bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4368: MicroRNAs miR-503 and -182 regulate FBXW7 contributing to the malignant transformation to colon adenocarcinoma
Authors: Li Lihua , Sarver Aaron , Khatri Rohini , Hajeri Praveensingh , Kamenev Iris , Thibodeau Stephen , Steer Clifford J. , Subramanian Subbaya 
Published: May 2015

Abstract
Progression from adenoma to colon cancer is a multi-step process and the role of microRNAs in this transformation is not completely understood.
We used both in vitro and in vivo approaches to demonstrate the role of miRNAs in the transformation of adenoma to adenocarcinoma. Reporter assays were used to show the direct interaction of miRNAs to target gene. A Tet-inducible TripZ system and miRzips constructs were used in the in vitro function and xenograft studies. Kaplan-Meier survival curves and Cox regression were used to analyze the survival data in colon cancer patients.
Here, we show that the combination of miR-503 and miR-182 contributes to the transformation of colon adenoma to adenocarcinoma by cooperatively regulating the tumor suppressor gene, FBXW7. We found that miR-182 was upregulated in both colon adenoma and adenocarcinoma, whereas miR-503 was upregulated only in adenocarcinoma, indicating a potential hierarchical and stepwise expression of these miRNAs in the regulation of FBXW7. Furthermore, we showed that colon adenoma derived non-tumorigenic AAC1 cells were transformative and tumorigenic in mice when expressing Tet-inducible miR-503. Finally, the combination of miR-503 and miR-182 transcript levels was predictive of poor outcome in colon cancer patients. We conclude that a step-wise expression of miR-182 and miR-503 in benign adenoma synergistically regulates the driver gene FBXW7, thus contributing to the progression of colon adenoma to adenocarcinoma.
Citation Format: Lihua Li, Aaron Sarver, Rohini Khatri, Praveensingh Hajeri, Iris Kamenev, Stephen Thibodeau, Clifford J. Steer, Subbaya Subramanian. MicroRNAs miR-503 and -182 regulate FBXW7 contributing to the malignant transformation to colon adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4368. doi:10.1158/1538-7445.AM2014-4368
Abstract 437: Novel function of the BAP1 nuclear deubiquitinase in the non-homologous end joining (NHEJ) pathway of double strand DNA repair
Authors: Ito Tatsuo , Kitano Shigehisa , Erdjument-Bromage Hediye , Ladanyi Marc 
Published: May 2015

Abstract
Background- The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of malignant pleural mesothelioma (MPM) and uveal melanoma and in subsets of sporadic cases of these cancers, as well as in clear cell renal carcinoma and intrahepatic cholangiocarcinoma.
Methods and Results- We found that BAP1 knockdown is associated with increased DNA damage and that this effect of BAP1 knockdown is further enhanced by both X-irradiation and concomitant DNA-PKcs inhibitor II treatment in normal human mesenchymal stem cells and the MPM cell line H-Meso. A BAP1 mutant deficient in deubiquitinase activity is also associated with increased DNA damage in the H-Meso cells. Interactional total peptide (ITOP) analysis based on proteins identified by Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS) of BAP1 protein complexes in H-Meso MPM cells and 293T cells identified known binding partners [HCF1, ASXL2, H2A] as well as possible novel interaction partners, notably PRKDC which encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and functions with the Ku70/Ku80 heterodimer in the non-homologous end joining (NHEJ) pathway of DNA repair. Double stranded DNA damage resulted in prominent nuclear expression of BAP1 protein in H-Meso cells and phosphorylation of BAP1 at Serine 395. Overexpression of dominant negative BAP1 C91W mutant in MPM cells caused instability of DNA-PKcs. Although strong polyubiquitination of DNA-PKcs was observed upon DNA damage in MPM cells expressing BAP1 C91W, this polyubiquitination was not observed in the presence of wild type BAP1. A plasmid-based NHEJ assay also confirmed a significant effect of BAP1 on NHEJ activity.
Conclusion- Functional complexes between BAP1 and the NHEJ family components point to a novel role in DNA repair and may shed light on BAP1's role as an important tumor suppressor
Citation Format: Tatsuo Ito, Shigehisa Kitano, Hediye Erdjument-Bromage, Marc Ladanyi. Novel function of the BAP1 nuclear deubiquitinase in the non-homologous end joining (NHEJ) pathway of double strand DNA repair. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 437. doi:10.1158/1538-7445.AM2014-437
Abstract 4373: Integrated microRNA and mRNA signature associated with the transition from the locally confined to the metastasized renal cell carcinoma
Authors: Billaud Jean-Noel 
Published: May 2015

Abstract
Background
MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression by interfering translation or stability of target transcripts. One miRNA can interact with several hundred mRNAs, while one mRNA can be regulated by several miRNAs. This interplay between miRNA and their mRNA has been proposed as an important process in cancer development and progression. We have investigated molecular networks impacted by predicted mRNA targets of differentially expressed miRNAs in patients with clear cell renal cell carcinoma (ccRCC) diagnosed with or without metastasis.
Material and methods
miRNA and mRNA microarray expression profiles derived from primary clear cell renal cell carcinomas from patients with (in total 16 samples) or without diagnosed metastasis (in total 22 samples) were used to identify anti-correlated miRNA-mRNA interaction in ccRCC. For this purpose, Ingenuity pathway analysis microRNA Target Filter, which enables prioritization of experimentally validated and predicted mRNA targets was used. By applying an expression pairing tool, the analysis was focused on targets exhibiting altered expression in our analysis, finding miRNAs and their target genes with opposite or same expression. The resulting identified interactions were revalidated by RT-qPCR in another cohort of RCC patients. The predicted miRNA-mRNA interactions were also tested by functional analyses using miRNA knock-down and over expression experiments in renal cancer cell lines.
Results
Among the significantly differentially expressed miRNAs, we have identified 3 miRNAs (miR-146a, miR-128a and miR-17-5p) that were upregulated in primary tumors from patients without metastasis and down regulated in primary tumors from patients with metastasis. We have further identified the mRNA targets which expression were inversely correlated to these 3 miRNAs, and have been previously experimentally demonstrated in cancer setting in humans. Specifically we showed that BRAC1, MCM10, CDKN3, UHRF1, IL8 were downregulated and targeted by miR-146a-5p. The relation between these identifies target genes and miRNA-146a was validated in cell culture experiments.
Conclusions
We identified novel target genes of dysregulated miRNAs, which are involved in the transition from primary RCC without metastases into tumors generating distant metastasis.
Citation Format: Jean-Noel Billaud. Integrated microRNA and mRNA signature associated with the transition from the locally confined to the metastasized renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4373. doi:10.1158/1538-7445.AM2014-4373
Abstract 4377: Novel RNAi agent can control HCV replication
Authors: Kuroda Masahiko , Takanashi Masakatsu , Ohno Shinichiro , Murakami Yoshiki 
Published: May 2015

Abstract
Technique of RNA interference (RNAi) is important for investigating functional gene research and drug target. miRNA-122 (miR-122) is expressed abundantly in liver tissue, and it can control the Hepatitis C virus (HCV) replication. Locked Nucleic Acid (LNA)-miR-122 was shown to suppress HCV replication through inhibiting miR-122 function. Recently, anti-HCV therapy for chronic hepatitis C by LNA-miR-122 has been applied for clinical study in phase II. We developed alternative chemically modified sponge oligonucleotides (SO) for inhibition of interest miRNA function. In order to find more effective anti-viral agent, we attempted to compare the inhibition effects for viral replication between LNA-miR-122 and SO for miR-122.
SO contained triplicated binding sites to miR-122, composed of either DNA or RNA, which were combined with terephthalate or glycine. We chose three types of sequences complementary to target miR-122: one perfect match sequence and two imperfect match sequences (bubble, and bulge). The effects of SOs on HCV replication were assessed by using HCV replicon cells (OR6), which contained full-genome HCV with genotype 1b and luciferase reporter genes.
We compared the luciferase activity, the expression of HCV RNA, and the expression of HCV core protein in OR6 cells treated with LNA-miR-122 and several SO constructions. SO composed of terephthalate-bound RNA sequences with bulge-type imperfect complementarity was most effective in inhibiting HCV replication. By real-time qPCR analysis, the expression level of ISG15 and RIG-I in the OR6 cell treated with SO was not significantly higher than those treated with negative control (NC) or LNA. By XTT incorporation assay, the cell proliferation level in OR6 treated with SO was not also significantly affected as compared that treated with NC or LNA.
We investigated novel RNAi agent termed SO that could effectively suppress HCV replication as compared LNA-miR-122. SO treatment did not activate the endogenous IFN pathway nor induce the cell mortality. Therefore SO is promising as a novel anti-vial agent.
Citation Format: Masahiko Kuroda, Masakatsu Takanashi, Shinichiro Ohno, Yoshiki Murakami. Novel RNAi agent can control HCV replication. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4377. doi:10.1158/1538-7445.AM2014-4377
Abstract 4379: Identification and characterization of therapeutic targets via microRNA profiling in HBV-related hepatocellular carcinoma
Authors: Park Keon U. , Kim Jin Young , Hwang Ilseon , Ryoo Hun M. , Kim Sang-Woo , Lee Yun-Han 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer and it accounts for about 600,000 cancer deaths worldwide. Chronic infection with hepatitis B virus (HBV) is known to be responsible for most of HCC cases. HBV infections are especially common in Africa and some of Asian countries, including South Korea where 75% of HCC patients are infected with HBV. With traditional therapeutic strategies, such as surgical dissection or chemoembolization, 5-year survival rate of HCC patients is about 18%, demanding better understanding of molecular and cellular biology of the disease.
MicroRNAs (miRNAs) are small noncoding single-stranded RNA molecules about 21-25 nucleotides long. miRNAs are involved in many cellular processes, including cell proliferation, apoptosis, and cell differentiation. Recently, it has been reported that deregulation of miRNAs contributes to the development of different types of human cancers but their role in HCC pathogenesis remains to be fully understood.
In the present study, we performed a microarray-based genome-wide analysis of miRNA expression in 9 tissue samples from HCC patients and 7 noncancerous liver tissues to identify differentially expressed miRNAs. The expression of 183 and 84 miRNAs was found significantly up- and down-regulated in HCC samples compared with normal liver tissues, respectively (p &lt; 0.05). Among prominent miRNAs are miR-17∼92 polycistronic oncomir, miR-200 family, miR-34, and miR-125b that are shown to be associated with HCC pathogenesis, demonstrating the validity of this miRNA profiling and warranting the identification and characterization of other miRNAs and their potential target genes.
Taken together, our study demonstrates miRNA profiling in HCC that may be used as a diagnostic purposes.
Citation Format: Keon Uk Park, Jin Young Kim, Ilseon Hwang, Hun Mo Ryoo, Sang-Woo Kim, Yun-Han Lee. Identification and characterization of therapeutic targets via microRNA profiling in HBV-related hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4379. doi:10.1158/1538-7445.AM2014-4379
Abstract 4381: MiR-205 and Trastuzumab: Potential as adjuvant therapeutic tool and predictive biomarker
Authors: D'Ippolito Elvira , Piovan Claudia , Plantamura Ilaria , Giussani Marta , Casalini Patrizia , Campiglio Manuela , Tagliabue Elda , Iorio Marilena V. 
Published: May 2015

Abstract
Despite the improvement in the management of HER2+ breast cancer patients with the approval of Trastuzumab in the clinical practise, and the success rate of this treatment, a still considerable percentage of patients do not respond or eventually develop a secondary resistance, leading to relapse and poor outcome. A crucial issue is represented by the urgent need of biomarkers able to predict the response to treatment, and certainly of new therapeutic tools to counteract the resistance mechanisms. It is known that resistance to anti-HER2 therapies can be due to escape mechanisms triggered by alternative receptors: here we show that HER3 silencing, either mediated by miR-205, known to directly target the receptor (Iorio MV et al., 2009) or by a siRNA specific against HER3, is able to improve the responsiveness to Trastuzumab, reducing tumor cell growth and colony formation capability. This effect seems to be mediated by impairment of the Akt-mediated pathway.
Finally, evaluating miR-205 expression in a series of 51 HER2+ breast cancer patients treated with Trastuzumab in adjuvant setting, we observed that miR-205 is significantly associated with outcome: setting the median expression as cut-off, and performing a contingency analysis (Fisher's exact test), miR-205 expression was above the median in a significantly (p=0.03) higher percentage of responders versus non responders patients (61% versus 26%).
In summary, here we show that miR-205 improves the responsiveness to Trastuzumab treatment at least partially though HER3 silencing, and associated to outcome of patients treated in adjuvant setting, thus representing a potential adjuvant tool and predictive biomarker.
Citation Format: Elvira D'Ippolito, Claudia Piovan, Ilaria Plantamura, Marta Giussani, Patrizia Casalini, Manuela Campiglio, Elda Tagliabue, Marilena V. Iorio. MiR-205 and Trastuzumab: Potential as adjuvant therapeutic tool and predictive biomarker. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4381. doi:10.1158/1538-7445.AM2014-4381
Abstract 4382: Relative expression of miR200 microRNAs and ERBB family negative regulator Mig6 in estimation of EMT status and erlotinib sensitivity
Authors: Izumchenko Eugene G. , Chang Xiaofei , Michailidi Christina , Kagohara Luciane , Ravi Rajani , Brait Mariana , Bedi Atul , Sidransky David 
Published: May 2015

Abstract
While sensitizing mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) render tumors more sensitive to EGFR tyrosine kinase inhibitors (TKIs), these genetic alterations are present in only a minority of patients who respond to treatment and are rare in tumors other than NSCLCs. Thus, clinical benefit of TKIs in a subset of patients with wild-type EGFR may be underestimated due to the lack of appropriate predictive markers to stratify them from larger number of patients who do not response. It has long been observed that the response of anti-EGFR agents is associated with epithelial and mesenchymal transition (EMT) in multiple types of tumors without known EGFR mutations. However, little is known about the molecular mechanisms underlying this association, and no EMT-associated biomarkers of clinical utility have been successfully developed. Here we show that during the TGFβ-induced EMT, upregulation of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR, by microRNAs 200 (miR200) family is leading to reduced EGFR dependence, initiation of kinase switch in mesenchymal cells and subsequent insensitivity of these cells to EGFR inhibition. Moreover, we found that the ratio between mRNA levels of Mig6 and miR200c highly correlated with erlotinib sensitivity and EMT status in panel of 25 cancer cell lines of different tissue origins. Furthermore, analysis of directly xenografted human lung and pancreatic tumors (tumorgrafts) bearing wtEGFR demonstrated a higher response to EGFR inhibitor erlotinib for models with low Mig6 (mRNA)/miR200 ratio. Collectively, our data demonstrates that during the EMT-associated evolution of resistance to EGFR inhibitors, Mig6 expression is highly correlated with EMT status and identifies the ratio of Mig6 mRNA to miR200 as a novel, reliable and cost-effective predictor of biologic and clinical response to TKIs.
Citation Format: Eugene G. Izumchenko, Xiaofei Chang, Christina Michailidi, Luciane Kagohara, Rajani Ravi, Mariana Brait, Atul Bedi, David Sidransky. Relative expression of miR200 microRNAs and ERBB family negative regulator Mig6 in estimation of EMT status and erlotinib sensitivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4382. doi:10.1158/1538-7445.AM2014-4382
Abstract 4383: Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma
Authors: Gregory-Bryson Emmalena J. , Parys Maciej , Kiupel Matti , Yuzbasiyan-Gurkan Vilma 
Published: May 2015

Abstract
Histiocytic diseases encompass a spectrum of proliferative diseases in humans and dogs. While these orphan malignancies are rare in the human, histiocytic diseases are relatively frequent in certain breeds of dog. In the dog, these diseases range from benign histiocytoma to malignant histiocytic sarcoma (HS). Disseminated HS has a poor prognosis and lacks effective treatment options in both humans and dogs. The overall goal of this study is to unravel the mechanisms of tumorigenesis in histiocytic diseases and identify better treatments. Our studies have focused on microRNAs (miRNAs), which are master regulators of gene expression and may have a significant role in tumorigenesis in histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, HS, and hemophagocytic HS. These samples were compared to normal canine histiocytes derived from peripheral blood or peritoneal fluid. Several miRNAs were identified to be upregulated in the disease samples and were selected for validation by qRT-PCR. From these results, two miRNA targets were selected for further evaluation. We are probing the significance of the upregulation of these miRNAs by inhibiting their function in canine HS cell lines using chemical miRNA inhibitors and sponge constructs designed to competitively bind the upregulated miRNAs, thus preventing them from acting on their targets. Our results to date indicate that inhibiting these miRNAs in the canine HS cell line, DH82, decreases growth rate by as much as 39%. Studies into other aspects of tumorigenicity potentially affected by the inhibition of these miRNAs are underway. Our preliminary data suggests these miRNAs themselves may be effective therapeutic targets for histiocytic diseases. Additionally, further analysis of the pathways regulated by these miRNAs may identify critical gene targets in HS tumorigenesis and thus increase our understanding of these malignancies and discover novel and effective therapies. Comparative studies have the potential to provide opportunities for advancement in these orphan malignancies, and in this case, improve clinical outcome in dogs and humans.
Citation Format: Emmalena J. Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan. Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2014-4383
Abstract 4387: Up-regulation of VHL by miR-1273C inhibits renal cell carcinoma
Authors: Lee Chang Woo , Kang Moo Rim , Yun Jieun , Oh Soo Jin , Kang Jong Soon 
Published: May 2015

Abstract
VHL (Von Hippel-Lindau) is a known tumor suppressor that binds to hypoxia inducible factor (HIF) and induces ubiquitin-mediated degradation. VHL is also involved in the regulation of tumor angigoenesis, cell cycle regulation, and apoptosis. Recent studies have reported that double strand RNA complementary to target promoter sequence can induce gene expression in several cancer cells and this is called small activating RNA (saRNA). By scanning gene promoters in silico for sequences complementary to known miRNAs, we identified 32 putative miRNAs target site in the promoter of VHL. Experimental validation identified two miRNAs (miR-1273C and miR-4512) that induce VHL expression in 769-P renal cancer cells. Another dsRNA molecule (dsVHL-101) complementary to the putative miR-1273C target site also induced VHL expression. Functional studies revealed that transfection of miR-1273C and dsVHL-101 inhibited cell proliferation and induced apoptosis in dose dependent manner. Furthermore, knockdown experiments confirmed that induction of VHL and apoptosis by miR-1273C and dsVHL-101 required the miRNA maturation protein Ago2 and nuclear transport protein TNRC6A. This study suggests that miRNAs play an inhibiting role in the progression of cancer cells by VHL gene expression, which may be a potential therapeutic approach in the future.
Citation Format: Chang Woo Lee, Moo Rim Kang, Jieun Yun, Soo Jin Oh, Jong Soon Kang. Up-regulation of VHL by miR-1273C inhibits renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4387. doi:10.1158/1538-7445.AM2014-4387