bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4061: A novel CXCR4-mediated mechanism of docetaxel resistance in prostate cancer cells.
Authors: Bhardwaj Arun , Srivastava Sanjeev K. , Arora Sumit , Hyde Stephen J. , Andrews Joel F. , McClellan Steven , Singh Seema , Singh Ajay P. 
Published: August 2014

Abstract
Docetaxel (DTX), a semi-synthetic analog of paclitaxel, has emerged as the standard of care for chemotherapy of hormone-resistant prostate cancer. DTX confers its anti-neoplastic activity by inhibiting microtubule depolymerization, which leads to G2/M cell cycle arrest and subsequent apoptosis. However, most patients treated with DTX ultimately develop resistance to the drug and succumb to the disease. Therefore, understanding the mechanisms underlying DTX resistance is a priority area in prostate cancer research. Increasingly, it is being suggested that cancer cells may use common pathways for disease aggressiveness/metastatic spread and chemotherapeutic resistance. Therefore, we investigated the role of CXCL12/CXCR4 signaling, which is known to promote invasion and metastasis, in DTX-resistance of prostate cancer cells. Our data demonstrated that CXCL12 treatment rescued the prostate cancer cells from DTX-induced cytotoxicity and G2/M mitotic arrest. Furthermore, the cytoprotective effect of CXCL12 was abolished upon pretreatment of prostate cancer cells with AMD3100 (a small molecule antagonist of CXCR4) or siRNA-mediated silencing of CXCR4, thus confirming the role of CXCR4 in DTX-resistance. Immunofluorescence analyses revealed enhanced polymerization of microtubules in DTX-treated prostate cancer cells. In accordance with this, immunoblot analyses demonstrated increased levels of detyrosinated (glu-) and acetylated (ace-) tubulins, specific markers of the polymerized tubulin, in prostate cancer cells treated with DTX. Co-treatment of CXCL12 abrogated DTX-induced stabilization of microtubules in the prostate cancer cells, an effect that was diminished when the cells were pre-treated with AMD3100. Altogether, these initial findings demonstrate the role of CXCL12/CXCR4 signaling axis in DTX-resistance of prostate cancer cells and thus could be an attractive target for therapeutic enhancement of DTX.
Citation Format: Arun Bhardwaj, Sanjeev K. Srivastava, Sumit Arora, Stephen J. Hyde, Joel F. Andrews, Steven McClellan, Seema Singh, Ajay P. Singh. A novel CXCR4-mediated mechanism of docetaxel resistance in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4061. doi:10.1158/1538-7445.AM2013-4061
Abstract 4062: Clusterin downregulation sensitize prostate cancer cells to taxane by modulating mitosis.
Authors: Al Nakouzi Nader , Beraldi Eliana , Shepherd Stuart , Loriot Yohann , Kim Soojin , Leichmann Lauren , Zoubeidi Amina , Gleave Martin E 
Published: August 2014

Abstract
Clusterin (CLU) is a stress-activated molecular chaperone closely linked to treatment resistance and cancer progression. CLU is a novel therapeutic anti-cancer target with both preclinical and phase II clinical proof of concept using the antisense OGX-011 inhibitor; phase III clinical trials of combination docetaxel + OGX-011 are underway.
Cytotoxic chemotherapy drugs like taxane are believed to gain selectivity by targeting cells that are in mitosis. When cultured cancer cells are treated with taxane, only cells that enter mitosis are killed or rendered senescent. Quiescent cells or cycling cells that do not reach mitosis during drug exposure are spared. In this sense, sentisizing cells to taxane can occur through mitosis regulation.
In this study, we show that CLU downregulation enhances cytotoxicity of the new generation taxane cabazitaxol. Treatment of PC3 human prostate cancer cells with cabazitaxol induces G2/M arrest followed by mitotic death. Downregulation of CLU accelerated these G2/M associated events and resulted in reduced cabazitaxol EC50 and clonogenic survival upon cabazitaxol treatment. To investigate the mechanisms that allow CLU deficient cells to respond to taxane and examine whether this response is linked to a role of CLU in the control of cell cycle progression, we knocked down CLU expression in PC3 and LNCaP cells and found an accumulation of cells in G2/M phase and a reduction in cell growth. The screening of different cell cycle effectors after CLU downregulation in different cell lines and xenografts shows that CLU specifically regulates Cdc25C, while the two other Cdc25 isoforms, A and B, are not affected. Interestingly Cdc25C is a key regulator of mitosis initiation and exit. Importantly, we show that Cdc25C and CLU expression negatively correlate in prostate cancer cell lines, xenografts and human biopsies. When CLU is down regulated, Cdc25C transcription increased resulting in protein accumulation; as a consequence, cells showed G2/M blockage and slower mitotic progression. Accordingly, we suggest that down regulation of CLU alters sensitivity to taxane by modulating exit from mitosis, which is controlled by Cdc25C.
Citation Format: Nader Al Nakouzi, Eliana Beraldi, Stuart Shepherd, Yohann Loriot, Soojin Kim, Lauren Leichmann, Amina Zoubeidi, Martin E Gleave. Clusterin downregulation sensitize prostate cancer cells to taxane by modulating mitosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4062. doi:10.1158/1538-7445.AM2013-4062
Abstract 4063: Histone methyltransferase G9a promotes the oral cancer cells recovery from drug-induced DNA damage.
Authors: Liu Chia-Wen , Cha Shih-Ting , Tan Ching-Ting , Kuo Min-Liang 
Published: August 2014

Abstract
Oral cancer is one of the serious life-threatening diseases in the world. In addition to surgery, the conventional treatment for oral cancer includes radiation and anti-cancer drugs, which usually act by induction of DNA damage. However, approximately one-third of treated patients will experience local or regional recurrence. G9a is a histone methyltransferase responsible for mono- or dimethylation of lysine 9 in histone H3. Our recent work has demonstrated that G9a level is highly correlated with aggressiveness and poor prognosis of lung, ovarian and colon cancer patients in Taiwanese population. Here, we report that knockdown of G9a resulted in decrease cell survival and cologenic capacity following DNA damage induced independently by etoposide and ionizing radiation. Depletion of G9a caused sustained phosphorylation of γ-H2AX after etoposide treatment. Together, our data suggest that a novel function of G9a may increase the DNA repair efficiency and promote the oral cancer cells recovery and survival from the DNA damage agents. We suggest that G9a may contribute to oral cancer proliferation by improvement of homologous recombination repair of DNA double break. Our study paves the way for exploring the blockade of G9a overexpression as a novel approach for the prevention and treatment of oral cancer.
Citation Format: Chia-Wen Liu, Shih-Ting Cha, Ching-Ting Tan, Min-Liang Kuo. Histone methyltransferase G9a promotes the oral cancer cells recovery from drug-induced DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4063. doi:10.1158/1538-7445.AM2013-4063
Abstract 4069: FGFR2 expression and mutation are rare in papillary renal cell carcinoma.
Authors: Tsimafeyeu Ilya V. , Wynn Nigel , Gordiyev Marat , Khasanova Alfia 
Published: August 2014

Abstract
Papillary renal cell carcinoma (pRCC) is the second most common type of renal cell carcinoma (RCC). Fibroblast growth factor receptor (FGFR) 1 signaling has been implicated to play a role in RCC (Tsimafeyeu et al. ASCO meeting 2010). We evaluated expression and mutational activation of FGFR2 as a potential target for therapy of pRCC.
Formalin-fixed, paraffin-embedded specimens of removed 71 primary tumors from untreated pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 62 paraffin-embedded pRCC samples.
Expression of FGFR2 was observed in 8.5% of primary pRCC (6/71). Intensity was 3+ in all cases. 2 of 71 (3%) patients had nuclear FGFR2 expression. FGFR2 S252W mutation was detected at low frequency (1/62, 1.6%) in pRCC (type I). No N549K mutation was detected in pRCC (0/43).
FGFR2 expression and mutation are rare across papillary types of RCC.
This study was supported by Mr. Sergey Kartashov.
Citation Format: Ilya V. Tsimafeyeu, Nigel Wynn, Marat Gordiyev, Alfia Khasanova. FGFR2 expression and mutation are rare in papillary renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4069. doi:10.1158/1538-7445.AM2013-4069
Abstract 4108: SGEF is overexpressed in glioblastoma and mediates TWEAK-Fn14 induced cell survival.
Authors: Fortin Shannon P. , Mathews Ian T. , Rollo Jonathan , Ross Julianna T.D. , Symons Marc H. , Sarkaria Jann N. , Tran Nhan L. 
Published: August 2014

Abstract
Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide (TMZ), GB tumors develop treatment resistance and recur, invading brain tissue. Impaired response to treatment occurs rapidly conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance and spread in order to develop targeted therapies to combat this refractory setting. Our lab has previously published a role for the TWEAK-Fn14 ligand-receptor system in GB cell invasiveness and survival. Here we report that SGEF, a RhoG specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and we hypothesize that SGEF plays an important role in promoting TWEAK-Fn14 mediated glioma invasion and survival. We show that upon TWEAK binding to Fn14, SGEF is recruited to the Fn14 cytoplasmic tail. The Fn14-SGEF interaction requires TRAF2 recruitment and leads to activation of Rac1. Importantly, SGEF mRNA expression is elevated in TMZ-resistant primary GB tumor grafts compared to those with known TMZ sensitivity. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-κB dependent manner and inhibition of SGEF expression via shRNA shutdown sensitizes glioma cells to TMZ-induced apoptosis and impairs colony formation following TMZ insult. Furthermore, gene expression analysis of SGEF depleted GB cells revealed impaired expression of a network of DNA repair and survival genes including ATM, ATR, BRCA2, and XIAP among others, as well as increased expression of the pro-apoptotic gene BAD. Understanding the role of SGEF in promoting chemotherapeutic resistance may direct the development of novel targeted therapeutics for TMZ refractory, invasive GB cells.
Citation Format: Shannon P. Fortin, Ian T. Mathews, Jonathan Rollo, Julianna T.D. Ross, Marc H. Symons, Jann N. Sarkaria, Nhan L. Tran. SGEF is overexpressed in glioblastoma and mediates TWEAK-Fn14 induced cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4108. doi:10.1158/1538-7445.AM2013-4108
Abstract 412: SEC11A contributes to malignant progression through promotion of EGF and TGF-α secretion in gastric cancer.
Authors: Oue Naohide , Hayashi Tetsutaro , Ito Reiko , Nagatsuma Akiko , Sentani Kazuhiro , Sakamoto Naoya , Anami Katsuhiro , Uraoka Naohiro , Naito Yutaka , Yanagihara Kazuyoshi , Ochiai Atsushi , Sasaki Hiroki , Yasui Wataru 
Published: August 2014

Abstract
Gastric cancer (GC) is one of the most common human cancers. We previously performed Serial Analysis of Gene Expression (SAGE) on four primary GCs and identified several GC-specific genes. In the present study, we have built an in-house oligonucleotide array on which 394 genes selected based on our SAGE data and previously reported array data to allow for the study of the genes that are most relevant to gastric carcinogenesis. We focused on the SEC11A gene, which encodes SPC18 protein. SPC18 is one of the member of signal peptidase complex. SPC18 mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in GC tissue samples. Expression and distribution of SPC18 protein was investigated by immunohistochemistry in two independent GC cohorts (Hiroshima cohort, n = 99 and Chiba cohort, n = 989). To determine the effect of SPC18 on cell growth and invasiveness in vitro, MTT and Boyden chamber invasion assays were performed. To evaluate the influence of SPC18 on cell growth in vivo, GC cells were injected into SCID mice. The levels of TGF-α and EGF in media from the GC cells were measured by ELISA. Overexpression of SEC11A mRNA was observed in 40% of GC cases by qRT-PCR. Immunohistochemical analysis of SPC18 revealed that 26% of GC cases were positive for SPC18 in Hiroshima cohort and 20% of GC cases were positive for SPC18 in Chiba cohort. SPC18-positive GC cases showed poorer survival than SPC18-negative GC cases in both Hiroshima cohort and Chiba cohort by Kaplan-Meier analysis. Forced expression of SPC18 activates GC cell growth in vitro and in vivo. The levels of TGF-α and EGF in culture media from GC cells were reduced by knockdown of SPC18. These results indicate that SPC18 contributes to malignant progression through promotion of EGF and TGF-α secretion in GC.
Citation Format: Naohide Oue, Tetsutaro Hayashi, Reiko Ito, Akiko Nagatsuma, Kazuhiro Sentani, Naoya Sakamoto, Katsuhiro Anami, Naohiro Uraoka, Yutaka Naito, Kazuyoshi Yanagihara, Atsushi Ochiai, Hiroki Sasaki, Wataru Yasui. SEC11A contributes to malignant progression through promotion of EGF and TGF-α secretion in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 412. doi:10.1158/1538-7445.AM2013-412
Abstract 4153: Arrayed microinjection of a ubiquitin activating enzyme inhibitor induces PD biomarker effects predictive of in vivo tumor responses to systemic drug delivery.
Authors: Hatton Beryl A. , Grenley Marc , Hedin Nathan , Caffo Nathan , Hyer Marc L. , Manfredi Mark , Blakemore Stephen , Klinghoffer Richard A. , Bence Neil 
Published: August 2014

Abstract
Presage technology enables simultaneous analysis of multiple cancer drug candidates, drug concentrations, and drug combinations within a single living tumor. The platform employs arrayed tumor microinjection technology that delivers multiple spatially defined “threads” of drug directly into discreet portions of a tumor. This enables rapid, reliable, and internally controlled cross comparisons of multiple cancer therapeutics using screening quantities of drug in an in vivo setting in which the local tumor microenvironment is maintained. Here, as an example, we apply the platform to investigate tumor responsiveness to an inhibitor of the ubiquitin activating enzyme UBA1 from Millennium Pharmaceuticals.
The ubiquitin activating enzyme UBA1 regulates ubiquitin activation and subsequent polyubiquitination of proteins necessary for their degradation by the proteasome, and functionally impacts cell signaling, DNA damage repair and cell cycle progression. In vivo tumor responses were evaluated in two human xenograft models, WSU-DLCL2 and MCF-7, grown as flank tumors in immune-compromised mice. Microdosing of multiple concentrations of the UBA1 inhibitor (UBAi) into both models led to localized, easily detectable, and drug concentration-dependent biomarker changes indicative of ubiquitin pathway perturbation in the area proximal to injected drug. This included loss of poly-ubiquitin, accompanied by the expected accumulation of cMyc in tumor regions exposed to the UBAi. Localized time-dependent tumor cell death responses were observed following pathway perturbation as quantified by staining for cleaved caspase-3 and gamma-H2AX staining. Furthermore, pathological evidence of UBAi-induced cell death was clearly visible in both tumor models upon histological examination of H&E stained slides. These results highlight the capacity of the Presage platform to perform multiplexed drug studies in live tumor models. This capability could readily be expanded for use in validating additional biomarker hypotheses, indication finding studies, or for efficient identification of novel drug combinations.
Citation Format: Beryl A. Hatton, Marc Grenley, Nathan Hedin, Nathan Caffo, Marc L. Hyer, Mark Manfredi, Stephen Blakemore, Richard A. Klinghoffer, Neil Bence. Arrayed microinjection of a ubiquitin activating enzyme inhibitor induces PD biomarker effects predictive of in vivo tumor responses to systemic drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4153. doi:10.1158/1538-7445.AM2013-4153
Abstract 416: S100P, a target gene of MACC1, contributes to colorectal cancer metastasis.
Authors: Schmid Felicitas , Wang Qing , Huska Matthew R. , Andrade-Navarro Miguel A. , Lemm Margit , Fichtner Iduna , Walther Wolfgang , Schlag Peter M. , Stein Ulrike S. 
Published: August 2014

Abstract
Colorectal cancer (CRC) is the second leading type of cancer in the Western world. About 90% of the deaths caused by this cancer arise from the formation of metastasis. We previously identified the new gene MACC1 (metastasis associated in colon cancer 1) as a prognostic marker for CRC metastasis. MACC1 regulates the expression of the well-known proto-oncogene Met (met proto-oncogene). An overexpression of MACC1 promotes in vitro and in vivo the metastatic potential of CRC cells. This project aims at the identification and functional characterization of new transcriptional target genes of MACC1. The genome-wide expression of SW480 CRC cells and a SW480/MACC1 clone was studied by microarray analysis. We found the gene S100P (S100 calcium binding protein P) as a highly upregulated gene in the MACC1 clone. S100P mRNA and protein expression levels in MACC1 transfected SW480 cells were significantly increased compared to control cells. A reduction of the endogenously high MACC1 expression in SW620 cells by MACC1-siRNA resulted in a decreased S100P expression. Furthermore, we showed that MACC1 bound to the promoter region of S100P in SW480/MACC1 cells. SW480 cells with an ectopic high S100P expression had a higher cell proliferation, migration and invasion compared to SW480 control cells. In contrast, a decrease of the high endogenous S100P expression in SW620 cells led to a lower proliferative, migratory and invasive potential. In a NOD SCID mouse model, animals intraspenically transplanted with control cells did not metastasize. In contrast, mice with S100P overexpressing cells developed liver metastasis (p&lt;0.0001). Finally, in human colorectal tumors the S100P expression was higher in tumors (stages II and III) which developed metachronous metastasis compared to non-metastasizing tumors (p=0.05). Colorectal cancer patients with a high S100P expression in their primary tumors had a shorter metastasis-free survival time compared to patients with S100P low expressing tumors (p=0.03, HR=0.37, 95% CI=0.13-0.90). Taken together, the gene S100P is a new transcriptional target gene of MACC1 and represents a biomarker for CRC metastasis as well as a target for therapeutical approaches.
Citation Format: Felicitas Schmid, Qing Wang, Matthew R. Huska, Miguel A. Andrade-Navarro, Margit Lemm, Iduna Fichtner, Wolfgang Walther, Peter M. Schlag, Ulrike S. Stein. S100P, a target gene of MACC1, contributes to colorectal cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 416. doi:10.1158/1538-7445.AM2013-416
Abstract 4162: MicroRNA-34 family is increased in human colon cancer and targets Peroxisome proliferator-activated receptor γ.
Authors: Hiyoshi Yukiharu , Schetter Aaron J. , Horikawa Izumi , Baba Hideo , Harris Curtis C. 
Published: August 2014

Abstract
Purpose: The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. The aim of this study is to elucidate the roles of miR-34 family in colon carcinogenesis.
Methods: MiR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR. We examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status, KRAS mutation status, promoter methylation and
Affymetrix microarray data. Ingenuity Pathway Analysis (IPA) identified transcriptional regulators that were involved with miR-34 expression. In vitro experiments were performed to identify the target gene of miR-34 family.
Results: All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression which is consistent with the proposed regulation of miR-34a/b/c by TP53. KRAS mutation status was associated with increased miR-34a expression. Hypermethylation of miR-34a and miR-34b/c was found in tumors. IPA found that the activity of the tumor suppressor gene Peroxisome Proliferator-Activated Receptor γ (PPARG) was negatively associated with miR-34 expression, and in vitro experiments identified PPARG as a direct target of miR-34 family.
Conclusion: miR-34 family may have important roles in colon carcinogenesis as oncogenic miRNAs by targeting PPARG.
Citation Format: Yukiharu Hiyoshi, Aaron J. Schetter, Izumi Horikawa, Hideo Baba, Curtis C. Harris. MicroRNA-34 family is increased in human colon cancer and targets Peroxisome proliferator-activated receptor γ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4162. doi:10.1158/1538-7445.AM2013-4162