bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3091: Functional screening of genes involved in carcinogenesis using a cDNA expression library of ovarian clear cell carcinoma cells
Authors: Miyamoto Tsutomu , Yamada Yasushi , Ida Koichi , Asaka Ryoichi , Kobara Hisanori , Ando Hirofumi , Kashima Hiroyasu , Suzuki Akihisa , Shiozawa Tanri 
Published: August 2018

Abstract
Background: Ovarian clear cell carcinoma (OCCC) is one of the 4 major histological types of ovarian carcinoma (OVC) and is frequently arising from ovarian endometriotic cysts. OCCC is rare in the United States and western countries, but it is more frequent in Japan and may be seen in almost 25% of OVC. OCCC commonly shows chemo-resistance which makes difficult to treat OCCC. In order to develop the new therapeutics for OCCC, genetic abnormalities that lead to the development of OCCC need to be elucidated in detail. The comprehensive analysis using next-generation sequencing has rapidly revealed the accumulation of genetic abnormalities in many cancers. However, the significance of each abnormality has not been elucidated. Therefore, functional screening using a cDNA expression library was performed in order to identify genes involved in the pathogenesis of OCCC.
Methods: The mRNA was extracted from an OCCC cell line, RMG-1, and a cDNA library was established using a retroviral vector. This cDNA library was transfected into mouse NIH3T3 cells, and then the transformed foci which formed multilayered growth were picked up and the inserted DNAs of those foci were detected by sequencing. The mRNA and protein expression and the transforming ability of the identified genes were confirmed by immunohistochemistry and focus-formation assay.
Result: Seven genes were isolated; Dishevelled 1(DVL1), beta subunit of Sec61 (SEC61B), K-specific demethylase 4A (KDM4A), chromosome 1 open reading frame 38 (C1ORF38), splicing factor 1 (SF1), ribosomal protein S2 (RPS2), and ribosomal protein S3A (RPS3A). Of these genes, RT-PCR and immunostaining revealed that the expression of SEC61B and C1ORF38 was stronger than that in other histological types of ovarian cancer. A mutational analysis of the DVL1 c-terminal region detected 3 point-mutations in RMG1 cells, whereas no mutation was found in 24 cases of OCCC. Focus formation was confirmed by the transfection of SEC61B, C1ORF38, and DVL1 into NIH3T3 cells.
Conclusion: These results suggest that SEC61B, C1ORF38, and DVL1 may be involved in the pathogenesis of OCCC.
Citation Format: Tsutomu Miyamoto, Yasushi Yamada, Koichi Ida, Ryoichi Asaka, Hisanori Kobara, Hirofumi Ando, Hiroyasu Kashima, Akihisa Suzuki, Tanri Shiozawa. Functional screening of genes involved in carcinogenesis using a cDNA expression library of ovarian clear cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3091.
Abstract 3097: Chemo prevention effect of Withaferin A, a natural compound, on mouse models of colorectal carcinogenesis
Authors: Pal Deeksha , Chandrasekaran Balaji , Baby Becca Von , Alatassi Houda , Ankem Murali , Damodaran Chendil 
Published: August 2018

Abstract
Introduction: Colorectal cancer (CRC) is the most common cancer and one of the leading causes of cancer-related deaths in United States as well as worldwide. Development of sporadic CRC takes an average of 15-20 years, so establishing preventive measures are possible. We are interested in a dietary compound, Withaferin-A (WA), which possesses both chemotherapeutic and chemopreventive properties. WA's effect was studied on both colitis-mediated colon and spontaneous-intestinal carcinogenesis mouse models.
Methods: In the present study, two animal models of colon cancer were used to study the chemo- preventive effect of WA. In intestinal tumorigenesis model C57BL/6-ApcMin/+ , mice at six weeks of age were orally fed with the vehicle or WA (4mg/kg body weight of mice) for five days per week for 12-14 weeks. The other model used was AOM/DSS (Azoxymethane/dextran sulfate sodium), which induces gut inflammation and tumorigenesis. Intraperitoneal injection of AOM (8mg/kg) was followed by three cycles of DSS. WA (3mg/kg body weight of mice) was administered five times per week for 8-10 weeks. After completion of the studies, the tumor tissues were subjected to histopathological and molecular analysis. An unpaired Student's t-test was used for statistical analysis.
Results: Oral administration of WA to ApcMin/+ mice leads to a significant decrease in the number of intestinal polyps and colon tumors (colon: 42%, p=0.025), proximal: 53%, p=0.0063, middle: 27.84%, p= 0.28, distal: 32.8, p= 0.001) when compared to vehicle-treated mice. Similarly, in AOM/DSS, oral administration of WA reduced polyp multiplicity by 40% (p= 0.02) compared to vehicle-treated controls. Moreover, the treatment group of both colon cancer models showed inhibition of pro-survival signaling markers (Notch1, pAKT and NFκB) as well as a decrease in proliferative markers.
Conclusion: Our results suggest that WA effectively suppresses intestinal polyp development and colitis-mediated colon carcinogenesis, suggesting a preventive and therapeutic role in colon cancer models. These findings warrant further investigation to develop novel strategies to achieve maximum benefit of dietary agents for cancer chemoprevention.
Citation Format: Deeksha Pal, Balaji Chandrasekaran, Becca Von Baby, Houda Alatassi, Murali Ankem, Chendil Damodaran. Chemo prevention effect of Withaferin A, a natural compound, on mouse models of colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3097.
Abstract 3113: Expression of autophagy- and mitophagy-related genes in clear cell renal cell carcinoma
Authors: Simon Adrian G. , Ellinger Joerg , Tolkach Yuri , Mueller Stefan C. , Kristiansen Glen , Toma Marieta I. 
Published: August 2018

Abstract
Objectives: First objective of this study was to establish primary cell cultures from renal cell carcinoma (RCC). Second objective was to analyze mRNA and protein expression of PINK1, PARK2, PACRG and a-Synuclein, genes involved in cell survival, apoptosis and mitophagy.
Methods: Tumor and non-neoplastic tissue from 15 patients undergoing surgery for clear cell renal cell carcinoma (ccRCC, n=9), papillary renal cell carcinoma (pRCC, n=3) as well as three retroperitoneal metastases (two clear cell, one papillary type) were obtained. After tissue digestion and filtration malignant and non-malignant cells were cultivated in two different media in order to establish an optimized cultivation procedure. DNA and RNA were extracted and immunohistochemical analyses (IHC) and qPCR from cultivated cells were performed for VHL and CAIX to verify tumor histotype. RNA was isolated from fresh-frozen primary ccRCC samples and corresponding non-malignant tissues from 50 patients (30 male, 20 female). Expression of PINK1, PARK2, PACRG and a-synuclein was measured by qPCR in the cultivated ccRCC cell lines as well as in the patient samples.
Results: All tumor specimens were successfully cultivated to first confluence. Six out of nine ccRCC cell lines and all other tumor specimens could be passaged more than two times. Cultivated RCC cells showed protein expression matching to their tumor of origin in IHC analyses, confirming tumor identity. QPCR demonstrated VHL expression downregulated or lost in all ccRCC cell lines and CA9 highly upregulated in most cases, which is both typical for ccRCC. The mRNA expression of PINK1, PARK2 and PACRG was downregulated in ccRCC cultures as well as in the 50 patient tumors in comparison to normal tissue. A-synuclein expression was highly variable.
Conclusions: We successfully established primary cell cultures from various renal tumor entities suitable for further investigation. Loss of PACRG and PARK2 are common events in ccRCC. PACRG and PARK2 might function as tumor suppressors in ccRCC and their loss may be involved in tumor progression as reported before for other tumor entities. Further investigation of PINK1, PARK2 and PACRG might allow new therapeutic approaches.
Citation Format: Adrian G. Simon, Joerg Ellinger, Yuri Tolkach, Stefan C. Mueller, Glen Kristiansen, Marieta I. Toma. Expression of autophagy- and mitophagy-related genes in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3113.
Abstract 312: Emodin inhibits colon cancer by modulating apoptotic and cell survival signals
Authors: Saunders Ian T. , Kapur Neeraj , Mir Hina , Singh Shailesh 
Published: August 2018

Abstract
Colon cancer remains a formidable health care concern and is the third most common cancer among men and women. Late diagnosis and development of resistance to chemotherapeutic regimens significantly impact overall outcome and survival. Various phytochemicals have been shown to have promising anti-cancer properties. Consequently, such natural agents are emerging as an alternative treatment modality for various cancers, including colon cancer. In this study, we have tested the effect of Emodin, an anthraquinone derivative of rhubarb, on human colon cancer cell lines. Our antibody microarray data and pathway analysis indicated that Emodin induced apoptosis in colon cancer cells by triggering both intrinsic and extrinsic apoptotic pathways. These effects of Emodin were associated with modulation of death receptor expression, changes in mitochondrial membrane integrity, and DNA degradation. Further, western blot analysis confirmed that Emodin significantly increased pro-apoptotic proteins (Bak, Bax, Bad) as well as activated caspase-3 and -8. Additionally, Emodin reduced ERK1/2, NF-κB, and STATs at transcript and protein levels, suggesting it also interferes with cell survival. Hence, the ability of Emodin to induce apoptosis and inhibit cell survival by altering molecular pathways underscore its potential as chemo-preventive as well as -therapeutic agent in combination with conventional chemotherapy.
Citation Format: Ian T. Saunders, Neeraj Kapur, Hina Mir, Shailesh Singh. Emodin inhibits colon cancer by modulating apoptotic and cell survival signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 312.
Abstract 314: A novel MDM2-p53 antagonist APG-115 induces p53-mediated apoptosis and enhances radiosensitivity in colorectal cancer
Authors: Yi Han-Jie , Yan Xiang-Lei , Luo Qiu-Yun , Yuan Luping , Li Baoxia , Pan Wentao , Zhang Lin , Qiu Miao-Zhen , Wang Guangfeng , Zhai Yifan , Yang Da-Jun 
Published: August 2018

Abstract
Background: Colorectal carcinoma is the third leading cause of cancer-related mortality in China. MDM2-p53 inhibitor APG-115 is a novel potential anticancer agent. We aim to investigate the anticancer effect and radiosensitivity enhancement of APG-115 in colorectal cancer.
Materials and methods: Human colorectal cancer cell lines (LOVO, HCT116, RKO, HT29, SW480 and SW620) were treated with the APG-115 alone or with radiation (0-8Gy). Transwell, clonogenic survival assays, CCK-8, flow cytometry, RT-qPCR, Western blot were used to assay cell invasion, cell survival, cell cycle progression, quantification of mRNA expression and DNA damage repair. In vivo, xenograft mouse models (RKO Cell line) were established to analyze the anticancer effect and radiosensitivity enhancement of APG-115.
Results: In vitro, APG-115 not only inhibited invasion and proliferation of colorectal cell lines, but also induced cell-cycle arrest in G1/S phase. Meanwhile, APG-115 increased the mRNA and protein expression of p53 downstream targets dependent on MDM2-p53 signal pathway. The combination of APG-115 and radiation caused cells to accumulate in G2/M and resulted in the accumulation of H2AX-related DNA damage, indicating an increasing of radiosensitivity. In xenograft mouse models, single therapy with either radiation or APG-115 was equivalent in delaying tumor growth, although APG-115 slightly outperforming therapy with radiation alone. Combination therapy delayed tumor growth more significantly compared with either single agent therapy. By analyzing proliferation marker Ki67 in xenograft tumor specimens, we found that the number of proliferating cells significantly decreased in tumors receiving combination treatment of APG-115 and radiation compared with tumors receiving single agent treatment. These results strongly confirmed the enhanced antitumor capacity of APG-115 when combined with radiation.
Conclusions: Our data strongly suggest that MDM2-p53 inhibitor APG-115 may serve not only as a stand-alone therapy, but also as an effective adjunct to current radiotherapeutic regimens for treating colorectal cancer dependent on MDM2-p53 axis.
Citation Format: Han-Jie Yi, Xiang-Lei Yan, Qiu-Yun Luo, Luping Yuan, Baoxia Li, Wentao Pan, Lin Zhang, Miao-Zhen Qiu, Guangfeng Wang, Yifan Zhai, Da-Jun Yang. A novel MDM2-p53 antagonist APG-115 induces p53-mediated apoptosis and enhances radiosensitivity in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 314.
Abstract 3151: Novel regulation of cancer cell migration by ABCG2-enhanced autophagy
Authors: Trivedi Kalkal Anil , Ding Rui , Scotto Kathleen W. 
Published: August 2018

Abstract
ABCG2 is an ABC multidrug transporter best known for its ability to efflux a wide variety of chemotherapeutic agents, resulting in tumor drug resistance. More recently, our laboratory has shown that ABCG2 plays an additional role in tumor cell survival by enhancing the rate of autophagy, a conserved, catabolic recycling process that breaks down damaged proteins and cellular organelles to form cellular building blocks (Ding et al., Autophagy, 2016).
Sporadic studies over the decades have led to somewhat conflicting reports about the impact of ABCG2 expression on migration. Likewise, autophagy can play either a pro-metastatic or anti-metastatic role depending on the context. In the present study, we confirm that ABCG2 enhances tumor cell migration in vitro, and provide novel data to suggest that this enhancement is due to the ability of ABCG2 to augment autophagy flux.
Two cell line pairs were used for these studies: the NSCLC line H460 and its drug-selected ABCG2-overexpressing subline H460/MX20, and the embryonic kidney HEK293 cells stably-transfected either with ABCG2 or an empty vector. Transwell assays were used to study in vitro migration and invasion. ABCG2-overexpressing cells exhibited a marked increase in both cell migration and invasion relative to their parental counterparts. Using gelatin zymography, we also showed that ABCG2 over-expressing cells had enhanced MMP-2 activity, consistent with increased invasion. Both siRNA-mediated knockdown of ABCG2 expression and pharmacological inhibition of ABCG2 transport reduced the migration of ABCG2-overexpressing cells. Moreover, blocking autophagy using either a pharmacological or genetic approach also inhibited migration. Further supporting the hypothesis that ABCG2-enhanced autophagy influenced tumor cell migration, wild-type (WT) and MEFs in which the autophagy essential gene ATG5 was knocked out (ATG5-/-) were transiently transfected with either an empty vector or ABCG2. The ABCG2-transfected WT MEFs showed significantly enhanced migration compared to the empty vector transfected WT MEFs. The autophagy compromised ATG5-/- MEFs, however, did not display a statistically significant difference in the migration of the ABCG2 and empty-vector transfected cells, supporting the hypothesis that ABCG2 requires functional autophagy to enhance cell migration. Taken together, our results demonstrate a novel role for ABCG2 in enhancing cell migration by augmenting autophagy flux. Studies to determine whether ABCG2-regulated autophagy enhances migration and metastasis in vivo are underway.
Citation Format: Kalkal Anil Trivedi, Rui Ding, Kathleen W. Scotto. Novel regulation of cancer cell migration by ABCG2-enhanced autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3151.
Abstract 3152: RhoA-myosinII axis protects circulating tumor cells from fluid shear stress-induced damage
Authors: Moose Devon L. , Krog Ben L. , Burke Gretchen , Zhao Lei , Rhodes Lillian , Henry Michael D. 
Published: August 2018

Abstract
Circulating tumor cells (CTCs) are exposed to hemodynamic forces, which have long been thought to be mechanically destructive to CTCs. However, recent studies show that cancer cell lines from diverse histologies exhibit resistance to brief (millisecond) pulses of high-level (750-6400 dyn/cm2) fluid shear stress (FSS), whereas nontransformed epithelial cells are sensitive to this mechanical insult (PMID: 23226552, 26447202). Moreover, exposure of cancer cells to FSS results in cortical stiffening (PMID: 25908902). Herein, we elucidate the mechanism of FSS resistance in cancer cells, and extend these findings to experimental models of CTCs. We show that although some cancer cell lines exhibit elevated levels of membrane repair relative to nontransformed counterparts, intrinsic resistance to plasma membrane damage is a more consistent feature distinguishing cancer cells. FSS resistance is detectable in cancer cells acutely isolated from primary mouse TP53/PTEN mutant prostate tumors, not just a feature of cultured cancer cell lines. Our findings indicate that cancer cells respond to FSS by activation of RhoA-myosinII contractility, which protects them from nanometer-scale damage to the plasma membrane. Moreover, we present evidence that the RhoA myosinII axis protects CTCs from mechanical damage in animal models. Treatment of PC-3 cancer cells with a nontoxic dose of the myosin II inhibitor blebbistatin (20μM; 3h) reduced the number of intact cells arrested in the lung microvasculature immediately following tail vein injection. Additionally, treatment of mice bearing orthotopically implanted, metastatic PC-3 derived prostate tumors with blebbistatin (2.5mg/kg; 3h) acutely reduced steady-state CTC levels by approximately 10-fold. Taken together, our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.
Citation Format: Devon L. Moose, Ben L. Krog, Gretchen Burke, Lei Zhao, Lillian Rhodes, Michael D. Henry. RhoA-myosinII axis protects circulating tumor cells from fluid shear stress-induced damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3152.
Abstract 3179: TORC1/2 inhibition sensitizes MYC-driven medulloblastoma cells to carboplatin chemotherapy
Authors: Maynard Rachael E. 
Published: August 2018

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of high medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. We performed an in silico analysis of these cells, which predicted that mTOR inhibitors would be potential therapeutic agents. The dual TORC1/2 inhibitor TAK228 (also known as MLN128 and INK128) is orally bioavailable and penetrates the brain. TAK228 is currently in early clinical trials for adults with glioblastoma. We hypothesized that TAK228 would have activity against MYC-driven medulloblastoma. We tested this hypothesis using the MYC amplified medulloblastoma cell lines D425 and D283 as well as our human neural stem cell models. We determined that TAK228 was effective in inhibiting both mTORC1/2 as measured by western blots showing decreased p-S6 and p-AKT473 expression. P-S6 expression is decreased by 90% and p-AKT expression is decreased by 70% in D425 cell lines treated with 20nM TAK228. We found that treatment with TAK228 decreases cell growth in D425 and D283 high-MYC medulloblatoma cell lines at concentrations of 20nM (D425 p&lt;0.005 vs vehicle, D283 p&lt;0.0005 vs vehicle). We also found that TAK228 induces apoptosis as measured by cleaved caspase 3 staining and an increased expression of cleaved PARP (D425 p&lt;0.05 vs vehicle, D283 p&lt;0.0005 vs vehicle). Because mTOR inhibition can suppress glutathione production, and glutathione is required to detoxify platinum containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin, which is part of the current standard treatment for high-risk medulloblastoma. TAK228 in combination with carboplatin inhibits cell growth as measured by MTS assay (D425 p&lt;0.05 vs vehicle, D283 p&lt;0.05 vs vehicle) and induces apoptosis as measured by cleaved PARP expression. Combination therapy of TAK228 and carboplatin treatment leads to a 7-fold increase in cleaved PARP compared to cells treated with the vehicle. In vivo testing in orthotopic xenografts is currently underway to determine the survival benefit of TAK228 in combination with carboplatin. TAK228 is effective at inhibiting growth and inducing apoptosis in high-MYC medulloblastoma cell lines and shows strong combinatorial efficacy with carboplatin.
Citation Format: Rachael E. Maynard. TORC1/2 inhibition sensitizes MYC-driven medulloblastoma cells to carboplatin chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3179.
Abstract 3184: A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor
Authors: Wang Jiawan , Yao Zhan , Jonsson Philip , Allen Amy , Qin Alice Can Ran , Uddin Sharmeen , Dunkel Ira J. , Petriccione Mary , Manova Katia , Haque Sofia , Rosenblum Marc , Pisapia David J. , Rosen Neal , Taylor Barry S. , Pratilas Christine A. 
Published: August 2018

Abstract
BRAF V600E hyperactivates ERK and signals as an RAF inhibitor-sensitive monomer. While RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAF V600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAF L514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAF V600E L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. A novel class of RAF dimer inhibitors and an ERK inhibitor are effective against BRAF L514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence.
Citation Format: Jiawan Wang, Zhan Yao, Philip Jonsson, Amy Allen, Alice Can Ran Qin, Sharmeen Uddin, Ira J. Dunkel, Mary Petriccione, Katia Manova, Sofia Haque, Marc Rosenblum, David J. Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas. A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3184.