bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4051: Prion protein and its ligand STI1/HOP modulate migration and invasion of cell lines derived from colorectal tumors
Authors: Lacerda Tonielli S. , Dias Marcos Vinicios S. , Baptistella Antuani Rafael , Giudice Fernanda S. , Roz Bruna R. , Rodrigues Iara S. , Martins Vilma Regina 
Published: May 2015

Abstract
The colorectal cancer is the fourth most common type of cancer in the world. The search for potential molecular targets for therapy has led to the Cellular Prion Protein (PrPC) as a possible candidate. Its activity depends on the interaction with the secreted form of the stress inducible protein 1 or heat shock organizing protein (STI1/HOP). Previous results indicated the importance of the PrPC-STI1/HOP complex in proliferation of glioblastomas and invasion of melanomas. Therefore, this work aims to understand how PrPC-STI1/HOP complex can influence the migration and invasion of WiDr and HCT8 colorectal tumor cells. PrPC is equally expressed at the cell surface of both cell lines. Cell migration assays were performed using boyden chambers and recombinant STI1/HOP as chemical attractant. For invasion experiments cells were seeded on boyden chambers covered with matrigel and treated with STI1/HOP. The results showed that when stimulated with recombinant STI1/HOP, both tumor cell lines showed higher migration and invasion potentials than non-treated cells or those treated with a STI1/HOP deletion mutant for the PrPC binding domain (STI1Δ230-245). Moreover, migration and invasion mediated by PrPC-STI1/HOP complex were blocked by a STI-1/HOP (230-245) peptide, which mimics STI1 binding site to PrPC or also by a neutralizing anti-PrPC antibody. STI1/HOP is secreted in the conditioned medium (CM) within extracellular microvesicles (MVs) and WiDr cells secreted more MVs and STI1/HOP than HCT8 cells. Remarkable, HCT8 cells treated with CM or isolated MVs from WiDr cells show a higher migration than that induced when the former cells were treated with their own CM or when WiDr cells were treated with CM or MVs derived from HCT8 cells. Together, these results indicate that the PrPC-STI1/HOP complex mediate migration and invasion of colorectal tumor cells and suggest that cellular migration is dependent on the concentration of secreted MVs. The role of STI1/HOP present in MVs on cell migration is still under investigation.
Citation Format: Tonielli S. Lacerda, Marcos Vinicios S. Dias, Antuani Rafael Baptistella, Fernanda S. Giudice, Bruna R. Roz, Iara S. Rodrigues, Vilma Regina Martins. Prion protein and its ligand STI1/HOP modulate migration and invasion of cell lines derived from colorectal tumors. [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 4051. doi:10.1158/1538-7445.AM2014-4051
Abstract 4052: Targeting PDK1 in breast cancer: kinase-dependent regulation of tumor growth and kinase-independent regulation of cell migration and invasion
Authors: Gagliardi Paolo Armando , Blasio Laura di , Seano Giorgio , Sessa Roberto , Puliafito Alberto , Bussolino Federico , Primo Luca 
Published: May 2015

Abstract
3-Phosphoinositide Dependent Kinase 1 (PDK1) is the kinase that phosphorylates the activation loop of several protein kinases such as Akt, PKC or SGK. In breast carcinomas PDK1 was found frequently overexpressed and this correlates with a more aggressive phenotype.
This study is aimed to understand the role of PDK1 in breast tumor progression and the molecular mechanisms involved.
Using stable gene silencing and kinase inhibitors, we studied PDK1 role in different in vitro and in vivo assays including anchorage independent growth, anoikis, xenografts, migration and invasion assays.
In our study we found that PDK1 promotes resistance to anoikis, anchorage independent growth and tumor growth in breast cancer cell lines through the phosphorylation of its substrates, since the kinase-dead mutant abrogates all the PDK1-mediated effects. For this reasons either PDK1 gene silencing or its kinase inhibition with small compounds are sufficient to promote anoikis, to reduce anchorage independent growth and tumor growth.
We also found that PDK1 silencing is able to reduce, while its overexpression to increase, cell migration and invasion in mammary cells. Surprisingly, the regulation of cell migration is operated in a kinase independent manner. In fact PDK1 kinase inhibitor failed to recapitulate the effects of gene silencing in cell migration. The molecular mechanism, underlying this unconventional kinase-independent regulation of cell migration, involves the binding of PDK1 to Myotonic Dystrophy kinase-related Cdc42-binding Kinase α (MRCKα). This binding increases MRCKα kinase activity on Myosin Light Chain-2 (MLC2) and on myosin phosphatase target subunit 1 (MyPT1). Both these phosphorylations increase of non-muscular myosin activity, which is required to pull forward the cell body during directional migration and invasion.
In summary, our findings unveil that PDK1 regulates tumor growth, survival in absence of adhesion, resistance to anoikis, but also migration and invasion of breast cancer cells by two different mechanisms. These findings should be taken in account for a rational targeting of PDK1 in cancer.
Citation Format: Paolo Armando Gagliardi, Laura di Blasio, Giorgio Seano, Roberto Sessa, Alberto Puliafito, Federico Bussolino, Luca Primo. Targeting PDK1 in breast cancer: kinase-dependent regulation of tumor growth and kinase-independent regulation of cell migration and invasion. [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 4052. doi:10.1158/1538-7445.AM2014-4052
Abstract 4058: Acid-sensing ion channel 1a (ASIC1a) contributes to cell proliferation and migration caused by acidic environment in human glioma cells
Authors: Liu Mingli , Guo Alyssa (Aihui) , Ghiathi Christopher , Xiong Zhigang 
Published: May 2015

Abstract
Due to an increased metabolic rate, an acidic environment is commonly observed in tumor tissues. The acidic environment likely has a significant impact on the viability and proliferation of tumor cells. Acid-sensing ion channel (ASIC)1a is the key proton receptor expressed in nervous systems, which regulates acidosis-induced neuronal injury in various neurological diseases, such as ischemic stroke. Glioblastomamultiforme (GBM) is the most common and aggressive primary brain tumor in adults with median survival time of 14.6 months. Since GBM are characterized by chronic hypoxia and poor perfusion that is likely to result in acidosis, acidosis may influence the growth behavior and response to cytotoxic therapy. In the present study, we examined the effects of acidosis on growth and migration of cultured human malignant glioma cells A172, and the role of ASIC1a in the cell death induced by extracellular acid. Methods: 1) We detected ASIC1a mRNA using reverse-transcription polymerase chain reaction (RT-PCR). 2) We then determined the presence of ASIC1a in A172 cells using electrophysiological recording (patch-clamp technique). 3) We assessed the effects of acidic environment on cell proliferation and maintenance of clonogenic capability using MTT assay and colony formation assay respectively. 4) Finally, we examined the effects of acidic environment on glioma cell migration by transwell invasion assay. Results: 1) RT-PCR detected the presence of ASIC1a and ASIC4 mRNA in A172 cells. 2) The inward current was recorded when treated with pH5.0 solution indicating the expression of functional ASIC1a in A172 cells. 3) Acidic environment decreased the number of surviving A172 cells, the colony formation, and also inhibited A172 cell migration. 4) Inhibition of ASIC currents by nonspecific inhibitor of ASICs amiloride or specific inhibitor PcTX1 protected A172 cell from death. Conclusions: Extracellular acid reduces proliferation and migration in glioma cells. Extracellular acid induces death of glioma cells via ASIC1a mechanisms. These results indicate the presence of ASIC1a in glioma cells and may play significant role in glioma progression. This work was supported by the National Institutes of Health grant numbers NIH R01NS047506, R01NS066027, UL1 RR025008, U54 RR026137, AHA 0840132N, and ALZ IIRG-10-173350.
Citation Format: Mingli Liu, Alyssa (Aihui) Guo, Christopher Ghiathi, Zhigang Xiong. Acid-sensing ion channel 1a (ASIC1a) contributes to cell proliferation and migration caused by acidic environment in human glioma cells. [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 4058. doi:10.1158/1538-7445.AM2014-4058
Abstract 4060: Androgen receptor is involved in the migration and invasion of triple-negative breast cancer cells
Authors: ZHENG Qiao-dan , Wu Wenyuan , Huang Cai 
Published: May 2015

Abstract
Triple-negative breast cancer(TNBC)is a major world health problem, accounting for more than 15% of breast cancer new cases each year. The 5-year survival rate for TNBC is approximately 54.5% and death usually occurs as a result of local invasion and regional metastases. A complete understanding of the molecular mechanisms that control the aggressive behavior of triple-negative breast cancer cells is essential in order to develop targeted therapies to manage the disease. Recent evidence has suggested a role of Androgen receptor (AR)in cellular motility and invasion. In this present study we examined the role of AR on the migration and invasion of triple-negative breast cancer cells. Detect the AR levels in 7 cell line of breast cancer cells including MCF-7, MDA-MB-157, MDA-MB-231, MDA-MB-435, MDA-MB-468, MDA-MB-549, HS-578T by Q-PCR, we demonstrate that AR is highly express in triple-negative breast cancer cells; shRNAs specific to AR have been generated and delivered into human breast cancer cells by lentiviral vectors. We showed that the total levels of AR can be decreased by AR shRNA and inhibit MDA-MB-231 cellular motility and large focal adhesion (FA) formation, the cell migration was determined by time-lapse cell migration assays, depletion of endogenous AR significantly reduced the velocity and directionality of cell migration, and strongly inhibited the net distance of cell migration, indicating that AR modulates cell migration by controlling the velocity and directionality of migration. We also showed that AR activation and the migration and invasion of MDA-MB-231 , MDA-MB-435, MDA-MB-468 can be strongly inhibited with commercially available AR blocker Bicalutamide by cell migration and invasion assay. These results suggest that AR in breast cancer cells is required for cellular migration and invasion.
Citation Format: Qiao-dan ZHENG, Wenyuan Wu, Cai Huang. Androgen receptor is involved in the migration and invasion of triple-negative breast cancer cells. [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 4060. doi:10.1158/1538-7445.AM2014-4060
Abstract 407: Targeted Hi-C and integrative analyses reveal functionality of colorectal cancer risk loci
Authors: Jäger Roland , Migliorini Gabriele , Henrion Marc , Whiffin Nicola , Broome Laura , Dryden Nicola , Nagano Takashi , Schoenfelder Stefan , Fraser Peter , Fletcher Olivia , Houlston Richard 
Published: May 2015

Abstract
Genetic risk factors identified by genome-wide association studies (GWAS) are thought to function through allele-specific regulation of gene expression. Long-range chromatin looping interactions, as revealed by chromosome conformation capture (3C)-based techniques, bring risk variants into spatial proximity with loci otherwise distal on the linear genome. Hi-C, using next generation sequencing (NGS), allows for genome-wide agnostic characterization of chromatin contacts, however, detection of functional enhancer-promoter interactions is precluded by its limited resolution. Here we apply Targeted Hi-C, a novel technique combining the unbiased coverage of Hi-C with target sequence capture to identify functional chromatin interactions for 15 colorectal cancer risk loci at high resolution. We depicted the CRC risk interactome as a set of generic highly significant genome-wide interactions, predominantly overlaying the strongest risk association signals. Integrative analyses involving profiles for epigenetic marks, evolutionary conservation and transcription factor binding, revealed regulatory function of long-range chromatin interactions. At the 8q24.21 risk locus, we could extend a previously reported contact between rs6983267 and the MYC promoter to a network of interactions involving CCAT1 (colorectal cancer associated transcript 1). At other risk loci, our data supports the central role of TERC, BMP4, GREM1, BMP2, SMAD7 and in CRC pathogenesis. Additionally, distal to the risk loci we identified contacts with the genes such as TRPS1, TPO, ETS1, VEZT and RAN, previously implicated in cancer and mutated in CRC. Our results demonstrate the capability of high resolution chromatin interaction analyses in conjunction with combinatorial integrative analyses to decipher disease risk loci.
Citation Format: Roland Jäger, Gabriele Migliorini, Marc Henrion, Nicola Whiffin, Laura Broome, Nicola Dryden, Takashi Nagano, Stefan Schoenfelder, Peter Fraser, Olivia Fletcher, Richard Houlston. Targeted Hi-C and integrative analyses reveal functionality of colorectal cancer risk loci. [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 407. doi:10.1158/1538-7445.AM2014-407
Abstract 4071: SAH-p53-mediated inhibition of cell migration via alteration of actin dynamics
Authors: Morrison Bethanie L. , Whiting Amanda L. , Bernal Federico 
Published: May 2015

Abstract
The mutation of p53 is critical for the increased metastatic potential of cancer cells. As such, it is essential not only to understand the mechanisms underlying the functional implications of p53 mutation, but also to identify ways to regulate their impact on cancer cell physiology. I have found that a hydrocarbon-stapled p53 transactivation domain peptide (SAH-p53) designed to disrupt the interaction of p53 with its negative regulators HDM2 and HDMX retains its function in cells harboring a mutant TP53. A common gain-of-function activity of the mutant p53 protein (mtp53) is the enhancement of cell migration and invasion; however, I found that SAH-p53 has the ability to inhibit the migration and invasion of HS578T and MDA-MB-231 breast cancer cells (mtp53), while exhibiting no change in proliferative ability at the same dose. This effect was accompanied by sustained alterations in actin stress fiber dynamics and inhibition of focal adhesion assembly and signaling. Furthermore, treatment of MDA-MB-231 cells with various growth factors (EGF, TGF-β, PDGF, HGF) was unable to rescue the migratory ability of cells in the presence of SAH-p53. The combination of SAH-p53 and TGF-β resulted in a decrease in the total expression levels of both EGFR and FAK. Moreover, it was shown that the combined treatment of SAH-p53 and TGF-β enhanced the localization of EGFR to early endosomes and eventually to lysosomes, prompting the use of fluorophore-capped SAH-p53 to track the localization of the peptide in relation to EGFR. It was determined that over time SAH-53 localizes to vesicles containing EGFR, but not other RTKs (ie. PDGFRβ). SAH-p53 was able to retain its ability to inhibit migration in the absence of functional HDMX/HDM2 or mutant p53, suggesting the possibility of an alternative target. We are currently using a photoactivatable and capped SAH-p53 that can cross-link to a target protein in the presence of UV in order to determine the identity of the target of SAH-p53 responsible for the anti-migratory effects seen in mutant p53- or p53-null cells. These data show that the use of a stapled peptide provides a novel avenue to study the molecular interactions that drive metastatic behavior in cancer cells.
Citation Format: Bethanie L. Morrison, Amanda L. Whiting, Federico Bernal. SAH-p53-mediated inhibition of cell migration via alteration of actin dynamics. [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 4071. doi:10.1158/1538-7445.AM2014-4071
Abstract 408: The relationship between LINE-1 hypomethylation and fibrosis status in noncancerous liver tissues of hepatocellular carcinoma patients
Authors: Baba Yoshifumi , Harada Kazuto , Kosumi Keisuke , Hayashi Hiromitsu , Nitta Hidetoshi , Hashimoto Daisuke , Chikamoto Akira , Beppu Toru , Baba Hideo 
Published: May 2015

Abstract
Background: The DNA methylation alterations that occur in human cancers include global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Global DNA hypomethylation plays an important role in genomic instability, leading to cancer development. Since LINE-1 or the L1 retrotransposon constitutes a substantial portion of the human genome, LINE-1 methylation status reflects global DNA methylation. Our previous study has revealed that LINE-1 methylation level is a potential surrogate marker for epigenetic field defects induced by tobacco smoking in esophageal cancer patients. Given that liver fibrosis can be one phenomena of field cancerization theory in hepatocellular carcinoma (HCC), we examined the relationship between LINE-1 methylation level and fibrosis status in noncancerous liver tissues of HCC patients.
Methods: Using histologically normal liver tissue samples and matched tumor tissue samples from 89 HCC cases, we measured LINE-1 methylation levels by pyrosequencing technology.
Results: LINE-1 methylation of noncancerous liver tissues range was 35.8-97.3 of a 0-100 scale (mean: 78.1; median: 81.0; standard deviation: 11.9). HCC tissues showed significantly lower levels of LINE-1 methylation than matched normal tissue (P&lt;0.01). LINE-1 methylation of noncancerous liver tissues was not associated with age, sex, Hepatitis B Virus infection, or Hepatitis C Virus infection. Interestingly, LINE-1 methylation level of noncancerous liver tissues with severe fibrosis (score 2-4) was significantly lower than that with mild fibrosis (score 0-1) (P=0.013).
Conclusion: Liver fibrosis in noncancerous liver tissues of HCC patients was significantly associated with LINE-1 hypomethylation. This result supports the potential of LINE-1 methylation level as an indicator of epigenetic field for HCC cancerization.
Citation Format: Yoshifumi Baba, Kazuto Harada, Keisuke Kosumi, Hiromitsu Hayashi, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba. The relationship between LINE-1 hypomethylation and fibrosis status in noncancerous liver tissues of hepatocellular carcinoma patients. [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 408. doi:10.1158/1538-7445.AM2014-408
Abstract 4089: Histone deacetylase 6 (HDAC6) as a regulator of PD-L1 expression through STAT3 modulation in melanoma
Authors: Lienlaf Maritza , Perez-Villarroel Patricio , Lee Calvin , Cheng Fengdong , Canales Jorge , Knox Tessa , Marante Danay , Sarnaik Amod , Horna Pedro , Seto Ed. , Smalley Keiran , Weber Jeffrey S. , Sotomayor Eduardo M. , Villagra Alejandro 
Published: May 2015

Abstract
In spite of the progress made in the understanding of the cell biology, genetics and immunology of melanoma, the outcome for patients with advanced-stage disease has remained poor with a median survival ranging from 2-16 months. Some optimism was recently provided in metastatic melanoma by the improved clinical outcomes observed in patients receiving PD-L1 blocking antibodies. A better understanding of the environmental, genetic and epigenetic factors limiting the efficacy of melanoma immunotherapy will provide appropriate partner(s) for combination with Ipilimumab or PD1/PDL1 antibodies. Among the epigenetic factors, we have found that one member of the histone deacetylase family, HDAC6, plays a critical role not only in the regulation of survival/apoptosis of melanoma cells but also in limiting their immunogenicity and recognition by immune effector cells. Particularly, we found a major role of HDAC6 as a modulator of the immunosuppresive STAT3/IL-10 pathway and down-regulation of tolerogenic PD-L1 molecules in melanoma cells. By analyzing HDAC6 knock-down melanoma cell lines (HDAC6KD) we demonstrated the inactivation of the STAT3 pathway and the subsequent down-regulation of its target genes, including the expression of PD-L1. We also observed that the PD-L1 expression and phosphorylation of STAT3 was decreased in melanoma isolated from xenograph tumor growth models after in vivo treatment with specific HDAC6 inhibitors
Fortunately, there are multiple HDAC6-selective inhibitors available to mechanistically study the role of HDAC6 on these processes and provide a viable therapeutic avenue, which may minimize undesirable side effects that are characteristic of pan-HDACi such as SAHA. By building on our understanding of HDAC6 and applying these findings to novel experimental design, we hope to identify innovative therapeutic options to benefit cancer patients.
Citation Format: Maritza Lienlaf, Patricio Perez-Villarroel, Calvin Lee, Fengdong Cheng, Jorge Canales, Tessa Knox, Danay Marante, Amod Sarnaik, Pedro Horna, Ed. Seto, Keiran Smalley, Jeffrey S. Weber, Eduardo M. Sotomayor, Alejandro Villagra. Histone deacetylase 6 (HDAC6) as a regulator of PD-L1 expression through STAT3 modulation in melanoma. [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 4089. doi:10.1158/1538-7445.AM2014-4089