bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1512: Functional validation of microRNA activity inferred by ActMiR in bladder cancer
Authors: Castillo-Martin Mireia , Collazo Lorduy Ana , Li EunJee , Zhu Jun 
Published: July 2016

Abstract
Background: MicroRNAs (miRs) play a key role in cancer, both in tumorigenesis and tumor progression. In the past years, miR expression signatures have been reported as prognostic biomarkers in different tumor types including bladder cancer (BC). However, miR's expression does not always correlate with activity. We recently developed a novel computational method, named ActMiR, for explicitly inferring the activity of miRs based on the changes in expression levels of target genes. The main objective of this study was to validate the inferred miRs’ activity using BC as a model.
Design: We applied ActMiR in 405 BC cases from The Cancer Genome Atlas (TCGA) database for which information from both mRNA and miR expression was available. Different BC cell lines (5637 and HT1376 for basal BC, SW780 and HT1197 for p53-like BC, and RT4 and RT112 for luminal BC) as well as the immortalized urothelial cell line [Human Urothelium cell (HUC)] were used to perform the in vitro functional validation. RNA was extracted from these cells basally and after inhibition of miR106-5p with specific anti-miR inhibitor (Taqman, Life Technologies); miR and target genes’ expression was assessed by qRT-PCR.
Results: ActMir analyses revealed that a subset of 306 out of 1044 miRNAs were differentially expressed between tumor and normal samples at p-value&lt;10-4. More importantly, at p-value&lt;10-4, 155 out of 556 miRNAs were functionally active. From these, only four (miR106b, miR532, mir556, and mir134) were significantly differentially expressed, functionally active and showed prognostic significance. We chose to further analyze mir106b because it showed the biggest and most significant difference in activity between normal and cancer cells (p-value&lt;2*10-11). As inferred by ActMir, mir106-5p was significantly overexpressed in all cancer cells when compared to HUC. Basal cells showed the highest fold increase (mean of 39; range: 31-47), followed by luminal (mean of 19; range: 5-32) and p53-like cells (mean of 8; range: 3-13). Inhibition of mir106b-5p was performed to assess whether the predicted target genes were consequently upregulated.
Conclusion: Our results underscore the value of ActMir for inferring miR activity in BC from a systems biology perspective. It endorses ActMir as a promising tool for studying casual effects of miR activity on target genes, and ultimately for determining survival outcomes of BC patients.
Citation Format: Mireia Castillo-Martin, Ana Collazo Lorduy, EunJee Li, Jun Zhu. Functional validation of microRNA activity inferred by ActMiR in bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1512.
Abstract 1513: Pan-cancer analysis of alternative splicing patterns and association to genomic aberrations
Authors: Häyrynen Sergei , Nykter Matti 
Published: July 2016

Abstract
Alternative splicing of pre-messenger RNA is responsible for the diversity of transcriptome and proteome, with the majority of multi exon genes producing multiple transcripts. Aberrations in regulative factors of alternative splicing are known to produce transcript isoforms associated with cancer progression and prognosis. Both mutations in the proximity of spliced regions and mutations in and regulation of previously identified splicing factor genes are known to alter splicing patterns.
In this study, we utilized publicly available TCGA data to study association patterns between alternative splicing and its regulatory elements across multiple cancer tissue types. We collected evidence of splicing patterns of annotated isoforms in addition to novel patterns identified using our previously developed tools using RNA-seq data. We mined for associations between somatic mutations and changes of splicing patterns as well as genome and transcriptome level changes in splicing factors. Selective transcriptome assembly was done in loci with differentially expressed patterns and novel patterns with sufficient evidence to identify transcript isoforms and quantify isoform specific expression.
In our study we compiled a catalogue of splicing patterns and their changes across multiple cancer types. Integration of this comprehensive set of quantified splicing patterns with data on proximal mutations and aberrations in splicing factors resulted in statistically relevant associations with clinical phenotypes. Our analysis enables identification of mechanisms behind splicing aberrations common to all cancers and cancer specific splicing patterns.
Citation Format: Sergei Häyrynen, Matti Nykter. Pan-cancer analysis of alternative splicing patterns and association to genomic aberrations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1513.
Abstract 1516: Biomedical informatics applied to the analysis of colon cancer genome: looking for a mutational pattern associated to infectious-origin cancer
Authors: Machicado Claudia , Machicado Enrique 
Published: July 2016

Abstract
Colon carcinoma, one of the most common malignancies globally, is the fourth cause of death due to cancer in Peru. Number of diagnosed cases have increased notably in the latest 5 years, which can be partially explained due to eating habits and environmental factors. In the present work we investigated the presence, in colon cancer genome, of genetic mutations reported in infectious-related cancer. Since most of gastric cancer is associated with chronic infection by Helicobacter pylori and Epstein-Barr virus (EBV), we investigated if the mutational pattern of gastric cancer caused by such infectious agents was similar to the colon carcinoma. Biomedical informatics tools were used to analyze the genomes of both gastric and colon carcinoma. Taken the 20 most frequently mutated genes both in gastric and colon cancer, a total of 8 genes in common resulted broadly mutated in both malignancies including p53, ATM, PIK3CA, ARID1A, CREBBP, KMT2D, KMT2C, and TRRAP. From such list, PIK3CA gene has been associated with gastric cancer caused by H. pylori and the mutational profile matched with that found in colon carcinoma. The point mutations of the oncoprotein PIK3CA identified equally in gastric and colon carcinoma were K111E, M1043I and E545G, all of them associated with gastric cancer caused by infection. Further screening of the gastric cancer genome allowed us to identify a point mutation of the oncoprotein β-catenin reported in infective-origin gastric cancer (D32N). Gene amplifications reported in infection-caused gastric cancer were also identified in the colon carcinoma genome in JAK2, CD274 and PDCD1LG2 genes. Finally downregulation of the tumor supresor gene FOXD3 associated to gastric cancer caused by pathogens was also found in colon carcinoma. Given that the origin of such genetic mutations have not been determined in colon cancer, our study brings evidence that colon carcinoma contain genetic mutations associated to infectious-related cancer. Further experimental studies will be required to verify the existence of mutations induced by parasites in colon carcinoma.
Citation Format: Claudia Machicado, Enrique Machicado. Biomedical informatics applied to the analysis of colon cancer genome: looking for a mutational pattern associated to infectious-origin cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1516.
Abstract 1519: Myb-regulated gene networks and signaling pathways in pancreatic cancer
Authors: Azim Shafquat , Srivastava Sanjeev K. , Bhardwaj Arun , Zubair Haseeb , Khan Mohammad Aslam , Singh Seema , Singh Ajay P. 
Published: July 2016

Abstract
The MYB proto-oncogene (a cellular progenitor of v-Myb oncogene) encodes an oncogenic transcription factor that regulates the expression of a wide array of genes responsible for different cellular functions. We have recently identified MYB as a key driver of pancreatic cancer (PC) pathogenesis. Our findings demonstrated that MYB was overexpressed in majority of PC tissues and cell lines, while remained undetectable in normal pancreatic cells. In addition, MYB overexpression was shown to be associated with pancreatic tumor growth and metastasis. To gain further insight into the molecular mechanisms involved in MYB-potentiated effects in PC cells, we conducted Next-Generation Sequencing of transcriptome of control and MYB-silenced MiaPaCa cells on an Illumina HiSeq 2500 platform. By keeping a cut-off of fold change &gt; 1.5 and p ≤ 0.05, we identified a total of 774 genes to be differentially expressed in MYB-altered MiaPaCa cells. Out of these, 485 genes were downregulated, while 289 genes exhibited upregulated expression. The differentially-regulated genes were subsequently analyzed for functions and cellular pathways alterations using Ingenuity Pathway Analysis (IPA) software. The top three networks to be affected in MYB knockdown PC cells included i) RNA post-transcriptional modifications, molecular transport, RNA trafficking, ii) cellular assembly and organization, cancer, and, iii) cell cycle, DNA replication, recombination and repair. These networks are centered on splicing factors, EGFR and NF-κB complex, respectively. IPA predicted pancreatic adenocarcinoma signaling as one of the most significantly affected canonical pathway upon MYB-silencing. Altogether, our findings identify novel MYB-regulated gene networks and signaling pathways in PC and thus suggest potential molecular mechanisms involved in mediating MYB action in pancreatic tumorigenesis.
Citation Format: Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh. Myb-regulated gene networks and signaling pathways in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1519.
Abstract 1552: Nucleotide excision repair gene expression in childhood acute lymphocytic leukemia is a predictor of early relapse
Authors: Ibrahim Omar , As Sobeai Homood , Grant Stephen G. , Latimer Jean J. 
Published: July 2016

Abstract
Double strand break repair and its relationship with genomic instability have been well studied in Acute Lymphocytic Leukemia (ALL). In contrast, base repair mechanisms, such as Nucleotide Excision Repair (NER) have not been well characterized in ALL. The NER pathway addresses base damage resulting in helix distortion and replication stalling, making it important for all types of cancer. Since increased NER is a known mechanism of chemotherapeutic drug resistance, we hypothesize that there will be an increase in the expression of the NER genes at the time of relapse in ALL patients. We have studied the role of NER in ALL by secondary analysis of 2 independent gene expression microarray studies performed by Staal et al. (Set A, GSE18497) and Hogan et al. (Set B, GSE28460). Both studies analyzed matched samples of ALL patients at diagnosis and relapse (41 and 49 pairs, respectively). In Set A we found that 17/20 NER genes have higher expression at the time of relapse, than at the time of diagnosis. 4 of these genes were individually significant. However, in a subset analysis of these data sets, based on the time to relapse, patients who have early (&lt;3 years) vs. late (&gt;3 years) relapse gave distinct results. In Set A, 18/20 NER genes were upregulated at the time of diagnosis in the early relapse group vs. the late relapse group. 4 genes were individually significantly increased. In set B, NER gene expression at the time of diagnosis of patients in the early relapse group was increased in all 20 NER genes when compared to the late relapse group. 7 genes showed individually significant increases in expression. In addition patients in the late relapse group showed an increase in expression of many of the NER genes at time of relapse when compared to time of diagnosis. In conclusion, there are two types of ALL. Early relapsing ALL manifests high NER gene expression at diagnosis with little change at relapse. Late relapsing ALL manifests low NER gene expression at diagnosis with substantial increase at the time of relapse. NER gene expression at the time of diagnosis may allow us to predict which patients are at greatest risk for earlier relapse. This will allow pharmacogenomic targeting of each type of ALL.
Citation Format: Omar Ibrahim, Homood As Sobeai, Stephen G. Grant, Jean J. Latimer. Nucleotide excision repair gene expression in childhood acute lymphocytic leukemia is a predictor of early relapse. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1552.
Abstract 1557: Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic TAMs
Authors: Rabe Daniel C. , Frankenberger Casey , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Becker Lev , Rosner Marsha R. 
Published: July 2016

Abstract
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. While physiological inhibitors of metastasis (metastasis suppressors) play key roles in regulating tumor growth, invasion and metastasis, their role in regulating the tumor microenvironment and immune system is unknown. We hypothesized that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) regulates stromal cells, which then affect tumor invasiveness.
Using species-specific RNAseq we determined that expression of RKIP in tumors markedly reduces the number and metastatic potential of infiltrating TAMs. While TAMs isolated from TNBC xenografts drive in vitro invasion, RKIP+ derived TAMs did not drive invasion and had decreased secretion of pro-metastatic factors including SLPI, OPN, MMP-12, Galectin-3, VEGF-A, VEGF-D, TNFR2, and PGRN. We determined that RKIP regulates TAM recruitment by blocking HMGA2, which activates CCL5 expression. CCL5 rescued pro-metastatic TAM infiltration as well as tumor intravasation. We additionally showed that factors decreased in RKIP-derived TAMs were restored in CCL5-derived TAMs. CCL5 derived TAMs were also able to promote metastasis when co-injected with MDA-MB-231 tumors. These tumor cells demonstrated permanent increases in both growth and invasive potential after co-injection with highly pro-metastatic CCL5 derived TAMs.
To determine the clinical utility of these TAM genes we combined their expression with RKIP signaling in the tumor to create a signature that strikingly separates TNBC patients based on outcome. Our results demonstrate for the first time that metastasis suppressors can regulate the microenvironment, regulating invasion through TAMs. Our results also suggest aggressive triple negative breast cancers could be controlled by attacking CCL5 derived TAMs crucial for promoting metastasis.
Funded by: GM087630, CA184494, and CA192780
Citation Format: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Lev Becker, Marsha R. Rosner. Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic TAMs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1557.
Abstract 1562: miRNAs in exosomes from prostate cancer cells modify normal fibroblasts and osteoblasts favoring tumor spread and metastasis
Authors: Andahur Eliana , Castellon Enrique A. , Ramos Chistian , Fulla Juan A. , Sanchez Catherine A. 
Published: July 2016

Abstract
Introduction: Exosomes from bulk and cancer stem cells (CSCs) from prostate cancer primary cultures present a differential pattern of miRNAs. The most abundant miRNA in all exosomes is miR-100, while miR-21 and miR-139 were the most abundant differentially expressed miRNAs in bulk and CSCs exosomes, respectively. Bioinformatics analysis suggested that these miRNAs were related with tumor progression. The functional effect of these miRNAs on targets related with changes at primary and pre-metastatic microenvironment was evaluated in prostatic stromal cells and osteoblasts.
Methods: Normal human undifferentiated osteoblasts (hFOB1.19) and prostate fibroblasts (WPMY-1) cell lines were transfected, by separated, with 25 nM of the following miRNas: miR-100-5p, miR-21-5p, miR-139-5p. let7c was included as transfection control. After 48 hours, changes in the expression of metalloproteinases (MMP)-2, -9 and-13, RANKL, OPG and IL-8 at mRNAs and protein levels were evaluated by qPCR and western blot, respectively. As transfection control, expression of specific targets previously described for each miRNA was evaluated. Besides, the effect of miRNAs in fibroblast migration was evaluated by transwell assay.
Results: In fibroblasts, transfection with miR-21, -100 and -139 increased significantly expression of RANKL, IL8 and all MMPs, with a higher effect in MMP-9. Besides, miR-21 increased fibroblast migration. In osteoblasts, transfection with miRNAs changed the balance that triggers vicious circle at the bone, increasing RANKL and diminishing OPG expression. miRNAs also increased MMPs expression. The greater effect was observed with miR-21 transfection.
Conclusions: Through exosomes, prostate cancer cells recruit normal cells to favor their growth and spread. miRNAs in exosomes increase expression of proteins (in particular, MMPs and RANKL) and cell migration of fibroblasts that create a favorable microenvironment for tumor progression at the primary niche. Besides, through bloodstream, tumoral exosomes can reach the bone, preparing the premetastatic niche. miRNAs from these exosomes change the balance RANKL/OPG that triggers osteoclast recruitment facilitating metastases by activation of the bone vicious circle. miR-21, overexpressed in bulk cells, the main cellular component of tumor, has the higher effect in modify microenvironment, being a potential therapeutic target. (FONDECYT 11121525 and 1140417).
Citation Format: Eliana Andahur, Enrique A. Castellon, Chistian Ramos, Juan A. Fulla, Catherine A. Sanchez. miRNAs in exosomes from prostate cancer cells modify normal fibroblasts and osteoblasts favoring tumor spread and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1562.
Abstract 1567: Prostate cancer-derived exosomes alter the metabolic microenvironment of bone marrow pre-metastatic niche through PKM2 to promote bone metastasis
Authors: Dai Jinlu , Lu Yi , Zhang Jian , Keller Evan 
Published: July 2016

Abstract
Tumor-derived exosomes are emerging mediators of tumor progression. We explored the role of prostate cancer (PCa)-derived exosomes (Ex) in PCa bone metastasis. Systemic pre-treatment of mice with PCa-Ex increased PCa tumor growth in bone, this was associated with increased early PCa cell seeding into the bone marrow. PCa-Ex had no direct impact on PCa growth or invasive ability in vitro; whereas, conditioned-media (CM) from PCa-Ex-treated stromal cells increased PCa cell growth, invasion and epithelial mesenchymal transition (EMT). PCa-Ex preferentially targeted bone marrow versus lung or liver stroma when injected IV. Proteomic analysis of PCa-Ex-treated cells revealed that PCa-Ex increased pyruvate kinase M2 (PKM2) protein expression in both ST2 stromal cells and primary bone marrow stromal cells, although PKM2 mRNA expression was not altered. PKM2 protein expression correlated with aggressiveness of PCa cell lines and was highest in serum of PCa patients with metastases compared to those with primary tumors. PCa-Ex induced both autophagy and β-hydroxybutarate (BHB) production from stromal cells. Knockdown of PKM2 in PCa cells resulted in production of PCa-Ex with low PKM2. The low PKM2 PCa-Ex had diminished ability to induce PCa cell growth, autophagy and BHB production. IV PCa-Ex and orthotopic tumors increased bone marrow BHB levels. PCa-Ex treatment of stromal cells induced the CM to (1) increase in oxygen consumption rate (OCR) by 80%; (2) extracellular acidification rate (ECAR) by 25%; and (3) increase ATP production in PCa cells. BHB induced OCR, but not ECAR in a dose responsive fashion. BHB administration induced a dose-responsive increase in intratibial tumor growth in mice. Our experiments indicate that primary tumor PCa-Ex can target the bone marrow microenvironment and educate stromal cells to promote PCa progression through increasing PKM2 expression in stromal cells resulting in ketone production that supports metastatic growth. Overall this demonstrates that primary tumor exosomes modulate the metabolic status of the distant pre-metastatic niche to promote metastasis.
Citation Format: Jinlu Dai, Yi Lu, Jian Zhang, Evan Keller. Prostate cancer-derived exosomes alter the metabolic microenvironment of bone marrow pre-metastatic niche through PKM2 to promote bone metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1567.