bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4442: Wilms' tumor 1-associating protein increases cancer cell proliferation and stem-cell like properties through RNA modification
Authors: Park Sae Whan , Oh Young Taek , Park Jong Bae , Kim Jong Heon 
Published: August 2018

Abstract
Purpose: Wilms' tumor 1-associating protein (WTAP) which is known for its role in RNA methylation machinery, is highly upregulated in the necrotic region of glioblastoma multiforme (GBM). The highly heterogenic nature of GBM is associated with the necrotic region within the brain, where many types of cells such as the stromal cell, immune cells, and cancer stem cells co-localize. The complex cellular network within the necrotic region is believed to cause the resistance of the conventional chemotherapy and radiotherapy. Here we attempted to identify the role of WTAP in GBM and what kind of RNA modification is associated with the proliferation and stemness in GBM. Improvement of our understanding about post-transcriptional regulation in GBM will allow us to find out the key oncogenic switch in GBM, and development of therapeutics targeting this mechanism will provide better survival benefits.
Methods: 23 Patient-derived cell lines, two established GBM cell lines, and astrocyte was arrayed to find out the correlation between WTAP and cancer stem cells. shWTAP and WTAP overexpression vector were infected into patient-derived GBM cancer stem cell lines to test the effect of WTAP. Western blot and polymerase chain reaction analysis was performed to find out the change in genes which are related to cell proliferation and stemness. Limiting dilution assay was performed to validate the function of WTAP in sphere-forming ability. RNA sequencing was performed on shWTAP infected patient-derived cancer stem cell to identify the type of RNA modification made by knocking down WTAP.
Results: Knocking down of WTAP using shWTAP in patient-derived cancer stem cell lines, we were able to see the decrease in cell proliferation and stemness-related genes while overexpressing WTAP in these cells slightly increased cell proliferation and stemness. WTAP knockdown cells had a significant decrease in sphere-forming ability. RNA sequencing of shWTAP cells has revealed the increase in intron retention and the decrease in exon skipping, which shows that WTAP has a role in decreasing intron retention while increasing exon skipping.
Conclusion: We have revealed that WTAP has an important role in increasing proliferation and maintaining stemness in GBM. We have also identified that WTAP decreases intron retention and increasing exon skipping.
Citation Format: Sae Whan Park, Young Taek Oh, Jong Bae Park, Jong Heon Kim. Wilms' tumor 1-associating protein increases cancer cell proliferation and stem-cell like properties through RNA modification [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 4442.
Abstract 4450: Integrative genomic and transcriptomic analysis of CHD family chromatin remodelers in human cancers: Initial evidence of an oncogenic role for CHD7
Authors: Yang Zeng-Quan , Chu Xiaofang , Guo hui , Jiang Yuanyuan , Yu Huimei , Liu Lanxin , Shan Wenqi 
Published: August 2018

Abstract
Chromodomain helicase DNA binding proteins (CHDs) are characterized by N-terminal tandem chromodomains and a central adenosine triphosphate-dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10 000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amplified and mutated, whereas CHD3 was the most deleted across the majority of tumor types, including breast cancer. Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis. CHD7 is required to maintain open, accessible chromatin, thus providing fine-tuning of transcriptional regulation of certain classes of genes. We found that CHD7 expression was positively correlated with a small subset of classical oncogenes, notably NRAS, in breast cancer. Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets, including NRAS, in breast cancer cell lines. Thus, our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer.
Citation Format: Zeng-Quan Yang, Xiaofang Chu, hui Guo, Yuanyuan Jiang, Huimei Yu, Lanxin Liu, Wenqi Shan,. Integrative genomic and transcriptomic analysis of CHD family chromatin remodelers in human cancers: Initial evidence of an oncogenic role for CHD7 [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 4450.
Abstract 4451: Dynamic translational regulation of cancer-associated genes through mRNA structure
Authors: Lackey Lela Lynn , Coria Aaztli , Laederach Alain 
Published: August 2018

Abstract
Our goal is to understand how disrupting translational regulation leads to cancer by analyzing the extent to which RNA structure contributes to the translational efficiency of mRNAs in different phases of the cell cycle. We hypothesize that RNA structure is a dynamic projection of the cellular environment and actively contributes to gene regulation by combining sequence-based and environment-induced structures to influence post-transcriptional regulation. We focus on cell cycle regulation as a common, dynamic cellular process that is highly relevant to cancer development and progression. Additionally, during the cell cycle the translational efficiency of many different mRNAs have been shown to change from one phase to the next. We have determined the secondary structures of eight translationally regulated 5'UTRs using SHAPE-MaP (Selective 2' Hydroxyl Acylation by Primer Extension and Mutational Profiling). This chemical structure probing technique is unique in that it reads through chemical modifications during reverse transcription and can be coupled to next generation sequencing and incorporated into RNA structural modeling. Furthermore, we are able to probe these structures in vivo during different stages of the cell cycle. Our data show important conformational rearrangements in 5'UTRs between G1-phase cells and S-phase cells. These results suggest that mRNA structure is a dynamic attribute that plays a role in translational regulation. Many genes involved in cell cycle regulation are implicated in cancer development and progression. Our results confirm that RNA structure of 5' UTRs is an important component of translation regulation and ultimately controls protein expression levels.
Citation Format: Lela Lynn Lackey, Aaztli Coria, Alain Laederach. Dynamic translational regulation of cancer-associated genes through mRNA structure [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 4451.
Abstract 4452: Musashi-2 regulates EGFR/HER3 expression in NSCLC, cell proliferation and response to EGFR inhibitors in EGFR-mutant NSCLC
Authors: Makhov Peter , Kudinov Alexander , Deneka Alexander , Egleston Brian L. , Nicolas Emmanuelle , Cai Kathy Q. , Brebion Rohan , Avril Eleanor , Hitrik Mark , Nikonova Anna S. , Serebriiskii Ilya G. , Khazak Vladimir , Borghaei Hossein , Golemis Erica A. , Boumber Yanis 
Published: August 2018

Abstract
Musashi-2 (MSI2) is an RNA-binding protein that regulates mRNA translation. We recently established that MSI2 is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade. Here, reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell lines identified a significant ~2.7-fold upregulation of HER3 (ERBB3) upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein was confirmed in multiple NSCLC models, based on analysis of MSI2 depletion or overexpression. Further, MSI2 positively regulated expression of the epidermal growth factor receptor (EGFR) protein in the same models. Comparing EGFR and KRAS driven models, we found that MSI2 depletion significantly impairs cell proliferation only in EGFR-mutant NSCLC cell lines. Using RNA immunoprecipitation analysis coupled with qPCR, we show that MSI2 directly binds to EGFR and, to a lesser extent, to HER3 mRNA. MSI2 mRNA binding was approximately correlating with the presence of predicted MSI2 binding sites in corresponding mRNAs. NSCLC lung tissue microarray analysis revealed that MSI2 total positivity by H-score, 2+/3+ and 3+ positivity correlated with EGFR 3+ staining. Finally, EGFR inhibitors erlotinib and afatinib synergized with MSI2 depletion in EGFR mutant models, suggesting that therapeutic targeting of MSI2 could be of clinical value, especially in EGFR-mutant lung cancer.
Citation Format: Peter Makhov, Alexander Kudinov, Alexander Deneka, Brian L. Egleston, Emmanuelle Nicolas, Kathy Q. Cai, Rohan Brebion, Eleanor Avril, Mark Hitrik, Anna S. Nikonova, Ilya G. Serebriiskii, Vladimir Khazak, Hossein Borghaei, Erica A. Golemis, Yanis Boumber. Musashi-2 regulates EGFR/HER3 expression in NSCLC, cell proliferation and response to EGFR inhibitors in EGFR-mutant NSCLC [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 4452.
Abstract 4454: Ecdysoneless, a novel regulator of cell cycle progression and oncogenesis
Authors: Saleem Irfana , Mirza Sameer , Sarkar Aniruddha , Band Hamid , Band Vimla 
Published: August 2018

Abstract
Precisely regulated cell proliferation is essential for embryonic development and for homeostasis in adult organs and tissues, whereas uncontrolled cell proliferation is a hallmark of cancer. We have identified the human orthologue of Drosophila Ecdysoneless (ECD) as a critical regulator of cell cycle progression and oncogenesis. ECD is overexpressed in cancers of several organs, and its overexpression correlates with shorter survival in breast cancer patients. Overexpression of ECD leads to an oncogenic phenotype in immortal mammary epithelial cells. ECD deletion in breast cancer cells on the other hand decreased the in vitro oncogenic phenotype and the in vivo tumorigenesis.
Mechanistically, we showed that ECD associates with a protein complex called R2TP, composed of RUVBL1, RUVBL2, RPAP3, PIHID1 proteins, which is involved in several biological functions, including the dynamic assembly of protein-protein and protein-RNA complexes. In addition, affinity purification followed by Mass Spec analyses showed that ECD binds to several proteins, including PRPF8, that are components of critical protein complexes required for RNA splicing. Based on these findings, we hypothesize that ECD interacts with the R2TP complex and protein complexes that control key steps in the cellular mRNA processing. We hypothesize that these complexes are required for the overexpressed ECD to regulate mRNA processing to promote cell proliferation and cell survival in cancer cells. We will present data to document the ECD complexes required for cell cycle regulation and cell survival. Our studies reveal novel roles of ECD in cancer cells, and support the rationale for use of overexpression of ECD and its interacting proteins as molecular biomarkers of tumor progression as well as explore the targeting of these complexes to develop novel cancer therapy agents.
Citation Format: Irfana Saleem, Sameer Mirza, Aniruddha Sarkar, Hamid Band, Vimla Band. Ecdysoneless, a novel regulator of cell cycle progression and oncogenesis [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 4454.
Abstract 4471: Pax9 regulates squamous cell differentiation and alcohol-associated carcinogenesis in the oro-esophageal epithelium
Authors: Xiong Zhaohui , Ren Shuang , Chen Hao , Liu Yao , Huang Caizhi , Zhang Yawan Lyvia , Odera Joab Otieno , Chen Tong , Kist Ralf , Peters Heiko , Garman Katherine , Sun Zheng , Chen Xiaoxin Luke 
Published: August 2018

Abstract
Pax9 is a transcription factor of the Pax family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of Pax9 in squamous cell differentiation and carcinogenesis of oro-esophageal epithelium. However, its functional role in differentiation and carcinogenesis remains unclear. In this study, Pax9 deficiency in mouse esophagus promoted cell proliferation, delayed cell differentiation and altered the global gene expression profile. Ethanol exposure down-regulated Pax9 expression in human esophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was down-regulated in human oro-esophageal squamous cell carcinoma (OESCC), and its down-regulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with an isocaloric Lieber-DeCarli liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted NMBA-induced squamous cell carcinogenesis in mouse tongue, esophagus, and forestomach. In conclusion, Pax9 regulates squamous cell differentiation in the oro-esophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. Pax9 down-regulation, at least in part, contributes to alcohol-associated oro-esophageal squamous cell carcinogenesis.
Citation Format: Zhaohui Xiong, Shuang Ren, Hao Chen, Yao Liu, Caizhi Huang, Yawan Lyvia Zhang, Joab Otieno Odera, Tong Chen, Ralf Kist, Heiko Peters, Katherine Garman, Zheng Sun, Xiaoxin Luke Chen. Pax9 regulates squamous cell differentiation and alcohol-associated carcinogenesis in the oro-esophageal epithelium [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 4471.
Abstract 4472: Downregulation of POTEG predicts poor prognosis in esophageal squamous cell carcinoma
Authors: Li Yan 
Published: August 2018

Abstract
POTE ankyrin domain family, member G (POTEG) belongs to POTE family. The POTE gene family encodes very closely related proteins that are highly expressed in prostate, ovary, testis, and placenta. Recent studies indicated that the POTE proteins have a pro-apoptotic function. To examine whether POTEG also underwent apoptosis in ESCC cancer cells and the functions of POTEG in the development of esophageal squamous cell carcinoma (ESCC), we determined the location and expression of POTEG in ESCC cancer cells. Clinical association studies determined that POTEG downregulation was associated with poor clinical outcomes. Ectopic re-expression of POTEG effectively suppressed the tumorigenesis and metastasis of ESCC cells in vitro and in vivo, including the inhibition of cell growth rate, foci formation, soft agar colony formation, migration, invasion and tumor formation in nude mice. Molecular analyses revealed that POTEG downregulated CDKs, leading to subsequent inhibition of Rb phosphorylation, and consequently arrested Cell Cycle at G1/S Checkpoint. Prospectively, POTEG can reduce the level of anti-apoptotic proteins, while promote the level of proapoptotic proteins and inducing apoptosis. On the other side, POTEG inhibit metastasis by reducing epithelial-mesenchymal transition in ESCCs. Taken together, our results revealed that POTEG has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies.
Citation Format: Yan Li. Downregulation of POTEG predicts poor prognosis in esophageal squamous 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 4472.
Abstract 4474: An intricate role of p53 and p21 in cellular alterations and drug penetration in spheroids of colorectal cancer cells
Authors: Das Viswanath , Annadurai Narendran , Hajdúch Marián 
Published: August 2018

Abstract
The tumor protein p53 and cyclin-dependent kinase inhibitor p21Waf1/Cip1 (p21) are two proteins with an intriguing and a paradoxical role in cancer. Through p53-dependent signals, p21 negatively controls cell cycle progression to protect cells against deleterious effects of DNA damage. Although p53 is a tumor suppressor protein, recent evidence shows that some patients with wild-type (wt) p53 develop aggressive and drug-resistant cancers. Similarly, recent studies also suggest the oncogenic role of p21. In a p53 deficient background, p21 results in the development of a subset of highly proliferative and resistant population of cancer cells.
In this study, we examined the role of p53 and p21 in inducing cellular alterations using a panel of colorectal carcinoma cell lines with different p53 and p21 background and spheroid and spheroid-derived cell cultures. First, our data show that despite the presence of proliferating cells, spheroid-derived cultures of HCT116/p53wt cells continue to display an elevated p21 level even after 6 days of culture as a monolayer. These p21-overexpressing proliferating cells show increased resistance to doxorubicin and paclitaxel in comparison to their parental monolayer counterpart. In contrast to HCT116/p53wt cells, DLD-1/p53mut cells did not show elevated p21 levels following reversal from spheroid to monolayer. The increased p21 level in spheroids and spheroid-derived cultures of HCT116/p53wt cells led us to examine the role of p53 and p21 in drug penetration. Spheroids of HCT116/p53wt cells were less permeable to doxorubicin and showed increased expression of intracellular junctional (IJ) proteins (adherens and tight junctions). Knocking-out p21 in HCT116/p53wt cells decreased the level of IJ proteins, resulting in an increased doxorubicin penetration. Re-expression of p21 in p21-knocked-out HCT116/p53wt cells restored IJ protein levels, reducing doxorubicin penetration and the subsequent effect of doxorubicin on spheroids. Interestingly, however, knocking-out p21 in DLD-1/p53mut cells neither altered intracellular junctions nor affected doxorubicin penetration. These data indicate that the effect of p21 on IJ proteins and drug penetration is pertinent only in cells with wt p53. Overall, the data from our study suggest an intricate interplay between wt p53 and p21 in inducing cellular alterations that affect the sensitivity of cells to anti-cancer drugs in spheroids.
Citation Format: Viswanath Das, Narendran Annadurai, Marián Hajdúch. An intricate role of p53 and p21 in cellular alterations and drug penetration in spheroids of colorectal cancer 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 4474.
Abstract 4475: Adenomatous polyposis coli like protein (APCLP) functions as a novel negative regulator of NF-kB signaling in colon cancer cells
Authors: Martin Matthew , Mundade Rasika , Lu Tao 
Published: August 2018

Abstract
Colon cancer (CRC) is the second leading cause of cancer related deaths in the United States. CRC is marked by aberrantly activated signaling of the nuclear factor of kappaB (NF-kB), a family of transcription factors which regulate wide varieties of cellular processes. Despite recent advances in comprehension of players of NF-kB signaling, deeper understanding of its regulation is imperative for the development of novel cancer therapeutics. Using the powerful validation-based insertional mutagenesis (VBIM) technique, we recently discovered APCLP as a novel negative regulator of NF-kB. The objective of this study is to elucidate the role APCLP in regulating NF-kB signaling in CRC at the molecular and biological levels and to understand the mechanism by which this regulation occurs. To determine the biological effect of APCLP on NF-kB signaling, we used lentiviral vectors to either overexpress or knockdown (shRNA) APCLP in human CRC cell lines (HT-29, HCT116, DLD-1). We show that overexpression of APCLP decreased the NF-kB activity, reduced cellular proliferation, migratory ability, as well as anchorage-independent growth of cells while knockdown of APCLP had an inverse effect. Furthermore, in vivo experiments in a xenograft mouse model confirmed that APCLP overexpression impeded whereas shRNA knockdown promoted tumor growth. To study the mechanism by which APCLP regulated NF-kB signaling, we conducted co-Immunoprecipitation experiments and confirmed that APCLP and the major subunit of NF-kB, p65, may complex or bind directly to each other. Studies are ongoing regarding the mechanism of interaction between APCLP and p65. In summary, discovery of APCLP and understanding of its molecular mechanism and biological function are significant because the knowledge acquired from this study could lead to utilization of APCLP as a potential biomarker and therapeutic target in CRC as well as other cancers that are driven by hyperactivated NF-kB.
Citation Format: Matthew Martin, Rasika Mundade, Tao Lu. Adenomatous polyposis coli like protein (APCLP) functions as a novel negative regulator of NF-kB signaling in colon cancer 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 4475.