bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1941: Distinct roles of c-Jun N-terminal kinase (JNK) isoforms in skin cancer
Authors: Du Lili , Zhang Tinghu , Kaoud Tamer , Gray Nathanael , Dalby Kevin , Tsai Kenneth Y. 
Published: August 2015

Abstract
The c-Jun-N-terminal kinases (JNKs), are activated by stress, growth factors and cytokines, and are encoded by three separate genes (JNK 1, 2, and 3), with 10 total isoforms. Our published data has demonstrated that off-target effects on JNK signaling by BRAF inhibitors (BRAFi) are important for the induction of cutaneous squamous carcinoma (cuSCC). Overexpression of JNK2, has been found to promote transformation of keratinocytes, also suggesting an important role of JNK signaling pathway in promoting tumor development. However, it is still unclear how different JNK isoforms, especially ubiquitously expressed JNK1 and JNK2, really function in skin cancer.
To delineate the specific roles of JNK1 and JNK2, we expressed C116S mutants, which rendered them insensitive to the pan-JNK inhibitor JNK-IN-8, without affecting their activity. Wild-type and mutant JNK1 and JNK2 were transduced into cuSCC (SRB1) and keratinocyte (HaCaT) cell lines and application of JNK-IN-8 enabled chemical-genetic dissection of JNK1 and JNK2 activity. JNK-IN-8 significantly attenuated UV-induced apoptosis by 80-90% in SRB1 and HaCat cells overexpressing WT JNK1, WT JNK2 or C116S JNK2 mutant compared to vehicle control while having only a slight effect (0-10%) on cells overexpressing C116S JNK1 mutant, suggesting JNK1 is the key player in UV- induced apoptosis. This difference served as the basis for a gene expression profiling study in which we identified differentially expressed genes regulated by JNK1 vs. JNK2.
We also showed that the Leucine-zipper and sterile-α motif kinase (ZAK), which is a MAP3K, is an important upstream activator of JNK-mediated UV-induced apoptosis in skin cancer. To probe how ZAK activates JNK signaling, we knocked down ZAK in SRB1 and HaCaT cells with lentiviral shRNA. Following UV exposure, we found that both JNK1 and JNK2 activation occurred with JNK1 activity peaking within 6 hours and JNK2 activity sustained over 24 hours. In ZAK knockdown cells, JNK1 activation was selectively suppressed, suggesting that ZAK preferentially activates JNK1 in this context.
In conclusion, our results indicate that JNK signaling pathway, part of which is regulated by ZAK, plays a critical role in skin cancer. JNK1 and JNK2 exert opposing influences that center on the regulation of apoptosis and cell proliferation in skin cancer.
Citation Format: Lili Du, Tinghu Zhang, Tamer Kaoud, Nathanael Gray, Kevin Dalby, Kenneth Y. Tsai. Distinct roles of c-Jun N-terminal kinase (JNK) isoforms in skin 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 1941. doi:10.1158/1538-7445.AM2015-1941
Abstract 1943: Integrin α6β4 promotes autocrine EGFR signaling to stimulate migration and invasion toward HGF
Authors: Carpenter Brittany L. , Chen Min , Knifley Teresa , Davis Kelley A. , Harrison Susan M. , Stewart Rachel L. , O'Connor Kathleen L. 
Published: August 2015

Abstract
Integrin α6β4 is upregulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion, in part, through its coordinated modulation of the transcriptome. Here, we find that integrin α6β4 signaling dramatically upregulates the expression of several genes involved in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (Areg), epiregulin (Ereg), and ectodomain cleavage protease MMP1. Notably, these genes correlate well with integrin α6β4 expression in publicly available pancreatic cancer databases. We previously reported that integrin α6β4 promotes HGF-stimulated migration and invasion; therefore, we tested the role of autocrine EGFR signaling in these processes. We discovered that blocking EGFR signaling with EGFR-specific blocking antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Furthermore, we found that both Areg and Ereg are required for these autocrine effects, as knocking down either ligand prevented migration and invasion. Notably, AsPC1 cells, isolated from abdominal metastases, are not dependent on EGFR signaling for migration or invasion; thus suggesting a mechanism exists for circumventing EGFR dependency. We also demonstrated that HGF stimulates the secretion of Areg, which is dependent on integrin signaling pathways including MAPK, PI3K and PKC and that Areg was transported to the leading edge of cells treated with HGF. Moreover, MMP activity and integrin α6β4 signaling are required for Areg secretion. Finally, we found that EGFR is phosphorylated in response to HGF stimulation which was dependent on EGFR protein kinase activity; however, Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, we show that integrin α6β4 stimulates invasion by promoting autocrine EGFR signaling through the upregulation of key genes and facilitating HGF-stimulated EGFR ligand secretion.
Citation Format: Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M. Harrison, Rachel L. Stewart, Kathleen L. O'Connor. Integrin α6β4 promotes autocrine EGFR signaling to stimulate migration and invasion toward HGF. [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 1943. doi:10.1158/1538-7445.AM2015-1943
Abstract 1946: Activating transcription factor 5 (ATF5) in highly expressed in Stage 4, MYCN-amplified neuroblastoma
Authors: Banerjee Debarshi , Zhang Shuobo , Lopez Gonzalo , Califano Andrea , Kadenhe-Chiweshe Angela , Yamashiro Darrell 
Published: August 2015

Abstract
Background: Activating transcription factor 5 (ATF5), a member of the ATF/CREB family transcription factor, has been shown to regulate the differentiation of neuroprogenitor cells into mature neurons. ATF5 has also been implicated in progression of glioblastoma multiforme. We have recently identified ATF5 as a potential synthetic lethal gene to MYCN-amplified neuroblastoma (NB) through a whole genome shRNA screen. In the present study we investigate the role of ATF5 in NB tumorigenesis.
Methods: We analyzed the human NB patient data GEO (GSE45480, Kocak et al.) to investigate and correlate the expression of ATF5 with different stages of NB. Immunohistochemical staining for ATF5 was performed on primary human NB tumors. Quantitative RT-PCR and western blot for ATF5 were conducted on a panel of NB cell lines. Immunocytochemistry was performed to determine the intercellular localization of ATF5. ATF5 was silenced by a tetracycline inducible (tet-on) shRNA construct in BE(2)-C and SK-N-DZ cells. The cells were subjected to cell viability assay and soft agar colony formation assay to assess the function of ATF5.
Results: Analysis of NB patient data GEO (GSE45480) from Kocak et al., demonstrated that ATF5 is highly expressed in Stage 4 MYCN-amplified tumors compared to Stage 4, MYCN-non-amplified tumors (P = 2.56e-10) or Stage 1 tumors (P = 7.30e-18). ATF5 is also highly expressed in Stage 4, MYCN-non-amplified tumors vs. Stage 1 tumors (P = 2.8e-7). High expression of ATF5 strongly correlated with poor survival of NB patients (P = 2.88e-6, NCI Oncogenomics, Obertheur data set). Quantitative PCR detected ATF5 transcript in all eight NB cell lines tested. Western blot analyses demonstrated high expression of ATF5 in the MYCN-amplified neuroblastoma cell lines BE(2)-C, SK-N-DZ, and IMR32. Nuclear ATF5 staining was detected in all three cell lines as well as in Stage 4 NB tumors. Silencing of ATF5 reduced BE(2)-C cell viability to 30%, 48 hr after the addition of doxycycline. Silencing of ATF5 significantly reduced the colony formation of BE(2)-C and SK-N-DZ cells in soft agar (p&lt;0.05)
Conclusions: Our study demonstrates that ATF5 is highly expressed in Stage 4 MYCN-amplified tumors, and that silencing of ATF5 inhibits proliferation. These results suggest that ATF5 has a role in NB tumorigenesis and it represents a potential therapeutic target in MYCN-amplified neuroblastoma.
Citation Format: Debarshi Banerjee, Shuobo Zhang, Gonzalo Lopez, Andrea Califano, Angela Kadenhe-Chiweshe, Darrell Yamashiro. Activating transcription factor 5 (ATF5) in highly expressed in Stage 4, MYCN-amplified neuroblastoma. [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 1946. doi:10.1158/1538-7445.AM2015-1946
Abstract 195: Insight into microRNA regulation of autophagy genes expression in crizotinib-treated Anaplastic Large Cell Lymphoma
Authors: Frentzel Julie , Mitou Geraldine , Brousset Pierre , Giuriato Sylvie 
Published: August 2015

Abstract
The anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase involved in 80% of Anaplastic Large Cell Lymphoma (ALCL), and 5% of non-small cell lung carcinoma (NSCLC), among other cancers. The ongoing therapies in ALK+ ALCL, based on aggressive chemotherapy, are not optimal. One compound so far, the crizotinib, is used in clinics for the treatment of ALK-dependent lung cancers. However, the first mutations conferring resistance to crizotinib, have been reported and hampered its use for the treatment of ALK+ ALCL. Thus, despite the therapeutic success of tyrosine kinase inhibitors in cancer treatments, acquired drug resistances universally develop. In this context, cytoprotective autophagy has been proposed as the next target for elimination of resistance to tyrosine kinase inhibitors. We recently demonstrated that cytoprotective autophagy is indeed activated shortly upon ALK inactivation in ALCL and that its inhibition enhances the anti-tumoral action of Crizotinib. A transcriptome analysis showed an increased expression of many genes from the autophagy machinery such as ULK1, MAP1LC3B, or ATG16L2 after crizotinib treatment in ALCL. Moreover, new preliminary results enabled us to identify a set of miRNAs differentially expressed in ALCL upon Crizotinib treatment. As miRNAs are known as fine regulators of gene expression, we anticipate that some of them could be efficient regulators of core autophagy genes expression. The aim of our study is to select a few miRNAs of interest and to confirm their regulatory role on the autophagic machinery. This could lead to the development of new therapeutical strategies which could ultimately help to overcome emerging resistances against crizotinib.
Citation Format: Julie Frentzel, Geraldine Mitou, Pierre Brousset, Sylvie Giuriato. Insight into microRNA regulation of autophagy genes expression in crizotinib-treated Anaplastic Large Cell Lymphoma. [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 195. doi:10.1158/1538-7445.AM2015-195
Abstract 1956: A subset of prostate cancer cells with loss of MST1 expression confers resistance to castration through YAP1-AR interactions
Authors: Cinar Bekir , Kuser Abali Gamze , Lewis Michael , Morrissey Colm , Garraway Isla 
Published: August 2015

Abstract
MST1 is a core kinase component of the Hippo tumor suppressor pathway. YAP1 is a transcriptional cofactor and a prominent nuclear effector of the Hippo signaling. YAP1 activation is linked to cancer promotion with poor prognosis. However, the role of MST1-YAP axis in prostate cancer (PC) progression remains unknown. Here we isolated MST1 high and MST1 low/- expressing cell subsets from a well-characterized LNCaP PC cell model by employing novel method that utilizes an epigenetically regulated-MST1 promoter-driven GFP reporter combined with FACS. We performed molecular and functional characterizations of these cells utilizing a wide variety of experimental approaches. We demonstrated that unlike MST1 high, MST1 low/- cells shared the features of cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotype, showed superior osteogenic abilities, and were resistant to androgen depletion and enzalutamide (ENZ), a potent inhibitor of androgen receptor (AR). Consistently, silencing of MST1 expression by siRNA recapitulated the above molecular and function behaviors of MST1 low/- cells. In addition, MST1 low/- cells showed superior invasive growth abilities in vitro and tumor-forming abilities with metastatic potentials in mice compared with those of MST1 high cells. Moreover, relative YAP1 expression and its nuclear localization were much higher in MST1 low/- cells than MST1 high cells. Likewise, YAP1 protein levels and its nuclear abundance were increased in PC clinical samples compared to non-cancerous counters. We further showed that YAP1 interacted with AR in an androgen-dependent manner in LNCaP cells, whereas the interactions between the two proteins were androgen-independent (AI) in C4-2 CRPC cells. Furthermore we found that unlike LNCaP, YAP1-AR interactions were resistant to ENZ exposure in C4-2 cells. Consistently, silencing of MST1 in LNCaP cells augmented AI interactions between YAP1 and AR proteins. Finally, the disruption of YAP1 signaling by RNAi and Verteporfin (VP) attenuated C4-2 cell growth and promoted apoptosis, accompanied with the attenuation of AR-dependent gene expression. In conclusion, our findings suggest that the Hippo-YAP1-AR signaling axis is one of the key mechanisms for metastatic PC progression and may represent as a promising therapeutic target for patients with the lethal disease.
Note: This abstract was not presented at the meeting.
Citation Format: Bekir Cinar, Gamze Kuser Abali, Michael Lewis, Colm Morrissey, Isla Garraway. A subset of prostate cancer cells with loss of MST1 expression confers resistance to castration through YAP1-AR interactions. [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 1956. doi:10.1158/1538-7445.AM2015-1956
Abstract 1960: Ginger consumption may delay the onset of prostate cancer
Authors: Lane Tonya S. , Richardson Ricardo M. 
Published: August 2015

Abstract
Ginger active components are widely known for being a potent antioxidant and recently as a potential anticancer agent. To date, the precise mechanism(s) for the antitumor effect of ginger is not well understood. An active chemical component of ginger, 6-gingerol, was recently shown to inhibit angiogenesis and tumorigenesis. In this study we investigated the role of ginger in prostate cancer growth and proliferation using PCa cell lines from African American (AA) and Caucasian American (CA) men. To that end, MDA-PCa 2b (AA), LnCap (CA) and PC-3 (CA) cells were treated with different concentrations of 6-gingerol or 6-shogaol for 24 hours and cell proliferations were measured by XTT assay. To determine the effect of 6-gingerol in cell signaling, cell lysates were assayed for β-arrestin 1 and 2 expression, MAP kinase and caspase activity by Western Blotting. The data demonstrated that 6-gingerol inhibits cellular proliferation and promotes apoptosis in both AA and CA PCa cell lines. These effects correlated with decrease in β -arrestin 2, not β -arrestin 1, expression and Akt phosphorylation but increased caspase activity. Taken together the data suggests that 6-gingerol inhibits PCa growth and promotes PCa apoptosis via a βarr-2/Akt-dependent mechanism. Since PC-3 cells do not express AR, the data likely indicates that 6-gingerol effect is independent of AR activation and PSA expression.
Citation Format: Tonya S. Lane, Ricardo M. Richardson. Ginger consumption may delay the onset of prostate 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 1960. doi:10.1158/1538-7445.AM2015-1960
Abstract 2016: Evaluation of prostate cancer biomarkers and therapeutic targets in FFPE specimens using the NanoString platform
Authors: Lee Jocelyn , Yan Wusheng , Young Denise , Song Yingjie , Chen Yongmei , Katta Shilpa , Mohamed Ahmed , Ravindranath Lakshmi , Srinivasan Alagarsamy , Cullen Jennifer , Kagan Jacob , Srivastava Sudhir , Dobi Albert , Rosner Inger , McLeod David G. , Sesterhenn Isabell A. , Srivastava Shiv , Petrovics Gyorgy 
Published: August 2015

Abstract
Introduction: Identification of prognostic indicators of disease progression is one of the highest priorities in prostate cancer (CaP) research. The majority of CaP tissue specimens available for biomarker discovery and validation are formalin fixed paraffin embedded (FFPE) specimens. The RNA quality of these tissues for traditional gene expression analysis approaches is not adequate, especially of cases with long term- follow up necessary for prognostic marker studies. We systematically evaluated and optimized the NanoString platform for CaP gene expression analysis in FFPE whole mounted prostate specimens with up to 15 years follow up.
Methods: NanoString readouts were compared between a series of input total RNA prepared through different tissue dissection methods. We then performed NanoString analysis of 151-CaP probe set on 63 archived CaP samples to evaluate this modified protocol. ERG gene expression was validated by immunohistochemistry (IHC) assay using CPDR ERG-MAb (9FY).
Results: We have performed NanoString analysis of CPDR designed 151- CaP gene panel on whole-mounted prostate tissue specimens using our optimized protocol. The prostate epithelial cell markers KLK3, MSMB and PAP had the highest signals in all samples reflecting the prostate epithelial origin of the specimens. Established CaP specific genes, such as AMACR, PCA3 and PSGR were most highly over-expressed in tumors compared to matched benign prostate epithelium. ERG positive tumors had strong expression of both TMPRSS2-ERG fusion probes and probes for several ERG splice forms (ERG 1,2,3 and 8), with no signals in the matched benign samples. The ERG gene expression status was consistent with blinded ERG IHC results.
Conclusions: The feasibility of NanoString profiling in archived whole mounted FFPE prostate specimens was demonstrated. This approach is well suited for a medium throughput evaluation and validation of prognostic biomarker and therapeutic target candidates in CaP.
Citation Format: Jocelyn Lee, Wusheng Yan, Denise Young, Yingjie Song, Yongmei Chen, Shilpa Katta, Ahmed Mohamed, Lakshmi Ravindranath, Alagarsamy Srinivasan, Jennifer Cullen, Jacob Kagan, Sudhir Srivastava, Albert Dobi, Inger Rosner, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava, Gyorgy Petrovics. Evaluation of prostate cancer biomarkers and therapeutic targets in FFPE specimens using the NanoString platform. [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 2016. doi:10.1158/1538-7445.AM2015-2016
Abstract 2017: Development of ultrasensitive Singulex immunoassays for CCL3 and CCL4, important biomarkers for the BTK inhibitor studies
Authors: Wu Jenny Q. , Burton Luciana , Raja Rajiv , McCaffery Ian , Penuel Elicia , Darbonne Walter 
Published: August 2015

Abstract
Disregulation of B-Cell Receptor (BCR) leading to activation has been associated with a number of B-cell malignancies including Chronic Lymphocytic Leukemia (CLL) [1]. In response to BCR activation, B-cells secrete chemokines CCL3 and CCL4 that foster interactions between CLL cells and the leukemia microenvironment and to recruit T-cells. High levels of CCL3 have also been correlated with poor prognosis in CLL [2]. Bruton tyrosine kinase (BTK) has long been known to be a key component of B cell receptor (BCR) signaling that regulates B cell proliferation and survival. BTK inhibitors such as lbrutinib have been shown to disrupt secretion of BCR-dependent chemokines (CCL3/CCL4) and thereby reduce plasma concentrations in patients [3]. Consequently, these chemokines have been measured as pharmacodynamic biomarkers in a number of studies of molecules that inhibit BCR signaling [3]. However, baseline CCL3/CCL4 levels in CLL patients vary widely and are less than 10 pg/ml in a large proportion of patient samples, making detection of these cytokines in clinical samples challenging using existing immunoassays. In an effort to improve sensitivity of CCL3/CCL4 measurements in plasma samples, we developed ultrasensitive assays for CCL3 and CCL4 using the Singulex immunoassay platform. A direct comparison of multiple, commercially available immunoassays technologies and our optimized CCL3/CCL4 Singulex assay were performed using plasma samples from both healthy donors and CLL patients. Singulex proprietary Single Molecule Counting (SMCTM) technology combining digital counting enables the quantification of CCL3 and CCL4 with sensitivity of 0.37pg/ml and 0.15pg/ml respectively in plasma. This ultrasensitive assay has the potential to enable more robust and quantifiable measurements of CCL3 and CCL4 in the context of clinical studies testing BTK inhibitors.
Citation Format: Jenny Q. Wu, Luciana Burton, Rajiv Raja, Ian McCaffery, Elicia Penuel, Walter Darbonne. Development of ultrasensitive Singulex immunoassays for CCL3 and CCL4, important biomarkers for the BTK inhibitor studies. [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 2017. doi:10.1158/1538-7445.AM2015-2017