leukemic cells in vitro, but had no effect on HL60 cells. Moreover, the administration of LNA pre-miR-520 in an AML xenografts murine model increased apoptosis of leukemic cells and reduced tumor burden without obvious toxicity. We are currently testing the effects of miR-520 and -373 on differentiation and proliferation of primary blasts from patients with the AML1-ETO translocation.
Our results suggest that small molecules such as miRNAs can be identified that directly target a frequent AML oncogene. miRNAs are naturally accruing molecules and have the potential advantage of producing modest side effects, with highly significant specificity. The approaches we developed in this study can be used to evaluate and optimize other pre-miRs and anti-miRs as therapeutic agents to target other types oncogenes not currently amenable to small molecule drugs.
Citation Format: Patricia A. Toniolo, Patrick M. Pilarski, Christian Bach, James D. Griffin, Sophia Adamia. MicroRNAs as potential therapeutic agents for AML: Targeting the AML1-ETO Oncogene by pre-miR-520 and -373. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3972. doi:10.1158/1538-7445.AM2015-3972
Abstract 3987: Exosomal microRNA in cell-free urine samples as a source for liquid prostate cancer biopsy
Authors: Blondal Thorarinn , Thomsen Anni R. , Krummheuer Jörg , Borre Michael , Fredsøe Jacob , Haldrup Christa , Andreasen Ditte , Teilum Maria W. , Tolstrup Niels , Sørensen Karina D. , Ørntoft Torben F. , Mouritzen Peter 
Published: August 2015

Abstract
MicroRNAs constitute a class of small cellular RNAs (typically 19-23 nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the human cellular transcriptome is regulated by this small class of RNA (∼2000 miRNA). MicroRNAs have been shown to be actively exported from tissues into the circulation through a variety of mechanisms including complexing with RNA binding proteins or HDL and through active exosome transport.
Exosomes are nanovesicles secreted into the extracellular environment by a wide range of cell types under normal and pathological conditions. As the profile of exosomal microRNAs may be a fingerprint of the releasing cell type and because they are released in easily accessible body fluids such as blood and urine, their microRNA content holds potential as biomarkers for early detection of malignancy.
Cell free urine samples are an obvious liquid biopsy source for microRNA markers in prostate cancer and could serve as diagnostic tools as well as treatment response markers. Yet microRNA levels in urine samples are extremely sparse and cannot be detected reliable by conventional sample preparation methods. It has been reported that tumour derived exosomes carrying genetic information specific for prostate cancer can be measured in urine samples following prostate massage. However, a methodology eliminating the need for prostate massage of every patient to be tested in a clinical setting is highly desirable.
The purpose of this study was to combine a simple exosomal enrichment method with our highly sensitive LNA™-based qPCR platform for detection of microRNAs and apply this to a cohort consisting of more than 300 cell free urine samples from prostate cancer cases and controls. In conclusion, cell free urine samples holds potential as a liquid biopsy source for exosomal microRNA markers in prostate cancer, showing miRNA signatures of strong diagnostic potential. Analysis is pending and data will be presented.
Citation Format: Thorarinn Blondal, Anni R. Thomsen, Jörg Krummheuer, Michael Borre, Jacob Fredsøe, Christa Haldrup, Ditte Andreasen, Maria W. Teilum, Niels Tolstrup, Karina D. Sørensen, Torben F. Ørntoft, Peter Mouritzen. Exosomal microRNA in cell-free urine samples as a source for liquid prostate cancer biopsy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3987. doi:10.1158/1538-7445.AM2015-3987
Abstract 3994: Herpes virus microRNA expression and significance in serous ovarian cancer
Authors: Pandya Deep , Mariani Marisa , McHugh Mark , Andreoli Mirko , Sieber Steven , He Shiquan , Dowell-Martino Candice , Fiedler Paul , Scambia Giovanni , Ferlini Cristiano 
Published: August 2015

Abstract
Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality.
Citation Format: Deep Pandya, Marisa Mariani, Mark McHugh, Mirko Andreoli, Steven Sieber, Shiquan He, Candice Dowell-Martino, Paul Fiedler, Giovanni Scambia, Cristiano Ferlini. Herpes virus microRNA expression and significance in serous ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3994. doi:10.1158/1538-7445.AM2015-3994
Abstract 40: HB-EGF‑mediated CITED4 signaling in lung cancer
Authors: Hsieh Cheng-Han , Chou Yu-Ting , Wu Cheng-Wen 
Published: August 2015

Abstract
Abnormal activation of the EGF receptor (EGFR) signaling is a hallmark of lung cancer. However, the role of heparin-binding EGF-like growth factor (HB-EGF), one of EGFR ligands, in lung tumorigenesis has been unappreciated. In this study, we showed that HB-EGF was highly expressed in a subgroup of lung cancer cells, the proliferation of which was dependent on HB-EGF signaling. Members of CITED family proteins respond to various cytokine signalings, regulating cell proliferation; among them, we identified CITED4 as a downstream effecter of HB-EGF. We revealed that CITED4 was upregulated by HB-EGF through a STAT3 dependent pathway. Moreover, CITED4-silencing attenuated HB-EGF-mediated lung cancer cell proliferation. ChIP analysis and promoter reporter assay showed that STAT3 bound CITED4 promoter, enhancing CITED4 transcription. Co-immunoprecipitation analysis identified MYC as a CITED4-interacting protein. Furthermore, we found that CITED4 expression promoted MYC-mediated transcription of cyclin D1 promoter, leading to increased G1/S cell cycle transition. Thus, our findings support that HB-EGF-CITED4 signaling cascade plays a critical role in aberrant proliferation in lung cancer with potential as a biomarker for lung cancer progression.
Citation Format: Cheng-Han Hsieh, Yu-Ting Chou, Cheng-Wen Wu. HB-EGF‑mediated CITED4 signaling in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 40. doi:10.1158/1538-7445.AM2015-40
Abstract 4015: miR-221 ans miR-222 expression in salivary gland tumors
Authors: Ianez Renata Carolina Fraga , Coutinho-Camillo Cláudia , Pinto Clóvis , Soares Fernando , Lourenço Silvia 
Published: August 2015

Abstract
Background: MicroRNAs (miRNAs) are a class of short noncoding RNAs, that regulate the gene expression by binding to the 3′ - untranslated region of target mRNAS and by blocking the translation or degradation of the mRNAs that mediate various pathophysiological process including the pathogenesis of diverse human cancers and important cellular functions such as proliferation, apoptosis, differentiation, and cell signaling. Salivary gland tumors are complex, due to their broad histological spectrum resulting from multiple tumor cell differentiation. We previously detected that the protein c-kit is involved in the process of salivary gland morphogenesis and tumorigenesis; other recent studies reported alterations in KIT gene in adenoid cystic carcinoma. The aim of the present study is to determine the expression of microRNAs targeting KIT in pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC), the most common benign and malignant salivary gland neoplasms, respectively, and that originate from the intercalated duct region. Material and Methods: Twenty-five pleomorphic adenoma, 14 adenoid cystic carcinoma and 10 non-neoplastic salivary gland samples were used and miRNA expression was evaluated by Real Time RT-PCR using TaqMan miRNA Assays (miR- 221 and 222). Results: Expression of miR-221 was detected in 13 CAC samples and 19 PA samples. In CAC, expression of miR-221 was downregulated in 4 out of 13 (30,77%) samples, upregulated in 4 out of 13 (30,77%) samples, and normal in 5 out of 13 (38,46%) samples. In PA, miR-221 expression was downregulated in 7 out of 19 (36,84%) samples, upregulated in 2 out of 19 (10,53%) samples, and normal in 10 out of 19 (52,63%) samples. Expression of miR-222 was detected in 14 CAC samples and 22 PA samples. In the majority of CAC samples, the expression of miR-222 was similar to that observed in non-neoplastic samples. In PA samples, expression of miR-222 was downregulated in 7 out of 22 (31,8%) samples, upregulated in 8 out of 22 (36,4%) samples, and normal in 7 out of 22 (31,8%) samples. Conclusion: The expression of miRNAs 221 and 222 do not present a definite pattern to discriminate PA from ACC. This might be due to different mechanisms involved in their tumor biology or due to their common site of origin (the intercalated duct) which could add some similar biological features to both neoplasms.
Citation Format: Renata Carolina Fraga Ianez, Cláudia Coutinho-Camillo, Clóvis Pinto, Fernando Soares, Silvia Lourenço. miR-221 ans miR-222 expression in salivary gland tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4015. doi:10.1158/1538-7445.AM2015-4015
Abstract 4016: c-MET associated with osteogenesis in multiple myeloma patients by induction of MMP9 expression by HGF in BMSCs
Authors: Park Hyejoo , Oh Jeong In , Ahn Kwang-Sung , Koh Youngil , Yoon Sung-Soo 
Published: August 2015

Abstract
HGF-mediated c-MET signaling plays a critical key in the progression of multiple myeloma. That signaling is associated with cell proliferation, drug resistance and osteoblast. In addition dynamic interplay between MM cell and bone marrow stromal cell regulates that signaling activation. The expression level of HGF in bone marrow plasma of MM patients is higher when compared to case control. However, the role of HGF-mediated c-Met was obscure in the progression of MM. In this study, we elucidate the role of c-Met signaling in osteogenesis in MM using co-culture system.
In our previous data, we found that the expression levels of HGF in bone marrow serum of multiple myeloma patients was correlated with the expression levels of OPN and RUNX2. Also, those expression levels were associated with bone lesion. It suggested that HGF might be one of regulators in the progression of osteogenesis. However, mechanisms by HGF-mediated c-MET activation modulate the expression of matrix metalloproteinases still remain unknown. In our study, we found that Our data show that PI3K inhibitor effectively inhibited the MMP9 mRNA expression in both OPN alone treatment and co-treatment with OPN and HGF in BMSCs. Induction of OPN and RUNX2 by HGF in MM cells could be one of the major factors for the progression of MM through interaction of MM cells and BMSCs. We suggested that induction of OPN/MMP9 strongly associated with osteoclast.
For further analysis, we performed co-culture system which MM cells were grown with BMSCs obtained from MM patients’ bone marrow specimen in order to verify the role of HGF mediated c-MET activation in the progression of MM patient's osteogenesis. To explore the detail mechanisms of HGF-mediated osteogenesis, various inhibitors was used and the expression levels of a set of genes was examined using real-time PCR. Subsequently, HGF-mediated c-MET activation was regulated the expression of OPN/MMP-9 via co-effects of PIK3 activation and activation of wnt signaling pathway in BMSCs from bone marrow of MM patients. In conclusion, cross-talk between PI3K/AKT pathway and wnt singaling pathway could be one of the major factors for the progression of MM through interaction of MM cells and BMSCs.
Citation Format: Hyejoo Park, Jeong In Oh, Kwang-Sung Ahn, Youngil Koh, Sung-Soo Yoon. c-MET associated with osteogenesis in multiple myeloma patients by induction of MMP9 expression by HGF in BMSCs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4016. doi:10.1158/1538-7445.AM2015-4016
Abstract 4019: Examining mechanisms by which macrophages enhance intravasation in breast cancer
Authors: Chiang Serena , Zhou Zhenni , Segall Jeffrey E. 
Published: August 2015

Abstract
Breast cancer is the most common invasive malignancy and a leading cause of cancer-associated deaths in women worldwide. Metastasis is the major cause of morbidity and mortality in women afflicted with breast cancer. In the metastatic process, intravasation is an important step and largely dependent on interactions between tumor cells and stromal cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), an integral component of the TME, have been found to associate and co-migrate with tumor cells during intravasation. Invasive TAMs that co-migrate with tumor cells in response to epidermal growth factor display a unique transcriptome in comparison to the general TAM population found in the TME. Furthermore, intercellular signaling between tumor cells and TAMs generates a positive feedback loop that promotes tumor cell invasion and intravasation. Chemokines play a major role in cell migration and are an important component of the TME. In particular, chemokine (C-X-C motif) receptor 2 (CXCR2) has been shown to be important in tumor growth and angiogenesis. MIF and IL8, two ligands of CXCR2, correlate with poor outcome in breast cancer. Our objective is to elucidate the role of macrophage CXCR2 in tumor cell intravasation.
We have used flow cytometry to characterize the basal expression of CXCR2 in a murine macrophage cell line, BAC-1.2F5 (BAC). We have also analyzed mRNA expression of CXCR2 in BAC and primary TAMs isolated from a murine model of breast cancer, the polyoma middle T oncoprotein (PyMT), by qRT-PCR. To test the functional significance of CXCR2 in intravasation, we have examined the effects of an inhibitor of CXCR2 on the ability of tumor cells to migrate through the endothelium using an in vitro transendothelial migration assay (iTEM). In this assay, MDA-MB-231 tumor cells, a human breast cancer cell line, are co-cultured with BAC cells and subsequently placed in an environment that is in contact with the basal surface of endothelial cells.
We have observed that BAC cells produce CXCR2 mRNA and express surface CXCR2. We have also found elevated expression of CXCR2 in invasive TAMs as compared to the general TAM population. When MDA-MB-231 cells are co-cultured with BAC cells in the iTEM assay in the presence of SB265610, an inhibitor of CXCR2, we have found a significant reduction (p&lt;10-4) in iTEM. Together, these results suggest that cellular signaling through macrophage CXCR2 is critical to tumor cell intravasation.
Citation Format: Serena Chiang, Zhenni Zhou, Jeffrey E. Segall. Examining mechanisms by which macrophages enhance intravasation in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4019. doi:10.1158/1538-7445.AM2015-4019
Abstract 402: Pasireotide reduces chemoresistance in pancreatic tumor cells by inhibiting the synthesis and secretion of growth factors from tumor associated fibroblasts
Authors: Duluc Camille , Moatassim Siham , Chalabi Mounira , Perraud Aurélie , Martineau Yvan , Breibach Florence , Delisle Marie-Bernadette , Mathonnet Muriel , Schmid Herbert A. , Pyronnet Stéphane , Bousquet Corinne 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is extremely rich in stroma. By secreting tremendous amounts of soluble and un-soluble proteins, stromal cancer-associated fibroblasts (CAFs) can induce tumor chemoresistance by activating survival signals in cancer cells and preventing drug delivery through increased fibrosis. Our results demonstrate that chemoresistance triggered by the CAF secretome is strongly reduced upon inhibition of CAF protein synthesis. This is achieved by impinging upon the PI3K/mTOR/4E-BP1 pathway that we found highly activated in primary cultures of alpha-SMA-positive CAFs isolated from human PDAC. CAFs, but not normal pancreatic fibroblasts, express primarily the sstr1 somatostatin receptor subtype whose activation by the somatostatin analogue SOM230 (Pasireotide) strongly inhibits the PI3K/mTOR/4E-BP1 pathway and the resulting synthesis of secreted proteins including IL-6 and collagen-I. As a consequence, the growth and chemoresistance of pancreatic tumors provided by co-injection of CAFs in nude mice are overcome when chemotherapy (such as gemcitabine) is combined to pasireotide treatment. While gemcitabine or pasireotide alone have marginal effects, the combined treatment markedly decreases fibrosis and strongly enhances cancer cell apoptosis due to increased cell sensitivity to gemcitabine. We propose that selective inhibition of CAF protein synthesis and secretion with sstr1-directed pharmacological compounds represents an anti-stromal targeted therapy with a promising potential in chemosensitization.
Citation Format: Camille Duluc, Siham Moatassim, Mounira Chalabi, Aurélie Perraud, Yvan Martineau, Florence Breibach, Marie-Bernadette Delisle, Muriel Mathonnet, Herbert A. Schmid, Stéphane Pyronnet, Corinne Bousquet. Pasireotide reduces chemoresistance in pancreatic tumor cells by inhibiting the synthesis and secretion of growth factors from tumor associated fibroblasts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 402. doi:10.1158/1538-7445.AM2015-402