bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3783: Role of microRNA 28-3p in prostate cancer progression
Authors: Sreekumar Amritha , Saini Sharanjot 
Published: April 2023

Abstract
Prostate cancer (PCa) is a leading cause of cancer incidence and mortality among men. Prostate cancer is driven by androgens acting via androgen receptor (AR). Therefore, this cancer is treated with androgen deprivation therapy (ADT) initially. However, the cancer rapidly evolves to be resistant to ADT and progresses to a more invasive stage referred to as ‘Castration Resistant prostate cancer’ (CRPC). CRPC is treated with second generation of AR pathway inhibitors such as Enzalutamide and Abiraterone. These treatments are effective initially. However, drug resistance develops in a significant fraction of patients and the cancer undergoes ‘neuroendocrine trans-differentiation (NED) to a lethal variant called ‘neuroendocrine prostate cancer’ (NEPC). As a result of NED, PCa cells express neuronal markers such as synaptophysin, chromogranin A and enolase. The molecular basis of NED is not yet fully defined. With a focus on identifying the role of microRNAs (miRNAs) in NEPC, we performed small RNA sequencing in CRPC tumors with and without NED. This sequencing identified miR-28-3p to be significantly downregulated in CRPC-NE samples as compared to CRPC-adenocarcinomas (CRPC-Adeno). In view of this, we examined the role of this miRNA in NEPC. Analyses of TCGA data of prostate adenocarcinomas suggest that miR 28-3p has an oncogenic role in primary prostate tumors. However, its expression declines in tumors with increasing Gleason score. We profiled the expression of miR-28-3p in patient-derived xenograft models and clinical CRPC-NE and CRPC-Adeno tissues by real time PCR. Our profiling showed a trend towards downregulation with increased NED. Basal expression of miR 28-3p in various prostate cancer cell lines showed an elevated level in androgen dependent cell lines whereas significantly less expression in NEPC cell lines, LASCPC-01 and NCI-H660. In this study, we generated PC3 cell line that stably expresses miR-28 for understanding its functional role in regulating PCa. Preliminary functional assays including cell viability assay, cell cycle studies and invasion and migration assay suggest a tumor suppressor role of miR-28-3p in advanced prostate cancer. In conclusion, our data shows that miR 28-3p potentially has a biphasic role in PCa, where it is oncogenic in early stages and acts as a tumor suppressor in late stage PCa.
Citation Format: Amritha Sreekumar, Sharanjot Saini. Role of microRNA 28-3p in prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3783.
Abstract 3821: Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma
Authors: XU CAIMING , SUI SILEI , Okuno Keisuke , Pascual-Sabater Silvia , Fillat Cristina , Goel Ajay 
Published: April 2023

Abstract
Background: Pancreatic cancer is one of the most devastating malignancies due to the development of intrinsic chemoresistance following chemotherapy. Extracellular matrix (ECM) proteins are intimately linked to cellular proliferation, invasion, and acquisition of chemoresistance in PDAC cells, making them promising therapeutic targets in this malignancy. Naturally occurring dietary botanicals, including berberine (BER) and emodin (EMO), have been shown to suppress ECM as one of the mechanism(s) for their anti-tumorigenic activity, along with their time-tested safety and cost-effectiveness. In addition, both BER and EMO are also known to induce apoptosis by modulating different pathways and regulating pro-apoptotic genes. Herein, we hypothesized that combined treatment with BER and EMO might exhibit synergistic anticancer efficacy by targeting the ECM and apoptotic pathways in PDAC cells.
Methods: We undertook genomewide transcriptomic profiling analysis to identify critical ECM-related genes differentially expressed in PDAC. Subsequently, the TCGA dataset was analyzed to identify the prognostic significance of ECM-associated genes with overall survival (OS) and disease-free survival (DFS) in PDAC. A series of cell culture experiments were performed using PDAC cells, followed by their validation in patient-derived organoids to examine the synergistic anti-proliferative and chemopreventive effects of BER and EMO against PDAC.
Results: Transcriptomic profiling identified that LAMB3 expression was significantly upregulated in PDAC tissue (P &lt; 0.01) and was significantly associated with poor OS and DFS in PDAC patients (P &lt; 0.01). The combination of BER and EMO displayed superior synergistic anti-tumor potential in PDAC cells vs. individual compounds, as revealed by cell proliferation, clonogenicity, migration, and invasion assays. The combination of BER and EMO also altered the expression of key proteins involved in cellular apoptosis, epithelial-mesenchymal-transition, and EGFR/ERK//AKT growth factor signaling pathways. Finally, these findings were successfully validated in PDAC patient-derived 3D organoids.
Conclusions: We provide the first evidence that combined treatment with berberine and emodin exerts synergistic anti-cancer activity in PDAC, primarily regulated through the LAMB3-mediated interaction with other members of the EGFR-signaling pathway.
Citation Format: CAIMING XU, SILEI SUI, Keisuke Okuno, Silvia Pascual-Sabater, Cristina Fillat, Ajay Goel. Berberine and emodin synergistically suppress the EGFR signaling cascade by targeting LAMB3 in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3821.
Abstract 3823: Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer
Authors: Sreekumar Amritha , Simmons Matthew , Lee Tae Jin , Sharma Ashok , Saini Sharanjot 
Published: April 2023

Abstract
Background: Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of prostate cancer (PCa) that often emerges after androgen receptor (AR)-targeted therapies such as enzalutamide and abiraterone. NEPC arises via trans-differentiation of prostate adenocarcinomas to neuronal lineage, a process referred to as ‘neuroendocrine trans-differentiation’ (NED), wherein prostate cancer cells show an altered expression of lineage markers such as decreased expression of AR and increased expression of neuronal markers. Currently, there is a lack of effective targeted therapies for NEPC. Current treatment options are limited to highly toxic platinum-based drugs. Hence, there is an urgent need to develop novel treatment strategies to treat NEPC. The focused objective of this study is to develop novel, non-toxic therapeutic intervention against NEPC. Towards this, we exploited the potential of plant-derived nanovesicles/extracellular vesicles as a novel therapeutic. Extracellular vesicles (EVs) are lipid-bilayer-delimited particles that are released from almost all types of cells, including plant cells, typically between 30-150 nm in size.
Methods: EVs/nanovesicles were isolated from plant-derived sources by ultracentrifugation. Isolated nanovesicles were characterized by Nanoparticle Tracking Analyses and electron microscopy. After characterization, the effects of nanovesicles were tested in NEPC cell lines in vitro. Effects on cell viability and apoptosis were assessed by MTS assay and flow cytometry, respectively. To understand the mechanistic basis of EV induced alterations, next generation RNA sequencing was performed in control vs EV treated NCI-H660 cells on Illumina HiSeq platform. Significant targets were further validated by real time PCR and Western blot analyses.
Results: Plant-derived nanovesicles reduced viability and induced apoptosis in NEPC cell lines. Genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by these vesicles in NEPC cell line. Remarkably, nanovesicles led to significantly attenuated levels of key proneural transcription factors including ASCL1, BRN2 and SOX2. In addition, neuronal markers ENO2 and NCAM1 were downregulated suggesting that treatment with nanovesicles reverse the ‘cardinal’ genetic alterations that drive NEPC.
Conclusion: Plant-derived nanovesicles can be employed as a novel treatment modality in neuroendocrine prostate cancer.
Citation Format: Amritha Sreekumar, Matthew Simmons, Tae Jin Lee, Ashok Sharma, Sharanjot Saini. Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3823.
Abstract 3841: Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation
Authors: Marsh Graham P. , Goggins Sean , Bosnakovski Darko , Kyba Michael , Ojeda Samuel , Harrison Drew A. , Ott Christopher J. , Maple Hannah J. 
Published: April 2023

Abstract
CREB-binding protein (CBP, CREBBP, KAT3A) and E1A-binding protein (EP300, p300, KAT3B) are paralogous multi-domain proteins that act as chromatin regulators and transcriptional co-activators. They contain a histone acetyltransferase (HAT) domain that catalyzes the histone H3, lysine 27 acetylation (H3K27ac) mark at regulatory elements such as enhancers and promoters. Transcription factors associate with stretches of H3K27ac marks (known as ‘super-enhancer’ elements) and result in gene transcription that ultimately establishes cell identity and fate. They are implicated in cancer pathology, and small molecule inhibition of the bromodomain (BRD) or HAT domain of CBP/p300 are considered promising therapeutic strategies for a number of cancer types.
CBP and p300 are highly homologous but have distinct roles that have to date been hard to delineate, since small molecule inhibitors developed to date are unable to selectively target each protein independently. Additionally, small molecule inhibitors that target individual domains are unable to entirely abrogate the full functionality of CBP/p300. A bromodomain-recruiting dual CBP/p300 PROTAC Degrader ‘dCBP1’ was therefore recently developed to provide a chemical tool to explore the phenotypic consequences of CBP/p300 chemical knockdown. A further study demonstrated that it is possible to degrade p300 with some selectivity by converting a CBP/p300 dual HAT-domain inhibitor into a PROTAC, called ‘JQAD1’.
We have used a different HAT-domain recruiting ligand to develop novel PROTACs that elicit proteasome-mediated degradation of p300 with significantly enhanced selectivity over CBP, compared with JQAD1. We additionally demonstrate a faster onset of degradation for lead PROTAC molecules and present data exploring the consequences of selective p300 degradation in CIC-DIX4 sarcoma.
Citation Format: Graham P. Marsh, Sean Goggins, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Hannah J. Maple. Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3841.
Abstract 3925: JunB regulates expression of HPV genes in head and neck cancer
Authors: Rehmani Hina , Schrank Travis P. , Issaeva Natalia , Yarbrough Wendell G. 
Published: April 2023

Abstract
The incidence of HPV-positive head and neck squamous cell carcinoma (HNSCC) is now being considered an epidemic in the US and Western Europe as rates have surpassed those for cervical cancer. For approximately 14,400 patients per year in the US, initial therapy is aggressive and often results in adverse lifelong side effects such as difficulty swallowing and speaking. Despite having a higher cure rate than HPV-negative HNSCC, the recurrence rate is still approximately 30%. Therefore, new treatment options need to be available for these relapsed patients. Our lab was prompted to explore demethylation as a therapeutic option as HPV-positive HNSCC have a more hypermethylated genome than HPV-negative cancers. 5-azacytidine (5-aza) is a synthetic cytidine analog that causes DNA demethylation by trapping methyltransferases to chromatin; it is FDA-approved for the treatment of myelodysplasia and acute myeloid leukemia. Our lab found that low doses of 5-aza delayed HPV-positive xenograft tumor growth and that HPV-positive tumor samples from patients treated with 5-aza in a window trial had increased apoptosis. They also observed a marked downregulation of HPV gene expression after 5-aza. Decreased HPV E6 expression, followed by reactivation of tumor suppressor p53, induced p53-dependent apoptosis in HPV-positive HNSCC. To further explore the mechanism of this sensitivity to 5-Aza, we first determined that 5-aza regulates the transcription of HPV genes, but not the stability of HPV transcripts. We found that the transcriptional regulation of HPV genes after 5-aza depends on the proto-oncogene JunB, a component of the transcription factor Activator Protein 1 (AP-1). Additionally, silencing of JunB abolished the expression of HPV E6/E7 genes and reactivated tumor suppressor p53 in HPV-positive HNSCC. Furthermore, we revealed that clonogenic survival of HPV-positive head and neck cancer cells is dependent on JunB expression. Our study exposes an important component of 5-Aza-associated sensitivity and toxicity in HPV-positive HNSCC and identifies a novel dependency on JunB, potentially providing a new rational targeted therapy.
Citation Format: Hina Rehmani, Travis P. Schrank, Natalia Issaeva, Wendell G. Yarbrough. JunB regulates expression of HPV genes in head and neck cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3925.
Abstract 3947: S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis
Authors: Kang Hye Seon , Kim In Kyoung , Yeo Chang Dong , Kim Jin Woo , Lee Sang Haak 
Published: April 2023

Abstract
Background: Cigarette smoke-induced chronic airway inflammation increases the risk of lung cancer, and plays a multifaceted role in lung cancer initiation and progression, and RAGE-ligand axis (HMGB1, S100A8/A9) contributes Cigarette smoke-induced persistent and progressive inflammation. The aim of the present study was to determine the inflammatory effect on S100A8/A9-RAGE pathway in smoke-induced carcinogenesis in lung cancer.
Methods: Human alveolar adenocarcinoma cells (A549) and normal bronchial epithelial cells (BEAS-2B) were co-cultured for 24 h with the PBMC and then, cells were incubated in the presence or absence of 1.5% cigarette smoke extract (CSE) for 24 h. The cells transfected with siRNA targeting S100A8/9 or RAGE. The cell viability, colony-forming ability, migration, invasion, metastasis and morphological changes were assessed. Female A/J mice were given a benzo(a)pyrene (100mg/kg) in 0.1 ml corn oil via oral gavage at once a week for 3 weeks, and administrated CSE (1.25 ul/g) via intratracheal (IT) at twice a week for 4 weeks. Tumor load was determined by averaging the total tumor volume in each group. BAL differential cells were counted to analyze inflammatory cells.
Results: Cellular growth and colony-forming were promoted by exposure to CSE, and significantly inhibited by S100A8/9 and RAGE-siRNA transfection, especially in A549 cells than BEAS-2B. Cell migration, invasion, MMP-2/9 activities, and the mRNA and protein expression of TLR4, NF-κB, RAGE, S100A8/9 and HMBG1 were higher in CSE exposed A549 cells. S100A8/9 and RAGE-siRNA transfection attenuated those expression, significantly. B(a)P induced an average tumor volume 7.28 mm3 per mouse, and CSE significantly increased tumor volume (8.10 mm3) compared to the B(a)P group. The total cell number and lymphocytes in BAL fluids tended to increase after CSE administration in lung cancer mouse group. Moreover, CSE significantly induced the levels of S100A8/9 and RAGE, p38 and p-ERK, and decreased JNK in serum and tumors with adjacent lung tissues (p &lt; 0.05).
Conclusions: We identified cigarette smoke-induced S100A8/A9-RAGE pathway promoted airway inflammation and lung carcinogenesis in vitro and in vivo. Although S100A8/A9 protein contributes to many types of disease, this study will help us gain a better understanding of the complexities of cancer progression. Further studies are needed for therapeutic target of cigarette smoke-induced inflammation and immunosuppression in tumor microenviornment.
Citation Format: Hye Seon Kang, In Kyoung Kim, Chang Dong Yeo, Jin Woo Kim, Sang Haak Lee. S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3947.
Abstract 3963: Mass spectrometry reveals a downregulation of calreticulin after neoadjuvant chemotherapy in pancreatic cancer
Authors: Stoffel Michael C. , Dingendorf Elisabeth BH , Kittel Dahlia L. , Kristiansen Glen , Lerbs Tristan 
Published: April 2023

Abstract
Introduction: Pancreatic ductal adenocarcinomas are one of the deadliest cancer types with limited response to current therapies. Thus, this study examined changes in the proteome of epithelial cells in pancreatic cancer after neoadjuvant chemotherapy with gemcitabine, to identify new therapeutic targets.
Methods: Upon receiving patient consent, fresh pancreatic cancer tissue was received from surgical tumor resections at the University Hospital of Bonn. We mechanically and enzymatically digested and purified the tissue to create single-cell suspensions. After staining the cells against CD45 und CD326, we purified epithelial cells, blood cells, and stroma through FACS. To analyze their proteome, the sorted cells were lysed in TEAB buffer and the protein lysates were measured by the mass spectrometry core facility at the University of Bonn. We then analyzed the data using DAVID and Shiny GO.
Results: Gene enrichment analyses showed a significantly reduced expression of calreticulin after neoadjuvant chemotherapy in epithelial cells. A direct comparison between untreated and treated epithelium cancer cells using a heat map showed a decreased expression of actin and enzymes of glycolysis in treated cancer cells. Moreover, untreated epithelial cells showed an increase of proteins related to MHC class Ib protein complex assembly and antigen processing and presentation of endogenous peptide antigen via MHC class. In contrast, treated cells showed a higher presence of proteins for nutrient supply from the blood. Furthermore, untreated stroma cells exhibited an increased number of proteins responsible for mesenchymal migration and for actin filament fragmentation.
Conclusion: This study shows that neoadjuvant chemotherapy with gemcitabine leads to distinct changes in the proteome of tumor cells in pancreatic cancers. In particular, a decreased expression of the “eat-me-signal” calreticulin impairs macrophage-mediated cancer cell phagocytosis, thereby indicating a mechanism by which cancer cells protect themselves after chemotherapy.
Citation Format: Michael C. Stoffel, Elisabeth BH Dingendorf, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs. Mass spectrometry reveals a downregulation of calreticulin after neoadjuvant chemotherapy in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3963.
Abstract 3964: APE1 protects SMAD3 against ROC1 ubiquitin mediated degradation in esophageal adenocarcinoma cells
Authors: Ballout Farah , Lu Heng , Peng Dunfa , El-Rifai Wael 
Published: April 2023

Abstract
Background: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades and continues to rise in the Western world. The 5-year survival rate for EAC patients is less than 20% which underscores the need to better understand the underlying mechanisms to identify new therapeutic approaches. This study aimed at investigating the potential role of APE1 in regulating SMAD3 and promoting EAC progression.
Methods and Results: Western blot data showed that APE1 and SMAD3 were highly expressed in EAC cell lines. APE1 silencing reduced SMAD3 nuclear expression and downregulated its downstream targets SERPINE1 and c-myc. These results were confirmed by immunofluorescence staining showing loss of nuclear accumulation of SMAD3 after APE1 knockdown. Mechanistically, immunoprecipitation and proximity ligation assays revealed a direct binding between APE1 and SMAD3 in the nucleus. Further investigation showed that APE1 binds to the C-terminal MH2 domain of SMAD3, and this binding protects SMAD3 from ubiquitin mediated proteasomal degradation by blocking its interaction with the RING finger protein, ROC1. Interestingly, APE1-redox-specific inhibition (APX2009) downregulated SMAD3 expression and the APE1 redox-deficient mutant (C65A) disrupted APE1-SMAD3 binding indicating that this regulation depends on APE1 redox activity.
Conclusion: Our findings establish a role of APE1 in regulating SMAD3 in EAC. These findings provide a potential therapeutic approach for the treatment of EAC by the pharmacological inhibition of APE1.
Citation Format: Farah Ballout, Heng Lu, Dunfa Peng, Wael El-Rifai. APE1 protects SMAD3 against ROC1 ubiquitin mediated degradation in esophageal adenocarcinoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3964.