bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1329: Inhibition of papillary thyroid cancer cells progression by targeting skp2 via ros-erk-chop-dr5 pathways
Authors: Poyil Pratheeshkumar , Bu Rong , Siraj Abdul K. , P Sandeep Kumar , Al-Kuraya Khawla S. 
Published: July 2017

Abstract
S-phase kinase protein 2 (SKP2), is an F-box protein with proteasomal properties and has been found to be overexpressed in a variety of cancers. However its role in papillary thyroid cancer (PTC) has not been elucidated. Therefore, inactivation of SKP2 could be a viable strategy for the treatment of PTC. In the present study, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in PTC using a tissue microarray cohort of 1022 PTC samples, PTC cell lines and Nude mouse model. Our immunohistochemistry data showed that SKP2 was over-expressed in 75.1% of PTC cases and was clinically, significantly associated with extra thyroidal extension (p=0.0331), Tall cell variant (p=0.0070), and presence in surgical margins (p=0.0347). Bortezomib as well as SKP2 specific siRNA caused downregulation of SKP2 leading to dose-dependent growth inhibition and induction of apoptosis via mitochondrial apoptotic pathway in PTC cell lines. Furthermore, we found that treatment of PTC cells with Bortezomib caused up-regulation of DR5 via generation of reactive oxygen species (ROS). Finally, Bortezomib treatment augmented TRAIL mediated anti-cancer effect on PTC xenograft tumor growth in nude mice. These data suggest that Bortezomib is a viable therapeutic option for the treatment of PTC either alone or in combination with other apoptotic agents such as TRAIL.
Note: This abstract was not presented at the meeting.
Citation Format: Pratheeshkumar Poyil, Rong Bu, Abdul K. Siraj, Sandeep Kumar P, Khawla S. Al-Kuraya. Inhibition of papillary thyroid cancer cells progression by targeting skp2 via ros-erk-chop-dr5 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1329. doi:10.1158/1538-7445.AM2017-1329
Abstract 133: Aloe-emodin as a potential lead targets lung cancer stem cells
Authors: Lee Pei-Jung , Chen Wan-Jiun , Ho Chao-Chi , Yang Pan-Chyr , Chen Huei-Wen 
Published: July 2017

Abstract
Cancer stem cells (CSCs) have been proposed to be responsible for tumor initiating, drug resistance, metastasis, and recurrence. Many novel therapeutic strategies have been designed to target and eliminate CSCs. According to our previous study, we have established a model of CSCs and cancer associated fibroblasts (CAFs) co-culture system for anti-CSCs drug screening. Here, we report one of the potential hits screened via this platform and the anti-CSCs activity was further investigated both in vitro and in vivo. Human lung CSCs and CAFs were primary cultured from patient with lung adenocarcinoma according to our previous study. Image-based high content screening system was used to analyze different parameters after drug treatment. Tumorogenicity and self-renew ability are examined by sphere forming ability. Aldehyde dehydrogenase (ALDH) activity was used to analyze stem cell population by flow cytometry. The expression level of stemness-related genes, Nanog, Oct3/4 and Sox2 were validated by real-time reverse transcriptase Q-PCR. The efficacy of the lead on tumor growth was examined by the xenograft model. Lung cancer stemness markers of the xenograft tumor tissues were also evaluated by immunohistochemistry. Using the image-based high content screening system to screen over one thousands of compounds, we have identified aloe-emodin (AE) shows higher potency targeting on lung cancer stem cells (under the concentration of 1 μM) and high specificity targeting on the cancer cell lines (IC50 &lt; 20 μM); compared to normal human bronchial epithelium cells and human normal fibroblast represented by IC50 (26.77 μM v.s. 39.13 μM). The level of stemness markers, Nanog, Sox2 and Oct3/4 were significantly down regulated after AE treatment compared to cisplatin treatment. AE could suppress tumor initiating abilities and self-renew capacities represented by the ability to grow as tumors spheres in CL152 ALDH+ cells. Besides, AE could inhibit ALDH population in CL152 cells (40% reduced). Also, the AE can inhibit the cisplatin-induced ALDH population as well. Furthermore, we found that AE combine with cisplatin could inhibit tumor growth as comparing to cisplatin treatment in subcutaneous models in NOD/SCID mice, whereas, AE can inhibit the level of Nanog in mice tumor tissues. According to these results, AE is a potential lead targeting on lung cancer stem cells. To discover the pharmacological mechanism of AE on cancer stem cells will be helpful to develop new strategy for lung cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Pei-Jung Lee, Wan-Jiun Chen, Chao-Chi Ho, Pan-Chyr Yang, Huei-Wen Chen. Aloe-emodin as a potential lead targets lung cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 133. doi:10.1158/1538-7445.AM2017-133
Abstract 1333: Cross talk between mitogen-activated protein kinase signaling cascades and Wnt/β-catenin in HER2+ overexpressing breast cancer cells
Authors: Nava Miguel , Amobi Nwamaka A. , Wu Yanyuan , Farias-Eisner Robin , Vadgama Jay 
Published: July 2017

Abstract
Introduction: The HER2-positive breast cancer is characterized by an amplification of the HER2 gene, resulting in an increase in HER2 presence on the surface of cells and magnification of downstream intracellular signaling. Treatment of HER2+ breast cancer with trastuzumab decreases tumor volume, reduces metastasis and increases overall survival. Unfortunately, HER2-positive breast cancers develop resistance to trastuzumab. The mechanism of resistance may involve the activation of compensatory networks of different cell signaling pathways. The purpose of the study is to examine the crosstalk between HER2/EGFR and Wnt signaling in HER2-positive breast cancer cells.
Methods: In order to address this, a HER2-positive breast cancer cell line (SKBR3) was used and induced with EGF. The phosphorylation of p38 and ERK1/2 was determined by Western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by western blot analysis.
Results: Our data demonstrated an early and transient peak of phospho-p38 at 30min post EGF treatment. Interestingly, both phospho-p38 and phospo-ERK1/2 were detected in the nuclear compartment at this time. β-catenin, the major effector molecule in Wnt signaling, was stabilized 30min post EGF treatment. β-catenin protein levels remained higher in EGF treated cells than untreated cells up to 4h post EGF treatment. It is likely that a stabilized β-catenin following EGF treatment potently modulates a subset of Wnt targets. We are assessing this possibility using chromatin immunoprecipitation based experiments for H3K18ac, H3K27ac, pol2 and β-catenin. Taken together, our data suggests that EGFR signaling promotes Wnt signaling in HER2-positive breast cancer cells. We hypothesize that this promotes cancer stem cell niche maintenance and an EMT phenotype.
Citation Format: Miguel Nava, Nwamaka A. Amobi, Yanyuan Wu, Robin Farias-Eisner, Jay Vadgama. Cross talk between mitogen-activated protein kinase signaling cascades and Wnt/β-catenin in HER2+ overexpressing breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2017-1333
Abstract 1352: The importance of the RASA1/R-Ras/Ral-A signaling axis in melanoma tumorigenesis
Authors: Hill Kristen Suzanne , Wang Xue , Kim Youngchul , Kim Minjung 
Published: July 2017

Abstract
The Ras family of small GTP binding proteins are frequently activated by mutations in melanoma, as shown for NRAS (20%), KRAS (2%) and HRAS (1%). Ras isoforms can also be activated by inactivation of Ras GTPase activating proteins (RasGAPs), such as NF1, RASA1, and RASA2. In our recent study, we observed that inactivation of RASA1 (RAS p21 protein activator 1, also called p120RasGAP) suppressed melanoma via its RasGAP activity toward the R-Ras (related RAS viral (r-ras) oncogene homolog) isoform and that R-Ras was required to promote anchorage-independent growth driven by RASA1 inactivation. Moreover, a low level of RASA1 mRNA expression is associated with decreased overall survival in melanoma patients with BRAF mutations. Based on these observations, we hypothesized that, although not mutated, R-Ras is activated in melanoma by inactivation of RasGAPs and that BRAF activation cooperates with this RasGAP/R-Ras pathway activation in melanoma tumorigenesis. In this study, we addressed the importance of R-Ras, a previously less appreciated member of the Ras small GTPases family, in melanoma tumorigenesis. We observed frequent activation of R-Ras in BRAF mutant human melanoma cell lines. In addition, RNAi-mediated reduced expression of R-Ras suppressed anchorage-independent colony growth and tumor growth. Moreover, among the 3 major RAS effector pathways, reduced R-Ras expression suppressed Ral-A activation, which may explain the mechanism of Ral-A activation in BRAF mutant melanoma. Interestingly, anchorage-independent growth driven by R-Ras activation downstream of RASA1 inactivation was suppressed by both genetic (siRNA targeting Ral-A) and pharmacological (Ral inhibitor BQU57) inhibition of Ral-A. To further investigate the impact of RASA1 loss, and thus R-Ras activation, on BRAF mutant melanoma development in vivo, we generated a RASA1L/L; BRAFCA/CA; Tyr-CreERT2 mouse model in which treatment with 4OHT results in expression of constitutively activated mutant BRAF and deletion of RASA1 in melanocytic lineage cells. Preliminary analysis shows hyperpigmentation of the ear, tail, and foot pad in RASA1L/L BRAFCA/CA mice compared to RASA1+/+ BRAFCA/CA littermates. Tumors generated in this animal model will be analyzed to determine the extent of R-Ras and Ral-A activity in vivo. This study demonstrates the importance of the RASA1/R-Ras/Ral-A signaling pathway in BRAF mutant melanoma and supports the possible combinatorial treatment strategy targeting both the BRAF/MAPK and Ral signaling pathways.
Citation Format: Kristen Suzanne Hill, Xue Wang, Youngchul Kim, Minjung Kim. The importance of the RASA1/R-Ras/Ral-A signaling axis in melanoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1352. doi:10.1158/1538-7445.AM2017-1352
Abstract 1367: The dynamic mechanism of SARAH domain in RASSF5 activation by K-Ras4B
Authors: Liao Tsung-Jen , Jang Hyunbum , Tsai Chung-Jung , Fushman David , Nussinov Ruth 
Published: July 2017

Abstract
RASSF5 is a tumor suppressor, which acts as an adaptor linking Ras and the Hippo pathways. RASSF5 activates MST1/2, a key upstream protein of the Hippo pathway, through SARAH domain heterodimerization, resulting in Hippo signaling. Signaling stimulates YAP1 phosphorylation, leading to its degradation and thereby cell apoptosis. Association with K-Ras4B promotes RASSF5 to release its SARAH which heterodimerizes with MST1/2. We aim to reveal how K-Ras4B regulates the Hippo pathway through RASSF5 by resolving the structure and conformational dynamics of RASSF5 complexes. Our modeling and simulations help elucidate the intrinsic dynamic interactions of RASSF5 RA (Ras binding) and SARAH domains. Surprisingly, we found that the residue E388 on RASSF5 SARAH plays a significant role in the dynamic mechanism of SARAH homo-/hetero- dimerization and the RA-SARAH association. The mutants E388A and E388K dramatically decrease the strength of RASSF5 homo-SARAH and RASSF5-MST2 hetero-SARAH, suggesting that the E388 mutation may be oncogenic. Simulations of selected RASSF5 configurations with GTP-bound K-Ras4B indicate that the interactions between RA and SARAH are reduced. We conclude that Ras binding weakens the RA-SARAH association, increasing the SARAH dynamic fluctuation. The released RASSF5 SARAH has high propensity to dimerize with MST1/2 SARAH, activating Hippo signaling thus cancer suppression. Funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH under contract HHSN261200800001E.
Citation Format: Tsung-Jen Liao, Hyunbum Jang, Chung-Jung Tsai, David Fushman, Ruth Nussinov. The dynamic mechanism of SARAH domain in RASSF5 activation by K-Ras4B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1367. doi:10.1158/1538-7445.AM2017-1367
Abstract 1370: EGFR-mediated Spred1 phosphorylation inhibits NF1 to sustain constitutive Ras/MAPK signaling
Authors: Markegard Evan , Mercado Ellen L. , Silva Jillian M. , Galeas Jacqueline , Trinidad Marena I. , Urisman Anatoly , McCormick Frank 
Published: July 2017

Abstract
Spred proteins negatively regulate Ras/MAPK signaling following growth factor stimulation. Inhibition of Ras primary occurs through Spreds ability to bind and localize NF1, a RasGAP and major tumor suppressor, to the plasma membrane. Spred1 and NF1 loss-of-function mutations occur across multiple cancer types including non-small cell lung carcinoma, glioblastoma, melanoma, stomach carcinoma, and uterine carcinosarcoma. Here we demonstrate that EGFR signaling disrupts Spred1-NF1 binding. Mass spectrometry was performed on cells overexpressing EGFRL858R to identify potential phosphorylation sites on Spred1 and NF1 that could disrupt Spred1-NF1 binding by steric hindrance. A serine phosphorylation site on Spred1 was identified in which a phosphomimetic and phosphodeficient mutant decreased or increased Spred1-NF1 binding, respectively. Phosphomimetic Spred1 is unable to suppress Ras-GTP following EGF stimulation. Therefore, phosphorylation of Spred1 at this site by a serine kinase downstream of EGFR may disrupt Spred1-NF1 binding. To identify the Spred1 kinase we are performing an in vitro kinase assay and an unbiased CRISPRa screen. Our findings provide one potential mechanism by which EGFR signaling disrupts negative feedback to sustain constitutive Ras signaling. Furthermore, this work may elucidate a novel therapeutic target for restoring NF1-mediated inhibition of Ras.
Citation Format: Evan Markegard, Ellen L. Mercado, Jillian M. Silva, Jacqueline Galeas, Marena I. Trinidad, Anatoly Urisman, Frank McCormick. EGFR-mediated Spred1 phosphorylation inhibits NF1 to sustain constitutive Ras/MAPK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1370. doi:10.1158/1538-7445.AM2017-1370
Abstract 1380: Expression and functions of ASH1L in liver cancer
Authors: Wei Lai , Tsang Felice H. , Ho Daniel , Law Cheuk-Ting , Chen Mengnuo , Tsang Long-Hin , Wong Carmen Cl , Ng Irene Ol , Wong Chun-Ming 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is a common cancer and ranks the third lethal cancer worldwide. However, the detail molecular mechanisms underlying the initiation and progression of HCC remain poorly understood. Liver carcinogenesis is a multistep process that is driven by the accumulation of genetic and epigenetic alterations. Mutational landscape and driver mutations have recently been delineated by high-throughput sequencing studies. On the other hand, our current knowledge about epigenetic deregulation in human HCC is limited. Histone modification is a major component of epigenetic regulation, and deregulation of histone medication could alter local chromatin structure and gene expression. We hypothesized that deregulation of histone methyltransferases might contribute to HCC development. In this study, we showed that trithorax-group protein ASH1L was frequently up-regulated in human HCC. Overexpression of ASH1L was detected in 40% of primary HCCs and significantly associated with larger tumor size, present of venous invasion and tumor microsatellite formation. Up-regulation of ASH1L also correlated with increased Ki67 expression. ASH1L is a histone methyltransferase specific for catalyzing transcriptional-active H3K4 and H3K36 methylation. We showed that stable knockdown of ASH1L significantly suppressed HCC cell proliferation and colony formation. We further demonstrated that knockdown of ASH1L inhibited HCC cell migration. In addition, we investigated the underlying mechanisms contribute to ASH1L up-regulation. We showed that up-regulation of ASH1L in human HCC was contributed by chromosome amplification at chromosome 1q22. Furthermore, we showed that ASH1L was negatively regulated by miR-142. Therefore, down-regulation of miR-142 contributed to ASH1L up-regulation in HCC. In summary, our findings suggested that ASH1L was frequently up-regulated in human HCC due to chromosome amplification and miRNA deregulation.
Citation Format: Lai Wei, Felice H. Tsang, Daniel Ho, Cheuk-Ting Law, Mengnuo Chen, Long-Hin Tsang, Carmen Cl Wong, Irene Ol Ng, Chun-Ming Wong. Expression and functions of ASH1L in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1380. doi:10.1158/1538-7445.AM2017-1380
Abstract 1388: SphK2/S1P axis regulates hypoxia-mediated HIF-α synthesis in breast cancer cells
Authors: Hait Nitai C. , Maiti Aparna 
Published: July 2017

Abstract
The hypoxia-inducible transcription factors (HIF)-1α and -2α play a critical role in cellular response to hypoxia in solid tumors. Elevated HIF-α expression correlates with poor patient survival in a large number of cancers including breast cancers. HIF-α activates expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. Understanding transcriptional regulation HIF-α under physiologically relevant hypoxic conditions would be helpful to reduce breast cancer growth. Our recent studies identified that intracellular bioactive sphingosine-1-phosphate (S1P) generated from nuclear sphingosine kinase 2 (SphK2) acts as an endogenous modulator of histone deacetylases (HDACs) epigenetically regulates gene transcription in breast cancer cells. We wonder whether nuclear S1P epigenetically regulates acetylated histones, positive transcription marks in hypoxia and regulate transcription of HIF-α and target genes in breast cancer cells. We have used estrogen receptor positive human breast cancer MCF-7 cells, triple-negative human breast cancer MDA-231 cells, and lung metastatic LM-2-4 cells derived from MDA-231 cells cells for our studies. We found that hypoxic condition enhances nuclear bulk histone acetylation in breast cancer cells and enhances HIF-α synthesis. Down regulation of SphK2 with siRNA or using selective inhibitor of SphK2 (K145 compound) reduces nuclear S1P as well as bulk histone acetylation and consequently reduces nuclear HIF-α synthesis in breast cancer cells. Downregulation of cytosolic sphingosine kinase 1 (SphK1) with siRNA reduces cytosolic S1P does not alter nuclear bulk histone acetylation neither significantly alter nuclear HIF-α synthesis in breast cancer cells. We also found that targeting SphK2 with K145 compound dramatically reduces in vitro tumorosphere formation in breast cancer cells. Our data suggested that targeting the SphK2/S1P signaling could represent an attractive strategy for therapeutic intervention in hypoxic breast cancers. Supported by Health Research, Inc. (HRI) Grant 71-4084 (NCH), National Cancer Institute Grant R01CA160688 (KT).
Citation Format: Nitai C. Hait, Aparna Maiti. SphK2/S1P axis regulates hypoxia-mediated HIF-α synthesis in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1388. doi:10.1158/1538-7445.AM2017-1388
Abstract 1391: The epigenetic regulator, G9a, is a KRAS-inducible protein and its inactivation inhibits PanIN formation by this oncogene
Authors: Mathison Angela , Salmonson Ann , Paradise Brooke , Missfeldt Mckenna , Iovanna Juan , Billadeau Daniel , Urrutia Raul , Lomberk Gwen 
Published: July 2017

Abstract
Pancreatic ductular adenocarcinoma (PDAC) ranks fourth as a cause of cancer death in the USA and is almost universally fatal, with the annual number of deaths equivalent to the number of newly diagnosed cases. Valuable research in the field has revealed genetic aberrations that contribute to PDAC development and progression, with KRAS being one of the most frequent mutations in more than 90% of patient samples. However, to date, any efforts to directly target KRAS have failed in the clinic. Thus, there is indisputably an urgent need to further improve our understanding of molecular mechanisms underlying PDAC development as to identify novel therapeutic targets, including druggable important downstream targets and nodes orchestrated by oncogenic KRAS. In particular, we are interested in epigenetic pathways involved in PDAC development and progression due to the potential reversibility of any alteration, unlike genetic mutation. In the current study, using a cell model that allows inducible expression of mutant KRASG12D, we find that protein levels of the dimethyl-K9H3 histone methyl transferase (HMT), G9a, and its complex partners are increased in response to activation of the oncogenic Kras pathway. Furthermore, the activation of this oncogenic pathway results in the formation of the G9a-GLP-Wiz trimer complex, as determined by affinity protein purification, combined with mass spectrometry. In vivo experiments involving the cross of the Pdx1-CRE/LSL-KRASG12D mice with G9afl/fl animals demonstrate that a loss of the H3K9Me2 mark in the nucleus of exocrine cells is accompanied by a significantly reduced number of PanIN lesions. RNA-Seq experiments from these animals reveal that these mice have reduced levels of typical molecular markers of PanINs. In addition, these experiments show changes in the levels in several genes, which have been previously been shown to synergize with Kras to mediate pancreatic cancer initiation. Congruently, pharmacological inhibition of G9a using BRD4770 displays an inhibitory effect on KRASG12D-induced cell proliferation. Combined, these data provide evidence for a key role of the meK9H3-G9a pathway as a mediator of the oncogenic Kras response and defines a novel point of potential therapeutic intervention for PDAC.
Citation Format: Angela Mathison, Ann Salmonson, Brooke Paradise, Mckenna Missfeldt, Juan Iovanna, Daniel Billadeau, Raul Urrutia, Gwen Lomberk. The epigenetic regulator, G9a, is a KRAS-inducible protein and its inactivation inhibits PanIN formation by this oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1391. doi:10.1158/1538-7445.AM2017-1391