bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3733: Disconnect between APOBEC3 expressions and mutations across cancers
Authors: Khosh Azad , Hamidi Hamid , Rahimi Hamzeh , Ebrahimi Diako 
Published: April 2023

Abstract
DNA of many tumors is barraged by C-to-T/G mutations within TCW (W:T,A). These mutations are attributed to the aberrant expression and activity of APOBEC3 enzymes. They have been shown to account for many driver mutations in genes such as PIK3CA, ERBB2, and PPP2R1A, however their precise source and also their roles in tumor development, evolution, and patient survival are debated. Currently, quantification of APOBEC3 expression changes in tumor cells is confounded by the ubiquitous expression of these enzymes in infiltrating immune cells. In this study, we used quantitative biology approaches to separate the expression profiles of APOBEC3 enzymes in tumor and tumor microenvironment cells and determine their associations with tumor mutational signatures. For this purpose, we analyzed diverse datasets including TCGA tumor/matched normal RNAseqs, tumor somatic mutations, cell line RNAseqs and mutations, estimates of tumor purities and immune cell compositions, and expression of purified cell populations to precisely determine how APOBEC3 enzymes are dysregulated across tumors and whether their dysregulations are proportional to tumor mutational signatures. Unexpectedly, we found that dysregulation of APOBEC3 enzymes is independent of tumor C-to-T/G mutational burden. Importantly, our data suggest that this disconnect is likely not due to the episodic bursts of APOBEC3-induced mutations in cancer.
Citation Format: Azad Khosh, Hamid Hamidi, Hamzeh Rahimi, Diako Ebrahimi. Disconnect between APOBEC3 expressions and mutations across cancers. [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 3733.
Abstract 3734: Neuroendocrine differentiation (ND) in sensitivity of neuroendocrine tumor (NET) cells to ONC201/TIC10 cancer therapeutic
Authors: Ding Elizabeth C. , El-Deiry Wafik S. 
Published: April 2023

Abstract
Neuroendocrine tumors (NETs) harbor neuroendocrine differentiation (ND) with specific markers including protein gene product 9.5 (PGP9.5) and Chromogranin A (CgA). In prostate cancers (PC), ND is induced by BRN2/SOX2 transcription factors. NET-like cells with low or absent androgen receptor (AR) signaling cause hormone therapy resistance and poor prognosis in PC. Small cell lung carcinoma (SCLC), a high-grade NET, presents with metastasis early and has poor survival. ONC201/TIC10 is a small molecule inducer of TRAIL signaling in clinical trials. ONC201 antagonizes dopamine D2 or D3 receptors (DRD2/DRD3) and is an agonist of mitochondrial caseinolytic protease P (ClpP) resulting in activation of DR5/TRAIL-dependent apoptosis involving the integrated stress response (ISR). ONC201 is active in various malignancies including H3K27M-mutated glioma and NETs expressing high levels of DRD2. We hypothesized that altered BRN2/SOX2 may impact NET apoptosis by ONC201 through the ISR and TRAIL/DR5. We analyzed the expression of neuroendocrine markers PGP9.5, CgA, SOX2, and BRN2, as well as markers of TRAIL signaling pathway markers ATF4, DR5, ClpP, ClpX, and DRD2/DRD3 in PC and SCLC cell lines (N=6) ± treatment with ONC201. Specifically, we compared pre-treatment protein expression levels with the IC50. Our results reveal that DU145 (IC50=3.11μM), PC3 (IC50=3.02μM), and LNCaP (IC50=1.33μM) are ONC201 sensitive. H1417 SCLC expresses CgA, unlike PC3 and DU145. PGP9.5 is expressed in these lines. PGP9.5 is expressed in PC3, DU145, H1417, and H1048 but not in LNCaP and 22RV1. BRN2 is expressed in PC3, H1417, and H1048 but not DU145, LNCaP, or 22RV1. ClpX is expressed in all 6 lines but at lower levels in SCLC. ClpP is expressed in the 6 lines. DR5 is expressed at higher levels in PC3, DU145, LNCaP, and 22RV1 PC versus H1417 and H1048 SCLC. SOX2 is expressed at high levels in H1417 cells. These results are establishing the landscape of ND in PC and SCLC lines for further experimentation and testing of our hypothesis. To characterize the association of BRN2 dysregulation with ONC201 sensitivity, we are performing BRN2/SOX2 knockdown experiments using siRNA and evaluating effects towards ONC201 sensitivity. Our results provide insights into molecular mechanisms of ND in PC and SCLC sensitivity to ONC201. We are also currently working to overexpress BRN2 and SOX2 in cell lines to analyze the impact on neuroendocrine differentiation and ONC201 sensitivity.
Citation Format: Elizabeth C. Ding, Wafik S. El-Deiry. Neuroendocrine differentiation (ND) in sensitivity of neuroendocrine tumor (NET) cells to ONC201/TIC10 cancer therapeutic. [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 3734.
Abstract 3747: Transcribed ultra-conserved regions (TUCRs): A first computational and molecular characterization of an understudied class of molecules in gliomas
Authors: Gibert Myron K. , Chagari Bilhan , Roig-Laboy Christian , Sarkar Aditya , Abounader Roger 
Published: April 2023

Abstract
Gliomas are the most common malignant primary brain tumors. Particularly, glioblastoma (GBM) is the most common and deadliest malignant brain tumor. Most glioma research has focused on protein-coding genes and much less on the non-coding transcripts that make up 98% of cellular RNA. Transcribed Ultra-Conserved Regions (TUCRs) represent an understudied class of molecules that are found highly conserved across multiple species, including 100% conservation in mouse and rat genomes. These 481 transcripts are highly resistant to variation and are commonly deregulated in cancer, which suggests regulatory and functional importance when considered along with their high degree of conservation. We performed the first-ever characterization of TUCRs in gliomas in silico. Using an elaborate workflow, we annotated and identified TUCRs that are deregulated in GBM and low-grade glioma (LGG), associated with patient outcomes, and predicted their function in glioma initiation and progression. Most TUCRs were long non-coding RNAs. Of these, we investigated the most highly upregulated intergenic TUCR, uc.110, in vitro and in vivo in glioma cell lines. Knockdown of uc.110 expression via siRNA resulted in reduced glioma cell accumulation, viability, and invasion in vitro while reducing tumor volume and increasing overall survival in vivo. Concurrent lentiviral overexpression of uc.110 partially rescued wild-type expression, accumulation, viability, and invasion in vitro. Therefore, it is likely that this TUCR is functioning as an oncogene within the context of GBM. Our study represents the first comprehensive characterization of TUCRs in gliomas and can serve as a foundation and framework for similar studies in gliomas and other cancers.
Citation Format: Myron K. Gibert, Bilhan Chagari, Christian Roig-Laboy, Aditya Sarkar, Roger Abounader. Transcribed ultra-conserved regions (TUCRs): A first computational and molecular characterization of an understudied class of molecules in gliomas. [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 3747.
Abstract 3749: Oncogenic role of Epstein-Barr virus lnc-BARTs in EBV associated tumors
Authors: JIAYAN LIU , Mok Bobo Wing-Yee , He Songtao , Chen Honglin 
Published: April 2023

Abstract
While majority of humans infected with Epstein-Barr virus (EBV) is asymptomatic for whole life, EBV is found to associate with several human cancers, including Burkitt’s lymphoma, Hodgkin’s diseases, post-transplant lymphoproliferative disorder (PTLD), nasopharyngeal carcinoma (NPC) and gastric carcinoma. Among these EBV associated tumors, EBV genome is found in 100% of NPC tumor cells. EBV establishes a latent infection in NPC cells, expressing few viral proteins, but elevated levels of non-coding RNAs transcribed from the BamHI-A region of the EBV genome, designated BamHI-A rightward transcripts (BARTs). The family of EBV BART RNAs comprises BART-microRNAs (miRNAs) and long non-coding RNAs (lnc-BARTs). While versatile functions of BART miRNAs have been revealed, little is known about the role of EBV lnc-BARTs. Here, we provided evidence to show that BARTs mRNA which derived from multiple exons of BART function as regulatory long non-coding RNA, namely lnc-BARTs, in modulating the core network for maintaining EBV latency and promoting NPC oncogenesis through epigenetic mechanisms. Our results showed that the apoptosis rate of NPC cell lines with knockdown of EBV lnc-BARTs was significantly increased, suggesting that lnc-BARTs have an anti-apoptotic effect in EBV associated tumors. MS analysis was performed to identify host factors which interact with EBV lnc-BARTs in NPC cells. Lnc-BARTs were shown to directly interact with several transcriptional regulators, including BRD4 and SC35. Notably, RNA-FISH assays demonstrated that lnc-BARTs co-localize with BRD4 and SC35 complexes in nuclear speckles, with these complexes being disrupted by treatment with JQ1, a BRD4 competitive inhibitor. RNA immunoprecipitation and RNA pulldown assays confirmed that lnc-BARTs bind to BRD4. ATAC sequencing analysis and transcriptome analysis further demonstrated that knockdown of BARTs in the EBV-harboring NPC cell line, C666-1, resulted in globally reduced chromatin accessibility downregulation of oncogenes like MYC and BCL2. In addition, ChIP sequencing analysis revealed that lnc-BARTs interfere PolII phosphorylation on promoters of genes. Our findings suggest that EBV lnc-BARTs are involved in epigenetic modulation of host gene expression through functional interaction with elongation regulatory machinery to maintain EBV latency and drive tumorigenesis in NPC.
Citation Format: LIU JIAYAN, Bobo Wing-Yee Mok, Songtao He, Honglin Chen. Oncogenic role of Epstein-Barr virus lnc-BARTs in EBV associated tumors. [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 3749.
Abstract 3750: miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM cells
Authors: Sall Sophie , Korleski Jack , Johnson Amanda , Johnson Maya , Lopez-Bertoni Hernando 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most lethal and aggressive primary brain malignancy with high recurrence rates and virtually no long-term survival. Despite our expanding knowledge regarding GBM at the genomic/molecular level, we still don’t fully comprehend the molecular mechanisms responsible for GBM recurrence. Current knowledge implicates tumor-propagating Glioma Stem Cells (GSCs) in the evolution of treatment resistance and tumor recurrence. Understanding these cellular/molecular events will inform strategies for preventing and/or treating recurrent GBM (rGBM). Gene set enrichment analysis (GSEA) of RNA sequencing datasets obtained from GSCs and clinical rGBM specimens identified TGFBR2 signaling as a high frequency and potentially targetable pathway in rGBM. We show that SMAD2/3 signaling, a downstream effector of TGFBR2, is enriched in rGBM and that patients with elevated TGFBR2 have statistically shorter long-term survival outlooks. The functional relevance of these findings was supported using ITD1, a selective TGFBR2 inhibitor, which decreased the GSC phenotype and cell viability of cells derived from clinical rGBM (rGBM cells), while simultaneously re-sensitizing them to temozolomide (TMZ) in-vitro. Since GBM is known to efficiently develop resistance to receptor-targeting monotherapies, we sought to simultaneously target multiple putative oncogenic drivers downstream of TGFBR2. To achieve this, we applied an unbiased miRNA-based network analysis that identified miR-590-3p as an inhibitor of SMAD2/3 signaling at multiple nodes and thus a potential tumor suppressor in rGBM. Transgenic miR-590-3p robustly decreased the expression of &gt;30 putative oncogenes, reduced the GSC phenotype and cell viability, as well as re-sensitized rGBM cells to TMZ. These results predict that blocking TGFBR2 signaling will negatively impact the tumor phenotype of rGBM as well as its GSC capacity. Ongoing directions for this research include comparing the efficacy of ITD1 monotherapy with miR-590-3p therapy in rGBM models in-vivo. These results identify a significant role of TGFBR2 signaling in both TMZ resistance and the GSC phenotype in rGBM and provide a miRNA-based strategy for simultaneously targeting multiple oncogenic nodes within the TGFBR2 and potentially other oncogenic signaling pathways.
Citation Format: Sophie Sall, Jack Korleski, Amanda Johnson, Maya Johnson, Hernando Lopez-Bertoni. miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM 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 3750.
Abstract 3760: MicroRNA-1 run down the growth and metastasis of small cell lung cancer
Authors: Khan Parvez , Siddiqui Jawed A. , Maurya Shailendra Kumar , Mirzapoiazova Tamara , Kshirsagar Prakash G. , Venkata Ramakanth Chirravuri , Chaudhary Sanjib , Kanchan Ranjana , Perumal Naveenkumar , Fatima Mahek , Khan Md Arafat , Rehman Asad Ur , Lakshmanan Imayavaramban , Mahapatra Sidharth , Kulkarni Prakash , Ganti Apar Kishor , Jain Maneesh , Salgia Ravi , Batra Surinder Kumar , Nasser Mohd Wasim 
Published: April 2023

Abstract
Small cell lung cancer (SCLC) is a highly aggressive and metastatic lung cancer subtype with universal relapse and poor prognosis. The lack of potential drug targets limits targeted therapies for SCLC patients. To track down the potential therapeutic molecules in SCLC, we performed micro-RNA sequencing from the serum samples of SCLC patients and compared with the bulk RNA-sequencing data from SCLC tumor tissues. A consistent downregulation of microRNA-1 (miR-1) was observed in the SCLC patient serum samples, cell lines, and tumor tissues compared to their matched normal control. Overexpression of miR-1 in SCLC cell lines decreased cell growth and oncogenic signaling. Metastatic studies using the intracardiac injection model of SCLC cell lines showed that miR-1 overexpression decreases distant organ metastasis. Interestingly, the loss of function studies using miR-1Zip/sponging showed increased tumorigenesis and metastasis in SCLC subcutaneous and intracardiac xenografts. Mechanistic investigations revealed the CXCR4/FOXM1/RRM2 axis as a unique downstream target of miR-1 in SCLC. We found that FOXM1 transcriptionally regulates the RRM2 expression by directly binding to its promoter site, and miR-1 modulates these interactions through CXCR4. The results of the present study provided a strong preclinical rationale that miR-1 has a high potential for developing innovative SCLC therapies.
Citation Format: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Prakash G. Kshirsagar, Ramakanth Chirravuri Venkata, Sanjib Chaudhary, Ranjana Kanchan, Naveenkumar Perumal, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. MicroRNA-1 run down the growth and metastasis of small cell lung 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 3760.
Abstract 3774: MiR-34b promotes cellular senescence and ROS generation in human cervical cancer cells
Authors: Sindhu K J , Karunagaran Devarajan 
Published: April 2023

Abstract
Background: Cervical cancer is one of the most common cancers in women worldwide, particularly in low- and middle-income countries. Due to low surveillance and late detection, it is one of the major health issues leading to high mortality rates. MicroRNA-34 family (miR-34a, b, c) is thought to be tumor suppressive in several cancers but the mechanistic basis is not clear.
Methods: Stable cell lines were generated with inducible hsa-miR-34b lentiviral vector from Dharmacon and maximal time and dose for induction of miR-34b with doxycycline were determined. Cell viability studies on HeLa, SiHa and C33A were investigated by MTT assay. Acridine orange/Ethidium bromide (AO/EB), senescence associated β-galactosidase (SA- β gal) assays for apoptosis and senescence and assessment of DNA damage (γH2AX) were performed. Total reactive oxygen species (ROS), superoxide, hydroxyl and peroxynitrite and H2O2 radicals were quantitated by DCFDA, DHE, HPF dyes and pHyper-dMito plasmid, respectively.
Results: Overexpression of miR-34b reduced cell viability in cervical cancer cell lines except SiHa. Further investigation by AO/EB staining revealed no significant increase in the proportion of apoptotic cells on overexpression of miR-34b. Analysis of SA- β gal on overexpression of miR-34b revealed an increase in the proportion of senescent population in all 3 cell lines. Increased DNA damage is also observed in agreement with an increase in cellular senescence. In addition, an increase in oxidative stress was observed in miR-34b overexpressing cell lines as total ROS was elevated in all 3 cell lines with increased superoxide, hydroxyl and peroxynitrite and H2O2 radicals in HeLa and C33A while SiHa showed increased levels of H2O2 radicals with no significant change in other radicals.
Conclusions: Overexpression of miR-34b can promote an increase in cellular senescence and oxidative stress in cervical cancer. The differential action in different cell lines may be due to the difference in expression of miR-34b in these cell lines. Our results highlight the potential of miR-34b to be used for therapeutic intervention in cervical cancer.
Citation Format: K J Sindhu, Devarajan Karunagaran. MiR-34b promotes cellular senescence and ROS generation in human cervical cancer 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 3774.
Abstract 3782: Targeting cancer cells using folate conjugated to a fully modified version of miR-34a (FolamiR-34a) to produce enhanced and sustained anti-tumor activity
Authors: Iyer Shreyas Ganesan , Abdelaal Ahmed M. , Sohal Ikjot Singh , Kasireddy Sudarsan R. , Kasinski Andrea L. 
Published: April 2023

Abstract
Due to the pleiotropic nature of miR-34a, including its ability to downregulate multiple genes that drive resistance to currently used anti-cancer therapies, we hypothesize that the best use of miR-34a in a clinical setting would be in combination with standard-of-care treatments. For in vivo use, such a molecule would necessitate the following: i) a stabilized version of miR-34a that can withstand the harsh environment in circulation and intracellular nucleases, and ii) a robust, specific, and safe delivery vehicle. With regard to stability, we successfully generated the first fully modified version of miR-34a. This new chemically modified molecule is over 400-fold more stable than the previously used partially modified version and induces enhanced and sustained target gene repression. To assess in vivo activity of fully modified miR-34a requires a suitable delivery vehicle. Indeed, while various approaches have been used to restore miR-34a in tumors, clinically relevant mechanisms for delivery of miR-34a have been a challenge due to poor tumor uptake, unfavorable bioavailability, and unwanted toxicity. Previously, we determined that a partially modified version of miR-34a can be delivered specifically and robustly to cancer cells in a targeted, vehicle-free manner through direct conjugation to folate, a ligand of the high-affinity folate receptors. Thus, we conjugated our fully modified miR-34a (FM-miR-34a) to folate generating FM-FolamiR-34a. Following in vivo delivery of FM-FolamiR-34a to mice with breast cancer xenografts we observed enhanced and sustained target gene repression, in comparison to our first-generation partially modified folate-miR-34a conjugate (FolamiR). Critical miR-34a target genes involved in promoting resistance, including MET, AXL, and CD44 were downregulated over 90% for at least 120 hours following a single 1.5 nmol dose of FM-FolamiR-34a. Our final objective is to evaluate FM-FolamiR-34a in combination with standard-of-care agents in vivo.
Citation Format: Shreyas Ganesan Iyer, Ahmed M. Abdelaal, Ikjot Singh Sohal, Sudarsan R. Kasireddy, Andrea L. Kasinski. Targeting cancer cells using folate conjugated to a fully modified version of miR-34a (FolamiR-34a) to produce enhanced and sustained anti-tumor activity. [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 3782.