bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3740: Exergame development for cancer prevention and intervention
Authors: Ahabue Blessing , Pullen Paula , Ogbesor Afebuameh , Seffens William S. , Lillard James W.
Published: August 2015

The current study utilized smart and connected technologies to assist difficult to reach populations with healthy lifestyle intervention for cancer prevention. Lack of physical activities and high body mass index are important cancer risk factors. We tested the hypothesis that a low cost gaming platform could be used to supplement therapeutic regimes for life style changes to affect risk factors associated with cancer. Using a 3D room sensor built into the Microsoft Kinect, we analyzed qualitative and quantitative measures of Yoga and Tai Chi postures and dance routines with the Kinect sensor. Specifically, we used Kinect version 2.0 Software Development Kit to capture skeleton image streams composed of X, Y, Z coordinates at 20 frames per second. The instructors performed a series of 17 hatha yoga postures, including a variety of standing and supine positions, 12 Tai Chi motions, or performed traditional African-based dance routines. Inaccuracy of data capture was measured by the number of imputed joint positions in the skeleton stream using two-sample equal variance t-test, along with time-average measurements for the dance routines. The accuracy of skeleton capture for sampled yoga postures was heavily dependent on the yoga practitioner view orientation and the particular yoga posture. Frontal view orientation was slightly more accurate than perpendicular, but not significantly different. Standing poses were significantly more accurate than seated or supine body orientations. Instability of joint positions in the skeleton stream was more severe for seated poses as evidenced by large fluctuations between image frames that resulted in visible displacements of joints that were described as jitter. Tai Chi and African dance routines were significantly more accurate for full range of postures. Multiplayer modes in other exergames show positive effect with motivation and physical exertion. Implementation of multiplayer capacity will help to establish a culturally appropriate electronic cohort focused on cancer prevention. In conclusion, the skeleton movement tracking algorithms embedded in Kinect were not appropriate for body positions that significantly deviated far from upright postures. Future studies will evaluate Tai Chi and African dance as an Exergame for multiple players. This app will be designed by peers of targeted populations at risk for cancer, linking GIS neighborhood characteristics for longitudinal tracking across metropolitan Atlanta over time. Acknowledge partial support from G12MD007602, 8U54MD007588, and U54 CA118638.

Citation Format: Blessing Ahabue, Paula Pullen, Afebuameh Ogbesor, William S. Seffens, James W. Lillard. Exergame development for cancer prevention and intervention. [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 3740. doi:10.1158/1538-7445.AM2015-3740
Abstract 3756: Identification of prognostic gene signatures of glioblastoma: a study based on TCGA data analysis
Authors: Kim Yong-Wan
Published: August 2015

The Cancer Genome Atlas (TCGA) project is a large-scale effort with the goal of identifying novel molecular aberrations in glioblastoma (GBM). Here, we describe an in-depth analysis of gene expression data and copy number aberration (CNA) data to classify GBMs into prognostic groups to determine correlates of subtypes that may be biologically significant. To identify predictive survival models, we searched TCGA in 173 patients and identified 42 probe sets that could be used to divide the tumor samples into 3 groups and showed a significantly improved overall survival. Kaplan-Meier plots showed that the median survival of group 3 was markedly longer (127 weeks) than that of groups 1 and 2 (47 and 52 weeks, respectively). We then validated the 42 probe sets to stratify the patients according to survival in other public GBM gene expression datasets (eg, GSE4290 dataset). An overall analysis of the gene expression and copy number aberration using a multivariate Cox regression model showed that the 42 probe sets had a significant prognostic value independent of other variables. By integrating multidimensional genomic data from TCGA, we identified a specific survival model in a new prognostic group of GBM and suggest that molecular stratification of patients with GBM into homogeneous subgroups may provide opportunities for the development of new treatment modalities. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (NRF-2013R1A1A2063115) and the MSIP (Ministry of Science, ICT and Future Planning), Korea, under the “IT Consilience Creative Program” (NIPA-2014-H0201-14-1002) supervised by the NIPA (National IT Industry Promotion Agency)]

Citation Format: Yong-Wan Kim. Identification of prognostic gene signatures of glioblastoma: a study based on TCGA data analysis. [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 3756. doi:10.1158/1538-7445.AM2015-3756
Abstract 3766: Identifying rational combination therapies with rapamycin for the treatment of epithelial cancers
Authors: Dawood Moez , Lu Yiling , Mills Gordon
Published: August 2015

Targeted therapies are designed to inhibit specific pathways driving the malignant phenotype while concurrently decreasing side effects on normal cells. However, very frequently, inhibition of the targeted pathway activates compensatory mechanisms designed to bring the pathway back into equilibrium allowing for cancer cell survival, a mechanism known as adaptive drug resistance. The purpose of this project is to identify and abrogate the adaptive drug resistance of epithelial cancers to rapamycin, an allosteric inhibitor of mTOR (mammalian target of rapamycin), and to rapamycin analogs in the PI3K (phosphoinositide-3-kinase) pathway, the most commonly dysregulated pathway in epithelial cancers. Using 3D- cultures, rapamycin-induced morphology changes and cell death were recorded. Changes in protein levels due to rapamycin-induced adaptive signaling were detected using reverse phase protein arrays (RPPA), verified by western blotting, and analyzed to determine potential adaptive mechanisms. Based on screening results from RPPA, rapamycin was combined with rationally selected drugs designed to thwart adaptive drug resistance to rapamycin. This co-extinction approach reinforced rapamycin into an effective inducer of cell death, ultimately bypassing drug resistance mechanisms and precluding the emergence of future therapeutic resistance. Successful combinations will be forwarded into animal studies to demonstrate in vivo efficacy for the treatment of epithelial cancers.

Note: This abstract was not presented at the meeting.

Citation Format: Moez Dawood, Yiling Lu, Gordon Mills. Identifying rational combination therapies with rapamycin for the treatment of epithelial cancers. [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 3766. doi:10.1158/1538-7445.AM2015-3766
Abstract 3770: The spindle assembly checkpoint requires phosphatase activity
Authors: Foss Kristen , Zhang Liguo , Robeson Alexander C. , Kornbluth Sally
Published: August 2015

The spindle assembly checkpoint (SAC) prevents activation of the anaphase-promoting complex (APC/C) until all chromosomes are correctly attached to the mitotic spindle. A defective SAC contributes to errors in chromosome segregation, which promotes aneuploidy and may eventually lead to cancer. Early in mitosis, the mitotic checkpoint complex (MCC) inactivates the APC/C by binding the APC/C activating protein cdc20 until the chromosomes are properly aligned, at which point the MCC dissociates and releases cdc20 to activate the APC/C. Once the APC/C is activated, it targets many substrates for degradation, including cyclin B and securin, and the cell progresses into anaphase. The precise molecular mechanisms regulating SAC inactivation are still poorly understood. We sought to determine the role of mitotic phosphatases in the SAC. To address this question, we treated mitotic cells with various phosphatase inhibitors to examine their effect on APC/C activation. Using this approach we identified two inhibitors, calyculin A and okadaic acid (1uM), that cause MCC dissociation and APC/C activation leading to cyclin A and cyclin B degradation in nocodazole-arrested cells. Although the cells are able to degrade cyclin B, they do not exit mitosis as evidenced by high levels of cdk1 substrate phosphorylation and chromosome condensation. Our results demonstrate that a calyculin A and okadaic acid (1uM) sensitive phosphatase is required for SAC activation.

Citation Format: Kristen Foss, Liguo Zhang, Alexander C. Robeson, Sally Kornbluth. The spindle assembly checkpoint requires phosphatase activity. [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 3770. doi:10.1158/1538-7445.AM2015-3770
Abstract 3798: KHF16, a new cycloartane triterpenoid isolated from Cimicifuga foetida, suppresses triple-negative breast cancer by inhibiting the NF-κB signaling pathway
Authors: Kong Yanjie , Chen Ceshi
Published: August 2015

Triterpenoids extracted from Cimicifuga foetida were reported to inhibit cancers by inducing cell cycle arrest and apoptosis. In this study, KHF16 (24-acetylisodahurinol-3-O-b-D-xylopyranoside), a new cycloartane triterpenoid isolated from the rhizomes of Cimicifuga foetida, showed potent anti-cancer activity in multiple ERa/PR/HER2 triple-negative breast cancer (TNBC) cell lines. KHF16 significantly induces cell cycle G2/M phase arrest and apoptosis in both MDA-MB-468 and SW527 TNBC cell lines. KHF16 reduces the expression levels of XIAP, Mcl-1, Survivin, Bcl-2 and Cyclin B1/D1 proteins. Importantly, KHF16 inhibits TNFα-induced IKKa/b phosphorylation, IKBa phosphorylation, p65 nuclear translocation and NF-κB downstream target gene induction in TNBC cells. These results suggest that KHF16 may inhibit TNBC through blocking the NF-κB signaling pathway.

Citation Format: Yanjie Kong, Ceshi Chen. KHF16, a new cycloartane triterpenoid isolated from Cimicifuga foetida, suppresses triple-negative breast cancer by inhibiting the NF-κB signaling pathway. [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 3798. doi:10.1158/1538-7445.AM2015-3798
Abstract 380: Capture of EpCAM-negative circulating tumor cells (CTCs) with a “Universal CTC-Chip”
Authors: Yoneda Kazue , Chikaishi Yasuhiro , Kawashima Eri , So Tomoko , Uramoto Hidetaka , Ohnaga Takashi , Tanaka Fumihiro
Published: August 2015

Background: Circulating tumor cell (CTC) can be a potentially useful clinical marker in early diagnosis and monitoring therapeutic effects for patients with malignant tumors. Our previous study showed that CTC detected by an EpCAM (epithelial cell adhesion molecule) based immuno-magnetic separation system “CellSearch” was useful in the diagnosis of malignant pleural mesothelioma (MPM), and also useful in the prognosis of epithelioid type MPM (Yoneda K, et al. Ann Surg Oncol. 2013). However, EpCAM-negative tumor cells cannot be principally captured with the system. Therefore, we have developed EpCAM-independent “Universal CTC-Chip System”, and assessed its capture capability.

Methods: PC-9 (lung cancer cell line) was employed as EpCAM-positive cells, ACC-MESO-1 and ACC-MESO-4 (mesothelioma cell lines) were employed as EpCAM-negative cells. The expression of cell surface antigen was confirmed by flow cytometry. A microfluidic devices made of resin was coated in two steps with bridging antibody and capture antibody. It is possible to use any antibody to capture. In this study, we use anti-EpCAM antibody, anti-podoplain antibody, anti-mesothelin antibody, and isotype control. First, we verified capture capability of this system using samples which were spiked tumor cells labeled with CFSE in PBS containing 5% BSA. Then, we measured in the same manner by adding the cells to the blood of healthy donor, and calculated capture rate.

Results: The expression analysis of cell surface antigens, PC-9 was EpCAM-positive, podoplanin, mesothelin were negative. On the other hand, MESO-1, 4 was EpCAM negative, podoplanin, mesothelin were positive. The capture efficiency in PBS containing 5% BSA with each cell using anti-EpCAM antibody, anti-podoplanin antibody and anti-mesothelin were PC-9: 101.1% / 2.3% / 2.9%, MESO-1: 3.5% / 52.7% / 4.3%, MESO-4: 3.0% / 78.3% / 5.4%, respectively. In the study of blood, each of the capture rate using anti-EpCAM antibody and anti-podoplanin antibody were PC-9: 88.0/ 6.9%, MESO-1: 4.0%/ 12.7%, MESO-4: 2.2%/ 38.4%, respectively.

Conclusions: The capture efficiency using this device depends on the expression intensity of cell surface antigens. In experiments with PBS samples, it was possible to capture targeting specific cell surface antigen. Mesothelioma cells in the blood ware captured with combination of this CTC-Chip system and anti-podoplanin antibody.

Citation Format: Kazue Yoneda, Yasuhiro Chikaishi, Eri Kawashima, Tomoko So, Hidetaka Uramoto, Takashi Ohnaga, Fumihiro Tanaka. Capture of EpCAM-negative circulating tumor cells (CTCs) with a “Universal CTC-Chip”. [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 380. doi:10.1158/1538-7445.AM2015-380
Abstract 3807: Capsazepine attenuates JAK/STAT3 signaling pathway, proliferation, survival of prostate carcinoma DU145 cells through induction of the protein tyrosine phosphatase epsilon (PTP-epsilon)
Authors: Lee Jong Hyun , Kim Chulwon , Lee Seok-Geun , Lee Junhee , Lee Jung-woo , Ahn Kwang Seok
Published: August 2015

Constitutive activation of signal transducers and activators of transcription (STAT) 3 is a major distinguishing feature of various human cancer cells and its activation leads to survival, proliferation, and metastasis of tumor cells. Whether the anti-proliferative, pro-apoptotic, and anti-invasive effects of capsazepine (Capz), a synthetic analog of capsaicin, are linked to its capability to inhibit STAT3 activation was investigated. We found that Capz suppressed both constitutive and IL-6-inducible STAT3 activation in human prostate carcinoma cells. Capz also suppressed nuclear translocation and DNA binding activity of STAT3. The suppression was mediated through the inhibition of activation of the upstream kinases JAK1/2 and c-Src. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate treatment reversed the Capz-induced down-regulation of STAT3, thereby suggesting the involvement of a PTP. Capz induced the expression of PTPϵ protein and mRNA. Moreover, knockdown of PTPϵ by small interfering RNA suppressed the induction of PTPϵ, reversed the inhibition of STAT3 activation, suggesting the critical role of PTPϵ in its possible mechanism of action. Capz downregulated the expression of STAT3-regulated proliferative, antiapoptotic, angiogenetic, and metastatic gene products; and this correlated with suppression of cell proliferation and invasion, the accumulation of cells in sub-G1 phase of cell cycle, and induction of apoptosis. Overexpression of phosphorylated STAT3 led to the attenuation of Capz-mediated cleavage of PARP as compared to the control. Thus, overall, our results suggest that Capz is a novel inhibitor of STAT3 activation and thus may have a potential in negative regulation of growth, metastasis, and angiogenesis of tumor cells.

Citation Format: Jong Hyun Lee, Chulwon Kim, Seok-Geun Lee, Junhee Lee, Jung-woo Lee, Kwang Seok Ahn. Capsazepine attenuates JAK/STAT3 signaling pathway, proliferation, survival of prostate carcinoma DU145 cells through induction of the protein tyrosine phosphatase epsilon (PTP-epsilon). [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 3807. doi:10.1158/1538-7445.AM2015-3807
Abstract 3824: Human pan-cancer variomes and their epigenetic profiles: Extending beyond the coding region
Authors: Torcivia-Rodriguez John P. , Mazumder Raja
Published: August 2015

The identification on different cancer lines of non-synonymous single nucleotide variations (nsSNVs) has exploded as sequencing technology has improved and decreased in expense. The impact of these variations on specific genes is being widely studied thanks to efforts to unify fragmented information about sequence functional sites into comprehensive databases. In additional to sequence functional sites, DNA functional elements have been found throughout the genome - estimates by the ENCODE project of upwards of 80% of the genome - and account for at least some of the biological complexity of life. In this study, we investigate the frequency of cancer related nsSNVs on tissue-independent DNA functional element sites comprised of 14 different functional elements. Out of 1 651 364 cancer related nsSNVs that matched one or more of 5 680 308 total DNA elements collected, we identified a number of variations that significantly affect a broad range of DNA functional elements. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across several different cancer types led to the identification of nsSNVs located in functional elements found in 3 or more cancer types.

Citation Format: John P. Torcivia-Rodriguez, Raja Mazumder. Human pan-cancer variomes and their epigenetic profiles: Extending beyond the coding region. [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 3824. doi:10.1158/1538-7445.AM2015-3824
Abstract 3870: Telomeric non-coding RNA causes genome-wide alteration of gene expression in cancer
Authors: Hirashima Kyotaro , Seimiya Hiroyuki
Published: August 2015

The end replication problem of linear chromosome DNA causes telomere shortening and eventual senescence of normal cells. Cancer cells reactivate telomerase to maintain their telomere length and exhibit an infinite replicative potential. However, telomerase activation does not necessarily increase the average telomere length in cancer cells. Actually, cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. We previously demonstrated that forced telomere elongation in cancer cells promotes their differentiation in a xenograft tumor and represses innate immune genes that are upregulated in various human cancers. This implies that short telomeres of cancer cells contribute to their malignancy. However, it is completely unknown how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated human cancer cells. Using three different cancer cell lines, including those from prostate, breast and stomach, we found that telomere elongation by hTERT overexpression up-regulates TERRA signals, which were detected by northern blot analysis, and down-regulates innate immune genes such as STAT1, ISG15, and OAS3 in vivo. These changes were caused by telomere elongation and not by enhanced telomerase activity or hTERT overexpression per se. Down-regulation of the innate immune genes was also observed in the telomere-elongated cells under three-dimensional (3D) culture conditions, which mimicked the tumor microenvironment in vivo. Introduction of TERRA oligonucleotides repressed the innate immune genes even in cells with short telomeres under 3D culture conditions. Intriguingly, this gene repression appeared to occur from the action of the non-canonical nucleic acid structure called G-quadruplex (G4) in TERRA, because non-telomeric (i.e., non-G4-forming) control oligonucleotides had no effect whereas another non-telomeric but G4-forming oligonucleotide phenocopied the TERRA oligonucleotides. Transcriptome analysis revealed that telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various human cancers. Taken together, these observations suggest that the telomeric non-coding RNA G4 counteracts cancer malignancy through suppression of innate immune genes, and give a new insight into our understanding of telomere shortening in human cancer.

Citation Format: Kyotaro Hirashima, Hiroyuki Seimiya. Telomeric non-coding RNA causes genome-wide alteration of gene expression in 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 3870. doi:10.1158/1538-7445.AM2015-3870
Abstract 3909: Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative breast cancer
Authors: Harmon Tia L. , Harbuzariu Adriana , Yang Lily , Gonzalez-Perez Ruben R.
Published: August 2015

Background:

Leptin is a cytokine secreted by adipose tissue that binds its receptor, OB-R, leading to increased growth and survival of cancer cells. High levels of leptin have been correlated with poorer outcomes in breast cancer patients, particularly those afflicted with triple negative breast cancer (TNBC).

We have created a leptin peptide receptor antagonist, LPrA2, which has been shown to block leptin signaling in several cancer types. To increase its effectiveness, LPrA2 was coupled to iron oxide nanoparticles (IONPs).

We aim to determine if IONP-LPrA2 will serve as an adjuvant treatment, when combined with chemotherapeutics, for human TNBC and mouse TNBC-like (Tamoxifen-resistant) breast cancer cells E0771-TAM.

Methods:

Conjugation of LPrA2 to IONPs was confirmed by Western Blot and inhibition assays. To evaluate the effects of IONP-LPrA2 in mouse TNBC-like cells, the E0771 cell line (progesterone receptor and HER2 negative) was made insensitive to estrogen stimuli by long-term treatment with Tamoxifen (TAM). Human TNBC and E0771 cells, both responsive and unresponsive to estrogen (E0771-TAM), were treated with recombinant leptin and culture medium containing fetal bovine serum plus chemotherapeutics and IONP-LPrA2.

Cell cycle progression, cell viability and apoptosis were analyzed using the Cellometer Vision Image Cytometer ®.

Results:

IONP-LPrA2 was found to cause significant decrease in DNA synthesis during the S phase of the cell cycle in TNBC and TNBC-like cells when compared to E0771 cells. Additionally, IONP-LPrA2 showed additive effects on reduction of cell viability and apoptosis when combined with chemotherapeutics.

Conclusion:

These findings indicate that IONP-LPrA2 may be useful in the treatment and prevention of TNBC. Further, IONP-LPrA2 treatment may increase the effectiveness and allow for reduction of the dosage of chemotherapeutics. This will in turn attenuate undesired side effects of chemotherapy. These results may be beneficial for breast cancer patients, particularly those with TNBC who are overweight or obese lacking targeted therapy thus suffering the poorest outcomes.

Citation Format: Tia L. Harmon, Adriana Harbuzariu, Lily Yang, Ruben R. Gonzalez-Perez. Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative 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 3909. doi:10.1158/1538-7445.AM2015-3909
Abstract 3915: Inhibition of cdc2 is linked to PMA-induced cell differentiation
Authors: Vasilyeva Daria , Dolinsky Pairat , Fielder Shashana , Nakasone Alice , Packert Gerhild , Hu Xiaotang
Published: August 2015

The critical role of cdc2 (CDK1) in G2-M transition of the cell cycle control in mammalian cells has been well documented. Recent studies have also demonstrated that cdc2 is capable of driving G1 progress and G1-S transition via association with multiple interphase cyclins and through the interactions with Rb proteins. However, whether this pluripotent CDK regulates cell differentiation is unclear. Thus, the effect of phorbol 12-myristate 13-acetate (PMA) on cell differentiation and the expression of cdc2 in a human myeloid leukemia cell line, TF-1a, was investigated. When TF-1a cells were treated with 10−5, 10−6, and 10−7 PMA for 48 and 72h, they showed marked (≥50%) macrophage-like changes, evidenced by significant decrease in nucleus/cytoplasm ratio and increase (1-3 folds) in the expression of IL-1β, a macrophage marker. PMA treatment also caused time-dependent inhibition of cdc2 in both cytosol and nucleus of the cells, with a maximal inhibition being observed by 48 and 72h, which paralleled with the cell differentiation course. In contrast, there was no significant cell differentiation and inhibition of cdc2 being observed in control human myeloid leukemia TF-1 cells treated with PMA. Previous studies suggest that prolonged activation of MAPK pathway is linked to cell differentiation. PMA treatment also rapidly induced phosphorylation of MAPK kinases (MEK and ERK), which persisted for 24h, after which phosphorylated MEK and ERK were returned to base level, while the expression of cdc2 was still significantly downregulated, as compared with the control cells treated with DMSO. Pretreatment of TF-1a cells with sense cdc2 oligo nucleotides partially inhibited PMA-induced differentiation and upregulation of IL-1β. Taken together, our data suggest that MAPK pathway may be responsible for initiation of cell differentiation whereas inhibition of cdc2 is required for late differentiation of TF-1a cells in response to PMA stimulation. Whether activation of the MAPK pathway inhibits expression of cdc2 is currently under investigation (Supported by Faculty Incentive Grant and NIH-NIGMS MBRS RISE: R25 GM059244-13, Barry University).

Note: This abstract was not presented at the meeting.

Citation Format: Daria Vasilyeva, Pairat Dolinsky, Shashana Fielder, Alice Nakasone, Gerhild Packert, Xiaotang Hu. Inhibition of cdc2 is linked to PMA-induced cell differentiation. [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 3915. doi:10.1158/1538-7445.AM2015-3915
Abstract 3931: Generation of tumorgraft models to characterize novel tumor suppressor genes implicated in lung carcinogenesis
Authors: Pereira Carolina , Gimenez-Xavier Pol , Gomez Gonzalo , Condom Enric , Villanueva Alberto , Pisano David , Sanchez Cespedes Montse
Published: August 2015

The extremely poor prognosis and lack of efficient treatments throw lung cancer (LC) to the top of the deadliest types of cancer worldwide. Throughout the years, the role played by host genetic variation has been constantly highlighted as the key in determining tumor onset and progression. In this regard, the discovery of LC-related genes paved the way to the development of targeted therapies that nowadays are benefiting patients harboring specific mutational patterns, such as EGFR mutations or ALK rearrangements.

Here, aiming to characterize novel tumor suppressor genes in LC, 8 patient-derived tumors were subcutaneously or orthotopically engrafted in nude mice for growing and subsequently carry out exome and transcriptome sequencing. The strategy avoided the common admixture exhibited by the presence of normal cells in the sample, which were successfully swept away in the engrafting step, as determined by microsatellite analyses. Among the 4430 mutations detected by exome-seq, we focused on the 79 ones that would presumably lead to biallelic gene inactivation, a common feature exhibited by tumor suppressors: homozygous frameshift indels, nonsense and splicing site mutations. We then chose to characterize one particular candidate gene, which codifies for a globular protein that might be involved in the ability of tumors to escape the action of the immune system. The genetic screening performed resulted in a mutation rate of 5.1% in 79 tested LC cell lines and of 3.9% in a panel of 179 lung primary tumors. The complete coding region was cloned in constitutive and inducible systems in order to restore the expression of the protein in gene-depleted LC-cell lines, and preliminary results pinpoint that it may indeed trigger an anti-tumoral effect. This in vitro approach is currently ongoing and hopefully, will enlighten us about its tumor suppressive potential in the near future.

Citation Format: Carolina Pereira, Pol Gimenez-Xavier, Gonzalo Gomez, Enric Condom, Alberto Villanueva, David Pisano, Montse Sanchez Cespedes. Generation of tumorgraft models to characterize novel tumor suppressor genes implicated in lung carcinogenesis. [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 3931. doi:10.1158/1538-7445.AM2015-3931
Abstract 3932: Using Sleeping Beauty transposon mutagenesis to identify CRC driver genes
Authors: Wei Zhubo , Takeda Haruna , Copeland Neal G. , Jenkins Nancy A.
Published: August 2015

In order to better understand the initiation and development of colorectal cancer (CRC), Sleeping Beauty (SB) transposon mutagenesis screens were performed in mice with mutations in genes that play important roles in differen stages of CRC. Functional validation assays, including invasion assay and xenograft assay, were carried out for the candidate genes that were selected by their potentials in tumor progression and/or human CRC. We identified six genes driving malignant tumor progression, and a new human CRC tumor suppressor gene, ZNF292, that may also function in other types of cancer. More detailed investigations are being done for those identified genes, including experiments using knockout mice. Our study provides a resource for the development of new CRC therapies.

Citation Format: Zhubo Wei, Haruna Takeda, Neal G. Copeland, Nancy A. Jenkins. Using Sleeping Beauty transposon mutagenesis to identify CRC driver genes. [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 3932. doi:10.1158/1538-7445.AM2015-3932
Abstract 3943: Genetic abnormalites in hypoxia sensing regulators cause human pheochromocytoma/paraganglioma and plolycythemia syndrome
Authors: Yang Chunzhang , Wang Herui , Pacak Karel , Zhuang Zhengping
Published: August 2015

Hypoxia inducible factors (HIFs) control the cellular response to hypoxia and when dysregulated, contribute to tumorigenesis. In the presence of oxygen, HIFs are strictly deactivated via EGLN/VHL/26S proteasome degradation mechanism. We identified that either gain-of-function mutations in HIF2A, or loss-of-function mutations in EGLN1/2, result in the multiple pheochromocytomas or paraganglioma associated with polycythemia. Mutation in HIF2A or EGLN1/2 cause compromised interaction of prolyl hydroxylase to HIF-α and lead to defects of HIF-α degradation. Stabilized HIF-α translocates into cell nucleus and function as a potent transcriptional factor, which induces constitutive transcriptional activation of hypoxia related genes, as well as pseudohypoxic change in cellular signaling and metabolism. Our finding provided direct evidence that genetic defect in intrinsic HIF-α and its regulatory proteins EGLN1/2 can be a key factor involved in the pathogenesis of this tumor-associated syndrome.

Citation Format: Chunzhang Yang, Herui Wang, Karel Pacak, Zhengping Zhuang. Genetic abnormalites in hypoxia sensing regulators cause human pheochromocytoma/paraganglioma and plolycythemia syndrome. [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 3943. doi:10.1158/1538-7445.AM2015-3943
Abstract 3946: Secretory ANXA3 endows liver cancer cells with tumorigenic and self-renewal abilities and promotes HCC development
Authors: Tong Man , Ma Stephanie
Published: August 2015

Hepatocellular carcinoma (HCC) is the third leading cause of mortality in Southeast Asia and in Hong Kong. Despite advances in treatment, the prognosis of advanced HCC patients remains dismal. Contemporary challenge in treating HCC has been the common chemotherapy resistance and recurrence after therapy.Therefore, the identification of valid targets and the development of new therapies are urgently needed for more effective clinical management of this deadly disease. We found secretory annexin A3 (ANXA3) to be up-regulated in HCC cell lines, compared with immortalized normal liver cell line MIHA. Clinically, secretory ANXA3 levels in the serum were found to be progressively elevated from non-HCC individuals to early and advanced HCC patients, with up-regulation of serum ANXA3 to be tightly associated with gender, number of tumor nodules, tumor sizes and tumor stages. More importantly, the diagnostic value of secretory ANXA3, as evident by ROC analysis, was found to be more superior to the commonly used biomarker alpha-fetoprotein (AFP). Subsequent functional studies found secretory ANXA3 to promote cancer and stem cell-like properties of HCC cells. Co-culture of conditioned medium from ANXA3-overexpressing cells with ANXA3-absent HCC cells potentiated the abilities of HCC cells to migrate, invade, self-renew, induce tube formation in endothelial cells, and resist apoptosis induced by staurosporine and chemotherapy. The in vivo tumor-initiating capacity was also significantly enhanced in HCC cells when co-cultured with ANXA3-containing conditioned medium compared with conditioned medium from cells transfected with empty vector control. Similar functional properties were also observed when MIHA cells were treated with recombinant ANXA3 proteins. In an effort to characterize the molecular mechanism by which ANXA3 drives cancer and stem cell-like properties in HCC, cDNA microarray profiling was performed to compare the gene expression between ANXA3-depleted and control cells. Pathway enrichment analysis found many of the deregulated genes to be closely associated with the JNK/AP-1 signaling cascade. Activation of JNK pathway was detected when cells were treated with recombinant ANXA3 proteins or ANXA3-containing conditioned medium. Collectively, our findings suggest that secretory ANXA3 plays pivotal roles in promoting tumor initiation, growth and chemoresistance through the activation of JNK signaling pathway in HCC.

Citation Format: Man Tong, Stephanie Ma. Secretory ANXA3 endows liver cancer cells with tumorigenic and self-renewal abilities and promotes HCC development. [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 3946. doi:10.1158/1538-7445.AM2015-3946
Abstract 3953: HORMAD1 plays an important role in the HNSCC carcinogenesis
Authors: Carlin Viviane , Rodrigues-Junior Dorival Mendes , Biassi Thais Priscila , Nozima Bruno Heidi Nakano , Buri Marcus Vinicius , Vettore Andre Luiz
Published: August 2015

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide. Approximately one-third of patients present with early-stage disease and these patients are treated with either surgery or radiotherapy, with cure rates of 70-90%. The majority of patients, however, present with locally advanced stage disease. Radical treatment in this situation requires multimodality therapy with surgery, commonly followed by postoperative radiotherapy or chemotherapy. These treatments are intensive and associated with severe acute toxicity and long-term sequelae. Despite recent advances in both surgical and radiotherapy delivery techniques, up to 50% of locally advanced tumours relapse usually within the first 2 years after treatment. The development of novel therapeutic approaches and their integration into the current forms of treatment is of great interest to improve the therapeutic efficacy. Immunotherapy may provide an alternative for current treatment approach. Cancer/testis antigens (CTAs) are a family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues except for testis and placenta. This tumor-restricted pattern of expression, together with their strong in vivo immunogenicity, identified CTA as ideal targets for tumor-specific immunotherapeutic approaches. A screening for CTAs expressed in HNSCC detected HORMAD1 recurrently expressed in these tumors. Objectives: The aim of this study is better understand the role of HORMAD1 in HNSCC by evaluating its influence in different tumorigenic processes, such as apoptosis, cell cycle and migration. Methods: The HORMAD1 expression was evaluated in HNSCC cell lines by RT-PCR and the presence of HORMAD1 protein was confirmed by Western Blot. HORMAD1 expression was silenced by shRNA and assays were conducted to evaluate the impact of HORMAD1 absence in cell cycle regulation and apoptosis. Results: The HORMAD1 gene was knocked-down in a HNSCC cell line and functional assays revealed a reduction in the proportion of the cells in the G1 phase of cell cycle and an induction of the apoptosis when HORMAD1 is absent. Conclusions: Our results demonstrate that HORMAD1 is frequently expressed in HNSCC and our in vitro observations indicate that this CTA may play an important role in the HNSCC carcinogenesis.

Citation Format: Viviane Carlin, Dorival Mendes Rodrigues-Junior, Thais Priscila Biassi, Bruno Heidi Nakano Nozima, Marcus Vinicius Buri, Andre Luiz Vettore. HORMAD1 plays an important role in the HNSCC carcinogenesis. [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 3953. doi:10.1158/1538-7445.AM2015-3953
Abstract 3960: The role and therapeutic potential of miRNAs in colorectal liver metastasis
Authors: Sahu Smiti Snigdha , Nabinger Sarah , Guanglong Jiang , Bates Allison , Lee Sangbin , Hiromi Tanaka , Liu Yunlong , Kota Janaiah
Published: August 2015

Colorectal cancer (CRC) is a leading cause of cancer related deaths worldwide. Liver metastasis occurs in 60% of CRC patients and usually responds poorly to treatment - contributing to mortality rate. MicroRNAs (miRNAs) are highly conserved, endogenously encoded small, non-coding RNA molecules regulating global gene expression. Their role in cancer pathogenesis, including CRC, has been well documented. Detailed miRNA expression analysis on a large cohort of CRC tumors is needed to identify clinically relevant miRNAs and explore their potential to target liver metastases.

We analyzed miRNA expression data of 406 CRC tumors from publically available CRC genome sequencing project and identified 58 miRNAs, which were significantly downregulated. Using miRNA target prediction analysis, 10 miRNAs were selected for further studies as they were either known to target genes in cellular pathways associated with CRC liver metastases, or located within a chromosomal loci commonly lost in colorectal liver metastases. qPCR analysis of these 10 selected miRNAs in primary and colorectal liver metastasis tissues and in CRC cell lines demonstrated four miRNAs; miR-132, miR-378f, miR-605, and miR-1976 that are significantly down-regulated with <2 fold change (p>0.05). To investigate the anti-tumorigenic and metastatic properties of miR-132, -378f, -605, and -1976, we transfected 3 different CRC cell lines (SW620, HCT-116, and CT-26) with miR-mimics and subjected them to cell proliferation, apoptosis, soft agar, invasion, and migration assays. Ectopic expression of miR-378f, -605, and -1976 suppressed CRC cell proliferation, anchorage independent growth, migration, and invasion and increased apoptosis. Interestingly, CRC patients with high miR-378f and miR-1976 had better survival compared to low expressing patients (p<0.044).

In conclusion, our in vitro findings suggest anti-tumorigenic/metastatic properties of miR-378f, -605, and -1976 in CRC. A further understanding of their function and in vivo therapeutic evaluation may help in developing novel therapeutic strategies for this malignancy.

Citation Format: Smiti Snigdha Sahu, Sarah Nabinger, Jiang Guanglong, Allison Bates, Sangbin Lee, Tanaka Hiromi, Yunlong Liu, Janaiah Kota. The role and therapeutic potential of miRNAs in colorectal liver metastasis. [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 3960. doi:10.1158/1538-7445.AM2015-3960
Abstract 399: Nanoparticle silencing of β1 and β3 integrins augments Dasatinib sensitivity
Authors: Parvani Jenny G. , Chu Vinson , Roelle Sarah , Lu Zheng-Rong , Schiemann William
Published: August 2015

Triple negative breast cancers (TNBCs) are an aggressive subcategory of breast cancers that currently lack FDA-approved targeted therapies. Previous studies have i) further subcategorized TNBCs into 5 distinct subtypes, each with a preferential response to specific chemotherapies and ii) identified beta1 and beta3 integrins to be key mediators of breast cancer EMT and metastasis. We surveyed beta1 and beta3 integrin expression in the 5 subtypes of TNBC with and without treatment of their proposed chemotherapies by western blot analysis. Using nanoparticles, we delivered beta1 and beta3 integrin-specific siRNAs to silence the expression of both integrins either with or without treatment of the proposed chemotherapies, and evaluated the effect of these treatment regimens on EMT, invasion, and 3D outgrowth. We demonstrated that beta1 and beta3 integrins are robustly expressed in the Mesenchymal Stem-Like, Mesenchymal, and Basal-Like2 subtypes of TNBCs. Furthermore, we observed elevated expression of beta1 integrin upon Dasatinib treatment of the Mesenchymal Stem-Like subtype. Lastly, we determined that delivery of beta1 and beta3 integrin siRNAs sensitized breast cancer cells to Dasatinib treatment. Collectively, our data suggests that delivery of beta1 and beta3 integrin-specific siRNAs in combination with Dasatinib treatment efficiently eliminates the aggressive characteristics of Mesenchymal Stem-Like breast cancer cell lines.

Citation Format: Jenny G. Parvani, Vinson Chu, Sarah Roelle, Zheng-Rong Lu, William Schiemann. Nanoparticle silencing of β1 and β3 integrins augments Dasatinib sensitivity. [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 399. doi:10.1158/1538-7445.AM2015-399
Abstract 3999: MicroRNA expression links obesity and recurrence in renal cell carcinoma
Authors: Shu Xiang , Hildebrandt Michelle A. , Gu Jian , Tannir Nizar M. , Matin Surena , Karam Jose A.
Published: August 2015

Obesity is an established risk factor for clear cell renal cell carcinoma (ccRCC) development and prognosis; however, the mechanisms underlying this link remain unclear. In the present study, we set to assess whether microRNAs (miRNAs) can serve as a molecular link between obesity and recurrence in ccRCC. Through bioinformatics tools and literature search, we identified 126 obesity-related miRNAs. Supplemented with 25 miRNAs which were differentially expressed between ccRCC from normal kidney, we tested the association of these miRNAs with ccRCC recurrence. Significantly decreased levels of hsa-miR-204-5p were found in recurrent ccRCC patients with an over 2-fold increased risk of recurrence (HR = 2.15, p = 0.028, MST = 25.6 vs. 47.2 months). Correlations between miRNA expression and the predicted target genes were tested using gene profiling data generated from these same patients. We found strong inverse correlations between miR-204 expression and several obesity-related genes, including IGF2BP2 (r = -0.40, p = 4.14×10−4), a member of the insulin growth receptor signaling pathway. This correlation was further validated in TCGA data (r = -0.58, p = 1.40×10−22). We also found that low level of hsa-miR-139-5p was significantly associated with increased recurrence risk (HR = 2.37, p = 0.026, MST = 32.2 vs. 51.3 months). In conclusion, we found a set of obesity-related miRNAs that are dysregulated in ccRCC tissues, and some of these miRNAs, such as hsa-miR-204-5p, were associated with the recurrence of RCC, potentially through regulating obesity-related gene expression.

Citation Format: Xiang Shu, Michelle A. Hildebrandt, Jian Gu, Nizar M. Tannir, Surena Matin, Jose A. Karam. MicroRNA expression links obesity and recurrence in renal cell carcinoma. [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 3999. doi:10.1158/1538-7445.AM2015-3999