bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4455: Identification of novel oncogene, copine-7 (CPNE7), in colorectal cancer
Authors: JEONG DONGJUN , Ban Seona , Kim Hyungjoo , Oh Seunghyun , Ji Sanghee , Kim Han Jo , Bae Sang Byung , Ahn Tae Sung , Kim Chang-Jin , Lee Moon Soo , Baek Moo-Jun 
Published: July 2017

Abstract
Background: CPNE7, a member of copine family, is composed of calcium-dependent membrane-binding proteins. The encoded protein may play a role in calcium-mediated intracellular processes and membrane trafficking mainly. Although this protein was known as tumor suppressor in breast cancer, we identified the possibility as an oncogene in colorectal cancer. In this study, we performed to evaluate the oncogenic functions of CPNE7 in the colorectal cancer cell line and the clinical significance of CPNE7 expression in colorectal cancer patients.
Method: The colorectal cancer cell lines (SW480, SW620, HCT116 and HT29) were transfected with siRNA for knockdown CPNE7. The oncogenic functions were identified in the transfected cell lines and compared them with CPNE7 highly expressing control cell lines. In vitro functional studies included cell proliferation assay, migration assay, invasion assay and semisolid agar colony forming assay. The clinical significance of CPNE7 expression was evaluated in 250 cases of colorectal cancer tissue by immunohistochemistry.
Results: The knockdowned cell lines significantly showed lower oncogenic function (proliferation, migration, invasion and colony forming) compared to the CPNE7 highly expressing control cell lines (p&lt;0.05). The overall survival rate was decreased in patients of CPNE7 high expression (p=0.03). Multivariate and univariate Cox-regression analysis showed that CPNE7 high expression was an independent prognostic factor in colorectal cancer (HR=1. 54, 95% CI=1. 00-2.38: p=0. 048 / HR=1. 58, 95% CI=1. 03-2.41: p=0. 032).
Conclusion: This study announces that CPNE7 is a novel oncogene, an independent prognostic factor and therapeutic target in colorectal cancer. In the future, studies on in vivo assay and identifying oncogenic signal pathways of CPNE7 in colorectal cancer are necessary.
Citation Format: DONGJUN JEONG, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Sang Byung Bae, Tae Sung Ahn, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek. Identification of novel oncogene, copine-7 (CPNE7), in colorectal 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 4455. doi:10.1158/1538-7445.AM2017-4455
Abstract 4511: HIF-1-dependent regulation of creatine kinase metabolism promotes breast cancer invasion and metastasis
Authors: Barch Hilaire , Brooks Danielle L. , Krutilina Raya , Schwab Luciana P. , Parke Deanna , Seagroves Tiffany N. 
Published: July 2017

Abstract
Dysregulated tumor cell metabolism is a hallmark of cancer progression and therapeutic resistance. In a screen for Hypoxia-Inducible Factor (HIF)-dependent genes regulating metabolism, we identified creatine kinase, brain isoform (CKB) as down-regulated in HIF-1 knockout mammary tumor cells. Creatine kinases (CKs) reversibly catalyze the transfer of a high-energy phosphoryl group from ATP to creatine, generating phosphocreatine in the forward reaction, and ATP in the reverse reaction. CKs are up-regulated in a variety of solid tumors, including ovarian, breast, colon, lung and brain. Knockdown of CKB in the polyoma middle T (PyMT) transgenic mouse model of metastatic breast cancer suppressed the production of intracellular ATP and invasion in vitro, and inhibited metastasis from the mammary gland to the lung in vivo. CK activity is known to be inhibited by cyclocreatine, a creatine kinase substrate that represses CK-dependent generation of ATP from phosphocreatine. When female FVB/Nj mice were injected with wild type PyMT cells in a tail vein assay and then treated with cCr (1g/kg/day, IP), lung metastasis was repressed to the same extent as Ckb gene knockdown. Moreover, when cCr therapy was administered 7 days after tail vein injection, cCr was effective in preventing the transition of lung micrometastases to macrometastases. To explore the role of CK activity in regulating cell proliferation, survival in suspension, cellular metabolism and invasion, we next created CKB loss- and gain-of-function models using human breast cancer cell lines, and compared phenotypes to cCr treatment. Whereas deletion of CKB had no effect on cell proliferation or survival in adherent conditions or in suspension, either deletion of CKB or cCr therapy potently reduced ATP levels and invasive potential in vitro. Preliminary data also indicate that pre-treatment of triple negative breast cancer cell lines with cCr sensitizes cells to doxorubicin. Together, these data suggest that inhibition of CK activity may be effective in treating stage IV breast cancer. We are currently testing whether cCr has anti-metastatic efficacy as a monotherapy, or in combination with conventional chemotherapies, using luciferase-labeled patient-derived xenograft (PDX) models.
This work was sponsored by the NIH (CA138488), the Dept. of Defense (BC150640), the METAvivor foundation, and the West Cancer Center in Memphis, TN.
Citation Format: Hilaire Barch, Danielle L. Brooks, Raya Krutilina, Luciana P. Schwab, Deanna Parke, Tiffany N. Seagroves. HIF-1-dependent regulation of creatine kinase metabolism promotes breast cancer invasion and metastasis [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 4511. doi:10.1158/1538-7445.AM2017-4511
Abstract 459: Targeting MUC1 mediated nucleotide metabolism sensitizes pancreatic tumors to radiation therapy
Authors: GUNDA VENUGOPAL , Souchek Joshua , Abrego Jaime , Goode Gennifer , Vernucci Enza , Shukla Surendra K. , DasGupta Aneesha , Chaika Nina V. , King Ryan , Yu Fang , Bessho Tadayoshi , Lin Chi , Shou Wang , Sicong Li , Singh Pankaj K. 
Published: July 2017

Abstract
Pancreatic cancer has the lowest survival rate of six perecent among all the cancers in the US and is projected to be the second leading cause of cancer related deaths in a decade. Radiation therapy provides only marginal increases in the survival rate in pancreatic cancer, due to poor responsiveness of pancreatic tumors. Clinical trials indicate a significant response to radiation only in twenty percent of primary pancreatic tumors. While multiple factors cause resistance to radiation therapy, the biological mechanisms mediating such innate resistance are currently being explored. Overexpression of MUC1 facilitates chemo and radiation resistance in pancreatic cancer. MUC1 overepxression also promotes pancreatic tumor growth through metabolic upregulation. We investigated the in vivo role of MUC1 mediated metabolic alterations in radiation response of pancreatic tumors. Our findings indicate that MUC1 expressing pancreatic tumors survive better upon radiation treatment. Metabolomic analysis through liquid chromatography coupled tandem mass spectrometry approach revealed that MUC1 expressing pancreatic tumors exhibit higher glycolytic and nucleotide metabolites upon irradiation. MUC1 expressing tumors also possess relatively higher PPP and nucleotide metabolites. Glycolytic inhibition using bromopyruvate revealed that MUC1 induced radiation resistance could be abrogated through inhibition of glucose carbon flux into nucleotide metabolism by BrPA. Treatment with BrPA effectively reduced glycolysis, pentose phosphate pathway and nucleotide levels in irradiated MUC1 expressing cells. Furthermore, a combination of BrPA and radiation reduced tumor growth in MUC1 expressing tumors. Metabolomic analysis showed a decrease in the glycolysis, PPP and nucleotide metabolites in MUC1 expressing tumors upon combination treatment with radiation and BrPA. Hence, our findings demonstrate that glycolytic inhibition could be used to effectively target MUC1 mediated radiation-resistance in pancreatic tumors.
Citation Format: VENUGOPAL GUNDA, Joshua Souchek, Jaime Abrego, Gennifer Goode, Enza Vernucci, Surendra K. Shukla, Aneesha DasGupta, Nina V. Chaika, Ryan King, Fang Yu, Tadayoshi Bessho, Chi Lin, Wang Shou, Li Sicong, Pankaj K. Singh. Targeting MUC1 mediated nucleotide metabolism sensitizes pancreatic tumors to radiation therapy [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 459. doi:10.1158/1538-7445.AM2017-459
Abstract 4768: A SHARP /Xist complex regulates breast cancer stem cells
Authors: Zhu Yongyou , Shang Li , Colacino Justin , Brooks Michael , Harouaka Ramdane , Lin Chang-Ching , Luo Ming , Wicha Max S. 
Published: July 2017

Abstract
Many cancers including breast cancer display hieratical organization and are driven by a cellular sub-population that displays stem cell properties. These cancer stem cells (CSC’s) mediate metastasis and contribute to treatment resistance highlighting the importance of elucidating CSC regulatory pathways. Nuclear proteins and lncRNAs involved in the maintenance of chromatin structure have been shown to play roles in CSC regulation. Among them the polycomb proteins bmi-1 and EZH2 are involved in epigenetic regulation of CSC’s in breast and other cancers. SHARP/SPEN, an RNA binding protein, has been previously been found to bind the lncRNA Xist which, by recruiting the PRC2 polycomb complex mediates transcriptional repression of the X chromosome. We utilized breast cancer cell lines and xenograft models to examine the role of the SHARP/Xist complex in the regulation of breast CSC’s. In a series of breast cancer cell lines including MCF7 (luminal )and SUM 159 (basal/claudin low) cells, SHARP mRNA and protein as well as the lncRNA Xist were more highly expressed in cells expressing aldehyde dehydrogenase as accessed by the Aldefluor assay than in ALDH -cells . Conditional knockdown of SHARP or Xist in SUM159 significantly decreased the ALDH+ CSC population without affecting cell growth in vitro. Furthermore, SHARP or Xist knockdown significantly reduced tumor initiating capacity and growth of SUM 159 cells in NOD/SCID mice. To determine the mechanism of breast CSC regulation by the SHARP complex we compared mRNA expression patterns of control and SHARP knockdown SUM 159 cells using RNAseq. There was significant overlap between the genes regulated by SHARP with genes regulated by the PCR1 and PRC2 polycomb complexes in addition to many histone genes. These studies suggest that the SHARP/Xist complex my regulate breast CSC’s through epigenetic regulatory histone and polycomb genes. Since SHARP expression is elevated in a number of cancers including breast cancer this pathway may represent a novel therapeutic target.
Citation Format: Yongyou Zhu, Li Shang, Justin Colacino, Michael Brooks, Ramdane Harouaka, Chang-Ching Lin, Ming Luo, Max S. Wicha. A SHARP /Xist complex regulates breast 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 4768. doi:10.1158/1538-7445.AM2017-4768
Abstract 482: miRNAs involved in LY6K and estrogen receptor-α contribute to tamoxifen susceptibility in breast cancer
Authors: Kim Yesol , Son Dasom , Yoo Kyung Hyun , Park Jong Hoon 
Published: July 2017

Abstract
Estrogen receptor-alpha is a clinically important therapeutic target for breast cancer. However, tumors that lose ERα are less responsive to anti-estrogens such as tamoxifen. MicroRNAs are small RNAs that regulate expression of their target gene and dysregulations of miRNA has been identified in many diseases including human cancer. However, only a few miRNAs associated with tamoxifen resistance has been reported. In this study, we found that lymphocyte antigen 6 complex, which is a member of the Ly-6/μPAR superfamily and related to breast cancer progression and metastasis, is inversely correlated with ERα expression. We, for the first time, found miRNAs involved in the regulatory molecular mechanism between ERα and LY6K and related to tamoxifen susceptibility in breast cancer. miR-192-5p, induced by LY6K, downregulates ERα directly and induced tamoxifen resistance in ERα-positive breast cancer cells. In addition, re-expression of ERα in ERα-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression. Ectopic expression of miR-500a-3p sensitized ERα-negative cells to tamoxifen by increasing apoptosis. Finally, we observed an inverse correlation between LY6K and ERα in primary breast cancer samples. We found that patients with recurrence showed high expression of miR-192-5p after tamoxifen treatments. In addition, expression of miR-500a-3p was significantly correlated to survival outcome. As miRNAs involved in the regulatory mechanism between LY6K and ERα can affect tamoxifen resistance, downregulating miR-192-5p or re-expressing miR-500a-3p could be a potential therapeutic approach for treating tamoxifen resistant patients.
Citation Format: Yesol Kim, Dasom Son, Kyung Hyun Yoo, Jong Hoon Park. miRNAs involved in LY6K and estrogen receptor-α contribute to tamoxifen susceptibility in breast 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 482. doi:10.1158/1538-7445.AM2017-482
Abstract 484: Epigenetic regulation of hsa-miR-3663 in colon cancer
Authors: Pique Laia , Ferrerira Humberto Jorge , Esteller Manel 
Published: July 2017

Abstract
Colon Cancer is the third most common cancer in the world and a major cause of morbidity and mortality. Molecular mechanisms of colon carcinoma have been deeply studied and current evidences indicate that microRNAs play a pivotal role in its tumorigenesis and progression. MicroRNAs (miRNAs) are small 19 to 22 nucleotides of RNA classified as non-coding RNAs that negatively regulate gene expression at the post-translational level controlling numerous biological processes including development, cell proliferation, apoptosis, differentiation and cell migration. Aberrant expression of miRNAs due to epigenetic alterations has been associated with carcinogenesis. Aimed to identify epigenetically regulated miRNAs involved in colon cancer, we analyzed DNA methylation profiles available in The Cancer Genome Atlas. One of the main hits identified was hsa-miR-3663, hypermethylated in 26% of colon cancer patients (n=286, p&lt; 0.001) in comparison with complete lack of methylation in normal tissues (n=38), suggesting its potential function as a putative tumor suppressor. In order to study the role of DNA methylation controlling hsa-miR-3663, HumanMethylation450K methylation profiles were generated for a panel of colon cancer cell lines (n=10), including the HCT116-DNA methyltransferase knock-out model (DKO, double knockout of DNMT1 and DNMT3B). We found a significant correlation between methylation status of hsa-miR-3663 and expression in colon cancer cell lines. Furthermore, epigenetic regulation of hsa-miR-3663 was confirmed in HCT116 methylated cell line by restored expression upon treatment with DNA demethylating agent 5-aza-2′-deoxycytidine and in the HCT116-DKO model. In order to elucidate the function of hsa-miR-3663, we stably expressed hsa-miR-3663 in a panel of five methylated colorectal cancer cell lines (HCT116, RKO, DLD1, SW48 and SW480). Our initial functional assays revealed that hsa-miR-3663 is not involved in cell proliferation or migration. We are now performing additional assays to further study hsa-miR-3663 and its potential role in colon cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Laia Pique, Humberto Jorge Ferrerira, Manel Esteller. Epigenetic regulation of hsa-miR-3663 in colon 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 484. doi:10.1158/1538-7445.AM2017-484
Abstract 5011: Tumor associated macrophages promote malignant phenotypes of disseminated human gastric cancer cells in intraperitoneal cancer immune microenvironment
Authors: Sakamoto Shuichi , Kagawa Shunsuke , Kuwada Kazuya , Ito Atene , Kagawa Tetsuya , Kikuchi Satoru , Kuroda Shinji , Yoshida Ryuichi , Tazawa Hiroshi , Fujiwara Toshiyoshi 
Published: July 2017

Abstract
Gastric cancer is the third leading cause of cancer-related death, and peritoneal dissemination is one of the most frequent site of recurrence. Although the role of tumor microenvironment is recognized, it is still unclear how intraperitoneal cancer-immune microenvironment contributes to peritoneal metastasis. Thus, we investigated the interaction between intraperitoneal cancer and immune cells, especially focusing on tumor-associated macrophages (TAM) in the peritoneal cavity. The peritoneal wash from gastric cancer patients was subjected to conventional cytology, flow cytometry, and immuno-fluorescent assay using antibodies against CD45 (leukocytes), CD14 (monocytes), CD80/163 (M1/M2 macrophages, respectively), in combination with genetically engineered cancer-imaging viral agent ‘TelomeScan’ which specifically expresses GFP in telomerase-positive cells. In cytology-positive samples, CD163-positive macrophages could be detected in approximately 70% of intraperitoneal macrophages with TelomeScan-positive cancer cells, while cytology negative samples contained few CD163-positive macrophages. In addition, peripheral blood mononuclear cells (PBMCs) from healthy volunteers were induced to differentiate into CD163-positive M2 macrophages (TAM-like macrophages), and co-cultured with gastric cancer cells to examine the effect on their malignant phenotype such as migration and invasion. We found that PBMCs-derived CD163-positive M2 macrophages significantly potentiated the ability of migration and invasion in gastric cancer cells. In case of existence of free cancer cells in peritoneal cavity, intraperitoneal macrophages appeared to differentiate into TAM and they potentially accelerate malignant phenotypes of gastric cancer cells. These results suggested that intraperitoneal cancer-immune microenvironment may play an important role to promote peritoneal disseminations in gastric cancer.
Citation Format: Shuichi Sakamoto, Shunsuke Kagawa, Kazuya Kuwada, Atene Ito, Tetsuya Kagawa, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara. Tumor associated macrophages promote malignant phenotypes of disseminated human gastric cancer cells in intraperitoneal cancer immune microenvironment [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 5011. doi:10.1158/1538-7445.AM2017-5011
Abstract 5186: Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells
Authors: Robb Ryan N. , Yang Linlin , Williams Terence 
Published: July 2017

Abstract
BRAF activating mutations act as oncogenic drivers and are highly prevalent in thyroid cancer, occurring in about 60% of papillary thyroid cancer (PTC) as well as 30-40% anaplastic thyroid cancer (ATC). MAPK signaling and treatment resistance is driven by BRAF mutations in thyroid cancer. Among the most common of these mutations is BRAFV600E, which can be selectively inhibited by vemurafenib.
Using a panel of PTC and ATC cell lines we assessed how the presence/absence of BRAFV600E impacts radiation sensitivity. We used radiation clonogenics, comet assays, nuclear foci formation, immunoblotting, and mouse xenografts models to determine the effect of vemurafenib on PTC and ATC cells. Analysis of radiation clonogenics implicated higher radioresistance in cell lines containing the BRAFV600E mutation as compared to wild-type BRAF. Additionally, forced expression of BRAFV600E in a wild-type thyroid cancer cell line induced radioresistance. Vemurafenib inhibited MAPK signaling in V600E mutant cell lines, but showed no effect in BRAF wild-type cell lines. Vemurafenib pretreatment selectively radiosensitized BRAFV600E mutants in vitro, as assessed by radiation clonogenic assays. Comet assays revealed impairment of DNA repair in BRAFV600E lines when treated with vemurafenib and radiation. Additionally, γ-H2A.x westerns and nuclear foci staining indicated that vemurafenib pretreatment decreases the tumor cell’s ability to repair DNA double-strand breaks (DSB) in BRAFV600E cell lines. Vemurafenib also appeared to alter the kinetics of formation and resolution of 53BP1 and Rad51 nuclear foci in these cell lines. Evaluation of DSB functional repair using GFP reporter constructs, suggests that BRAFV600E induces NHEJ repair, which can be attenuated by vemurafenib treatment. Finally, vemurafenib effectively increases radiosensitivity of BRAF V600E tumors in vivo.
From our results, BRAF activating mutation appears to be associated with radioresistance. Vemurafenib selectively radiosensitizes both PTC and ATC cells through inhibition of DNA repair mechanisms. Combining vemurafenib and radiation may improve therapeutic control for BRAFV600E mutant thyroid cancers.
Citation Format: Ryan N. Robb, Linlin Yang, Terence Williams. Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma 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 5186. doi:10.1158/1538-7445.AM2017-5186