bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1888: Protein kinase C beta II suppresses colorectal cancer by regulating IGF1 mediated cell survival
Authors: Dowling Catriona M. , Phelan James , Callender Julia A. , Cathcart Mary Clare , Mehigan Brian , McCormick Paul , Dalton Tara , Coffey John C. , Newton Alexandra C. , O’Sullivan Jacintha , Kiely Patrick A. 
Published: July 2016

Abstract
Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II in an IGF-1 dependent manor showed a downregulation of AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome.
Citation Format: Catriona M. Dowling, James Phelan, Julia A. Callender, Mary Clare Cathcart, Brian Mehigan, Paul McCormick, Tara Dalton, John C. Coffey, Alexandra C. Newton, Jacintha O’Sullivan, Patrick A. Kiely. Protein kinase C beta II suppresses colorectal cancer by regulating IGF1 mediated cell survival. [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 1888.
Abstract 190: Mechanism of CDKN3 overexpression in cancer
Authors: Fan Chao , Chen Lu , Huang Qingling , Shen Tao , Welsh Eric A. , Teer Jamie K. , Cress W Douglas , Wu Jie 
Published: July 2016

Abstract
The cyclin-dependent kinase inhibitor 3 (CDKN3) is a dual specificity protein tyrosine phosphatase (PTP) known to dephosphorylate CDK1/2 on the activating Thr-161/Thr-160. Paradoxically, CDKN3 mRNA is often overexpressed in human cancer. It was reported that CDKN3 overexpression may be associated with splicing variants or mutations that produce dominant-negative CDKN3. We found that CDKN3 is overexpressed in non-small cell lung cancer (NSCLC) and that CDKN3 overexpression is prognostic of poor overall survival in three cohorts of lung adenocarcinoma. We next analyzed CDKN3 transcripts in a panel of 24 cell lines and lung adenocarcinoma tissues and also examined CDKN3 mutations in the Cancer Genome Atlas (TCGA) and the Moffitt Cancer Center's Total Cancer Care® (TCC) projects. Two CDKN3 transcripts were detected in all samples. These CDKN3 transcripts represent the full length CDKN3 mRNA and a normal transcript lacking exon 2, which encodes an out of frame 23-amino acid peptide with little homology to CDKN3. CDKN3 mutations were very rare and no disruptive mutation was found. Significantly, in synchronized cell cultures, CDKN3 mRNA and protein were elevated during the mitosis phase of cell cycle. Furthermore, CDKN3 expression had the highest correlation with mitotic-associated genes in lung adenocarcinoma tissues. Knocking down of CDKN3 prolonged the mitotic phase of cell cycle. Thus, CDKN3 overexpression in lung adenocarcinoma is not attributed to alternative splicing or mutation but is due to increased mitotic activity. Our data also suggest that CDKN3 is important for mitotic exit.
Citation Format: Chao Fan, Lu Chen, Qingling Huang, Tao Shen, Eric A. Welsh, Jamie K. Teer, W Douglas Cress, Jie Wu. Mechanism of CDKN3 overexpression in 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 190.
Abstract 1901: Leptin modulation of PCSC, HDAC, and microRNA in pancreatic adenocarcinoma
Authors: Tchio Cynthia M. , Harbuzariu Adriana , Harmon Tia , Beech Derrick , Gonzalez-Perez Ruben 
Published: July 2016

Abstract
Background: Obesity is an important risk factor of Pancreatic Adenocarcinoma (PA) and it is characterized by the accumulation of excessive body fat and a Body Mass Index (BMI) value greater than 30. Obesity is also characterized by high levels of leptin, which has been consistently associated with the development of many different cancer including PA. Leptin can induce the proliferation of Pancreatic Cancer Stem Cells (PCSC), which are responsible for chemoresistance, invasiveness and reoccurrence of PA. PCSC express specific cell markers and can form tumorspheres in vitro. Obesity can alter the DNA acetylation and microRNA activity which are also linked to PA progression. We hypothesized that high level of leptin could modulate Histone Deacetylase (HDAC) and microRNA activity in PA cells, which induce PCSC changes and tumor progression.
Methods: The PA cell lines were cultured in mammocult media that contained heparin and hydrocortisone, which will allow the proliferation of tumorspheres enriched with PCSCs. The cells were cultured with leptin, chemotherapeutic drug, and leptin signaling inhibitor IONP-LPrA2. Tumorspheres formation (number and size) was determined after 1 week of treatment. Additionally, the levels of PCSC markers, HDAC1, HDAC2, HDAC3, and HDAC8 in tumorspheres were determined using flow cytometry, western blot, and RT-PCR. In addition, the effects of treatments on miR21 and miR200a/c levels were determined using RT-PCR.
Results: Leptin induced PA tumorspheres formation and size, which was accompanied by higher level of PCSC markers (CD24, CD44, ESA, and ALDH1). Moreover, leptin affected the level of HDACs, miR21 and miR200a/c in PA tumorspheres. IONP-LPrA2 abrogated leptin effects and decreased PCSC which were spared by chemotherapeutics.
Conclusion: Obesity signals via leptin could be involved in the increase PA aggressiveness and chemoresistance, which may be linked to the increase of PCSC. Leptin could induce PA progression and chemoresistance via modulation of HDAC and miRNA.
Acknowledgement: This work was supported by the DOD W81XWH-13-1-0382; NIH/SBIR1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP; Calvin Johnson Jr. Foundation Pancreatic Cancer Research Scholarship to CITM, and facility and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR03034 and 1C06 RR18386).
Citation Format: Cynthia M. Tchio, Adriana Harbuzariu, Tia Harmon, Derrick Beech, Ruben Gonzalez-Perez. Leptin modulation of PCSC, HDAC, and microRNA in pancreatic adenocarcinoma. [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 1901.
Abstract 1904: MiR641 regulates EMT, ovarian cancer stem cell and angiogenesis by targeting p63/miR200 axis
Authors: Li Yajuan , Richards Edward , Coppola Mark , Xu Cheng-Xiong , Cheng Jin Q. 
Published: July 2016

Abstract
MiR641 is an uncharacterized miRNA which locates intron 1 of AKT2, a gene residing in the chromosome 19q13.2 amplicon and frequently amplified/overexpressed in refractory ovarian cancer. Here, we demonstrated that frequent upregulation of miR641 was observed in human ovarian cancer tissues and in ovarian cancer cell lines. Knockdown of miR641 inhibited cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) as well as angiogenesis and ovarian cancer stem cell growth. Enforced expression of miR641 had opposite effect. In addition, ectopic expression of miR641 promoted VEGF protein expression and secretion but had no effect on VEGF mRNA level. Mechanistically, we found that miR641 directly targeted the 3’UTR of p63 and reduced p63 expression, which leads to a decrease of miR200a/b. As a result, ZEB1 and VEGF, two validated targets of miR200, were upregulated by miR641 overexpression. Furthermore, expression of miR641 induced anchorage-independent growth. Taken together, these findings suggest that miR641 is an onco-miRNA and plays a pivotal role in ovarian oncogenesis.
Citation Format: Yajuan Li, Edward Richards, Mark Coppola, Cheng-Xiong Xu, Jin Q. Cheng. MiR641 regulates EMT, ovarian cancer stem cell and angiogenesis by targeting p63/miR200 axis. [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 1904.
Abstract 1911: ΔNp63α promotes TGFβ-induced metastasis by silencing a microRNA network restraining wound healing
Authors: Rodriguez Calleja Lidia , Jacques camille , Lamoureux Francois , Baud’huin Marc , Quillard Thibault , Verrecchia Franck , Heymann Dominique , Ellisen Leif , Ory Benjamin 
Published: July 2016

Abstract
Primary cancer cell dissemination is the key event in metastasis, yet context-specific determinants remain largely undefined. Multiple reports have suggested an anti-metastatic role for the p53 family member p63 linked to its minor epithelial isoform, TAp63. However, the role and contribution of the major p63 isoform, ΔNp63α, remain largely undefined. Here we report a distinct and TAp63-independent mechanism in which ΔNp63α-expressing cells, in a TGFβ-rich microenvironment, are positively selected for metastatic dissemination. We define the molecular mechanism of this effect, through ΔNp63α-mediated repression of miR-527 and miR-665 and the subsequent upregulation of two TGFβ pathway major effectors, SMAD4 and TβRII. Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound healing response. We show that ΔNp63α and miR-527/665 control the TGFβ-dependent signaling that switches off anti-migratory miR-198 by downregulating the regulatory factor KSRP. Collectively, these findings reveal a novel microRNA network orchestrated selectively by ΔNp63α that is involved in the physiological regulation of wound healing but is hijacked by tumors to promote metastatic dissemination.
Citation Format: Lidia Rodriguez Calleja, camille Jacques, Francois Lamoureux, Marc Baud’huin, Thibault Quillard, Franck Verrecchia, Dominique Heymann, Leif Ellisen, Benjamin Ory. ΔNp63α promotes TGFβ-induced metastasis by silencing a microRNA network restraining wound healing. [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 1911.
Abstract 1912: Combinatorial targeting of PI3K and MAPK signaling pathways using microRNAs to inhibit tumor growth and metastasis in breast cancer
Authors: Mutlu Merve , Saatci Ozge , Eyupoglu Erol , Raza Umar , Sahin Ozgur 
Published: July 2016

Abstract
PI3K/Akt and MAPK signaling pathways, regulating cancer cell proliferation, apoptosis and metastasis, are among the top most deregulated pathways in cancer. Current kinase inhibitors used in clinics have limited success since one of these pathways gets activated when the other is suppressed. Alternatively, simultaneous silencing of both pathways results in high toxicity. Here, we aimed to establish a microRNA-based, non-toxic approach to inhibit these pathways simultaneously in breast cancer. By analyzing our previously published Reverse Phase Protein Array (RPPA) data showing differential expression of 26 proteins upon overexpression of 733 different miRNAs, we selected top miRNAs significantly deregulating PI3K and MAPK pathways as well as cell cycle. We narrowed down the list by selecting miRNAs whose predicted targets were among the PI3K and MAPK pathway elements. We came up with a tumor suppressor miRNA affecting both in vitro viability and migration/invasion of breast cancer cells. We identified the set of differentially expressed genes in breast cancer patients under low and high expression of the miRNA. A significant association was observed between the expression of the miRNA or its identified gene signature and clinico-pathological properties of breast cancer patients. Combinatorial knockdown of targets of the miRNA that are in PI3K and MAPK pathways as a cocktail phenocopied the tumor suppressive effects of the miRNA in breast cancer cell lines. Notably, low expression of the target cocktail predicts a better outcome in breast cancer patients. Overall, we identified a tumor suppressor miRNA to be used an alternative to current kinase inhibitor-based therapies for major subtypes of breast cancer by suppressing both PI3K and MAPK pathways and as a result inhibiting proliferation and migration/invasion in breast cancer.
Citation Format: Merve Mutlu, Ozge Saatci, Erol Eyupoglu, Umar Raza, Ozgur Sahin. Combinatorial targeting of PI3K and MAPK signaling pathways using microRNAs to inhibit tumor growth and metastasis in breast 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 1912.
Abstract 1919: Nitric oxide stimulates expression of miRNA-155 through the BRCA1-dependent pathway
Authors: Hawley Justin , Yakovlev Vasily A. 
Published: July 2016

Abstract
Previously we demonstrated that nitric oxide (NO), generated in macrophages or released from the NO-donors, inhibits expression of the breast cancer type 1 susceptibility protein (BRCA1) in the different cell lines (Yakovlev, Cancer Res., 2013). BRCA1 protein contributes to cell viability in multiple ways, including homologous recombination repair (HRR) of DNA double-stand breaks (DSBs), cell-cycle checkpoint control, mitotic spindle assembly, and regulation of chromosome segregation. In addition BRCA1 protein (in association with histone deacetylase 2) epigenetically suppresses oncogenic microRNA-155 (miR-155) expression (Chang, Nature Med., 2011). miR-155 is an established multifunctional oncomiR, which regulates many pro-oncogenic pathways. miR-155 gene was found to be over expressed in several solid tumors, such as thyroid carcinoma, breast cancer, colon cancer, cervical cancer, pancreatic ductal adenocarcinoma, and lung cancer, where it is considered to be a marker of poor prognosis.
We hypothesized that overproduction of NO can stimulate expression of miR-155 through the BRCA1-dependent pathway. A-549 (lung cancer) and MCF-10A (normal breast epithelial) cell lines were incubated with different concentrations of NO-donor DETA NONOate (0 - 300μM). After 24 or 48 hours of incubation cells were analyzed for the BRCA1 and miR-155 expression. Both cell lines demonstrated significant dose- and time-dependent downregulation of BRCA1 expression along with significant stimulation of miR-155 expression. Cell lines infected with adenovirus vector expressing the wild type BRCA1 abolished stimulation of miR-155 in response to NO-donor treatment, compared with the cell lines infected with an empty adenovirus vector.
To analyze the effect of NO-dependent stimulation of miR-155 expression, we measured the protein levels of miR-155 targets: DNA mismatch repair (MMR) proteins - MSH2, MSH6, MLH1; SH-2 containing inositol 5’-polyphosphatase 1 (SHIP1); and suppressor of cytokine signaling 1 (SOCS1). Western blot demonstrated time- and dose-dependent amount decrease for all targeted proteins with the one exception: expression level of SHIP1 protein in A-549 cell line was undetectable even in the non-treated control.
In future studies we will investigate the role of NO-BRCA1-miR-155 pathway on the MMR capacity and stimulation of microsatellite instability.
Citation Format: Justin Hawley, Vasily A. Yakovlev. Nitric oxide stimulates expression of miRNA-155 through the BRCA1-dependent pathway. [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 1919.
Abstract 1920: miR-211 directly targets pyruvate dehydrogenase kinase 4 to inhibit cellular growth and glucose metabolism in triple negative breast cancer
Authors: Guda Maheedhara R. , Asuthkar Swapna , Das Soumen , Seal Sudipta , Tsung Andrew J. , Velpula Kiran K. 
Published: July 2016

Abstract
Deregulated metabolism and aerobic glycolysis are common to many kinds of tumors including, breast cancers driven by a plethora of transcription factors. One such is hypoxia-inducible factor-1α (HIF-1α) known to drive the expression of glycolytic target genes. Here, we identify
PDK4 (pyruvate dehydrogenase kinase 4) as a key regulator of HIF-1α signaling. In triple-negative human breast cancer (TNBC) cell lines, we investigated the contribution of PDK4 and HIF-1α to experimental tumor growth, core glucose metabolism and ionizing radiation effects. When these TNBC cells were exposed to 4, 6 and 8Gy treatment, we observed a linear increase in the expression levels of PDK4 and HIF-1α genes. In this study we also report that miR-211, a microRNA predicted to target PDK4 is suppressed in TNBC patient specimens as evidenced by in situ hybridization analysis. The expression levels of PDK4, HIF-1α and RICTOR were reduced with miR-211 over expression while the levels of PDH and FH were observed to be increased. Further, we observed that miR-211 conjugated to cerium oxide nanoparticles (nanoceria) showed increased cytotoxicity. Similar effects were observed when these TNBCs were treated with 5mM DCA, a potent metabolic inhibitor of PDK. Combinatory suppression of PDK4 and HIF-1α exerted synergistic inhibition of lactate released suggesting of reversal of aerobic glycolysis. Alternatively, TCGA datasets were predictive of patient survival, with a PDK4/miR-211 signature robustly predicting poor patient prognosis. Overall, our findings suggest that combined targeting of PDK4 signaling cascade with miR-211 and DCA in combination specifically regulate core glucose metabolism in TNBC.
Citation Format: Maheedhara R. Guda, Swapna Asuthkar, Soumen Das, Sudipta Seal, Andrew J. Tsung, Kiran K. Velpula. miR-211 directly targets pyruvate dehydrogenase kinase 4 to inhibit cellular growth and glucose metabolism in triple negative breast 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 1920.
Abstract 1926: Hippo pathway effectors YAP/TAZ integrate tissue mechanics and Wnt signaling to regulate microRNA biogenesis
Authors: Han Siyang , Nelson Celeste M. 
Published: July 2016

Abstract
Although mechanical cues including extracellular matrix (ECM) stiffness are known to regulate cell and tissue behavior, it remains unclear how these mechanical cues integrate with biochemical signals to control these processes. The Hippo pathway and its transcriptional coactivators YAP and TAZ, which have emerged as major regulators of organ size, proliferation and cancer development, are thought to be involved in this integration. In addition to being regulated by the canonical Hippo pathway, YAP/TAZ have been found to mediate responses to both biochemical and mechanical signals including ECM stiffness and Wnt signaling. Moreover, recent studies have shown that microRNAs (miRNAs) are sensitive to mechanical cues and YAP/TAZ may regulate miRNA biogenesis through mechanotransduction. Although misregulation of YAP/TAZ and miRNA expression are frequently observed in multiple cancers, which appears to be associated with the altered mechanics of the tumor microenvironment, the signaling mechanisms controlling these processes remain poorly understood and controversial. Here we examine how YAP/TAZ integrate biochemical and mechanical signals to regulate miRNA biogenesis. We found that Wnt3A and stiff ECM synergistically lead to nuclear accumulation and activation of YAP/TAZ. Surprisingly, ECM stiffness induces miRNA-18a expression while Wnt3A signaling has an opposite effect on miRNA-18a expression depending on the stiffness of the cellular microenvironment. Thus, YAP/TAZ activity may define a mechanism by which cells respond to ECM stiffness and Wnt signaling to control miRNA biogenesis.
Citation Format: Siyang Han, Celeste M. Nelson. Hippo pathway effectors YAP/TAZ integrate tissue mechanics and Wnt signaling to regulate microRNA biogenesis. [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 1926.
Abstract 1937: Dysregulation of lincRNAs is a major driver of aberrant epigenomes during tumorigenesis
Authors: Merry Callie R. , Forrest Megan E. , Markowitz Sanford , Khalil Ahmad M. 
Published: July 2016

Abstract
It has now been unequivocally demonstrated that the process of tumorigenesis is driven by both genetic and epigenetic alterations, but the mechanisms of epigenetic dysregulations remain to be elucidated. Work in our laboratory has demonstrated that numerous long intergenic non-coding RNAs (lincRNAs) become dysregulated in human cancers, and a significant subset of these lincRNAs are associated with histone-modifying enzymes and DNA methyltransferases in healthy, non-tumor cells. Based on these observations, we tested an exceptionally novel hypothesis that dysregulation of chromatin-associated lincRNAs is a major mechanism driving cancer-associated aberrant epigenomes. To test this novel concept, we have performed experiments to modulate the expression of specific chromatin-associated lincRNAs in cancer cells, and assessed their impact on the epigenome. Consistent with our hypothesis, modulating the expression of lincRNAs in cancer cells resulted in massive reprogramming of their epigenomes. These epigenomic changes impacted the growth of cancer cells and global gene expression. Mapping the genomic occupancy sites of lincRNAs, and intersection of those sites with altered genomic regions in tumors, further supported direct roles of lincRNAs in modulating chromatin structure. These findings demonstrate key roles of chromatin-associated lincRNAs in suppressing tumorigenesis in normal human tissues by regulating the epigenome.
Citation Format: Callie R. Merry, Megan E. Forrest, Sanford Markowitz, Ahmad M. Khalil. Dysregulation of lincRNAs is a major driver of aberrant epigenomes during tumorigenesis. [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 1937.