bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3703: Multimodal metabolic imaging and proteomics of radiation resistance in head and neck squamous cell carcinoma
Authors: Ivers Jesse D. , Dadgar Sina , Rajaram Narasimhan 
Published: April 2023

Abstract
Radiation resistance can halt a well-curated treatment plan in its tracks, but it may take weeks to realize this lack of efficacy resulting in lost time and unnecessary side effects. In this study, we sought to elucidate novel biomarkers of radiation resistance to predict treatment response in head and neck squamous cell carcinoma (HNSCC) at much earlier timepoints. We grew tumor xenografts from radiation-resistant UM-SCC-47 (n=25) and -sensitive UM-SCC-22B (n=37) cells in nude athymic mice. Each group was randomly divided into treatment and control groups, which were further subdivided into four timepoints for tumor excision: pre-treatment baseline, 1-, 24-, and 48-hours post-treatment. Prior to excision, we injected pimonidazole to quantify tumor hypoxia. We determined the two-photon excited fluorescence intensity and lifetime of NADH and FAD and quantified the optical redox ratio, ratio of free to bound NADH, and mean NADH lifetime of frozen sections of each tumor. We observed spatial and temporal heterogeneity in these high-resolution optical maps that indicated different metabolic programs in radiation-resistant and -sensitive tumors. A histogram-based heterogeneity analysis revealed time dependent shifts toward glycolysis in the radiation-resistant UM-SCC-47 treatment group, while the sensitive UM-SCC-22B treatment group showed the opposite trend. Proteomics performed on both cell lines identified multiple dysregulated proteins that are often implicated in HNSCC and associated with metabolic reprogramming — specifically, EGFR and SMAD4. We also found elevated levels of hypoxia and HIF-1 in the UM-SCC-47 tumors compared with the UM-SCC-22B tumors prior to and post-radiation. Using spatially co-registered optical imaging and immunohistochemical maps of the same field of view, we will present correlations between our optical markers and EGFR, SMAD4, and HIF-1. These studies will provide evidence of how protein dysregulation causes changes to optical metabolic imaging markers.
Citation Format: Jesse D. Ivers, Sina Dadgar, Narasimhan Rajaram. Multimodal metabolic imaging and proteomics of radiation resistance in head and neck squamous cell carcinoma. [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 3703.
Abstract 3706: The significance of cholesteryl ester profiles in hepatocellular carcinoma
Authors: Rahmanov Nazar , Liu Zhirong , Mao Jinghe , Kyle Patrick , Zhou Xinchun 
Published: April 2023

Abstract
Introduction: The association between cholesteryl ester (CE) profiles in the liver and oncogenesis, gender, and age disparities in hepatocellular carcinoma (HCC) has not been studied to date. This study aims to compare CE profiles between benign liver tissue (BLT) and HCC, and to correlate these findings with oncogenesis and disparities in patients with HCC.
Methods: Paired BLT and HCC samples obtained from 32 patients with the diagnosis of HCC were used for lipid extraction. Electrospray ionized mass spectrometry (ESI-MS) was used to determine CE profiles, including 22 individual CE species and the total levels of CE. The CE profiles in BLT and HCC were compared and stratified between subgroups based on the gender and age of the patients. The student T-test was used for statistical analysis and the significant p-value was set at 0.05.
Results: Total CE levels were higher in HCC than in BLT, but not statistically significant (1.8-fold, p=0.16). Interestingly, 5 saturated CE individual species and 2 mono-unsaturated individual CE species (C14:0, C16:0, C16:1, C18:0, C18:1, C19:0, and C20:0) were significantly higher in HCC than in BLT (2.4 to 14-fold higher). None of the individual poly-unsaturated CE species showed a statistical difference between HCC and BLT. In males, the levels of 3 saturated individual CE species (C16.0, 16:0, and C20:0) were significantly higher in HCC than in BLT (1.9 to 21.3-fold higher levels). In contrast, CE 16:1 was significantly lower in HCC than in BLT (0.9-fold, p=0.02) in males. In females, none of the CE profiles showed a significant difference between HCC and BLT. Total CE levels were 2.1-fold higher in males with HCC than in females with HCC (18.6nM vs. 8.92nM). In young patients (&lt;66-year-old), individual CE species C14:0 was significantly higher in HCC than in BLT (19.1-fold, p=0.038). In old patients (≥66-year old), individual CE species C20:0 was significantly higher in HCC than in BLT. Total CE levels were 2.1-fold higher in young HCC patients than in old HCC patients (13.68nM vs. 6.45nM).
Conclusion: This study reveals that an increase in hepatic total CE levels and individual CE species are associated with the oncogenesis of HCC and show gender and age disparities. These findings could be helpful in prevention, treatment, exploring biomarkers, and understanding disparities in HCC.
Citation Format: Nazar Rahmanov, Zhirong Liu, Jinghe Mao, Patrick Kyle, Xinchun Zhou. The significance of cholesteryl ester profiles in hepatocellular carcinoma. [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 3706.
Abstract 3716: RNA N6-methyladenosine binding protein, YTHDF1 regulates DNA repair and cancer immunity in protein synthesis levels
Authors: Jang Dongjun , Jung Hae Rim , Oh Jaeik , Cho Sung-Yup 
Published: April 2023

Abstract
N6-methyladenosine RNA methylation is one of the most abundant post transcriptional modifications in eukaryotic messenger RNAs and plays crucial roles in cancer development and progression. YTHDF1 is an m6A reader protein and has been reported to increase the translation of mRNAs in cooperation with YTHDF3. In gastric cancer, YTHDF1 was reported to be overexpressed in cancer tissues, but detailed effects of YTHDF1 in cancer immunity have not been fully elucidated. In RNA sequencing data from a TGCA gastric cancer cohort, the expression of YTHDF1 was inversely correlated with the cytotoxic T cell markers, such as CD8A, GZMA, and GZMB. To investigate the effect of YTHDF1 overexpression on gene expression regulation in protein levels, we performed the proteomic analysis for newly synthesized proteins using non-canonical amino acid azidohomoalanine and click chemistry tagging reaction in the presence of interferon-γ (IFN-γ). Protein synthesis of genes in ‘DNA damage response’ and ‘DNA repair’ gene sets increased in YTHDF1-overexpressed samples. On the contrary, protein synthesis of genes in ‘Allograph rejection’, ‘NK cell mediated cytotoxicity’, and ‘NF-κB signaling’ gene sets decreased in YTHDF1-overexpressed samples. Especially, YTHDF1 reduced basal expression of DNA damage marker, γH2AX, suggesting that DNA damage repair was enhanced by YTHDF1 overexpression. Our study suggests that YTHDF1 plays pervasive roles in DNA repair and cancer immunity by regulating gene expression in protein levels.
Citation Format: Dongjun Jang, Hae Rim Jung, Jaeik Oh, Sung-Yup Cho. RNA N6-methyladenosine binding protein, YTHDF1 regulates DNA repair and cancer immunity in protein synthesis levels. [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 3716.
Abstract 3721: The C1 domain of capicua has functional importance in human CIC-DUX4
Authors: Luck Cuyler , Jacobs Kyle A. , Okimoto Ross A. 
Published: April 2023

Abstract
Genomic rearrangements between the HMG-box family transcriptional repressor capicua (CIC) and multiple partner genes result in fusion oncoproteins that activate transcription to drive sarcoma growth and progression. In the case of CIC-DUX4, the most common CIC-rearranged fusion oncoprotein, the fusion often retains over 90% of the wild type CIC protein structure including the HMG box and C-terminal C1 domain. Structure-function studies in Drosophila have suggested that the C1 domain of CIC, a non-HMG box DNA binding domain, is important for the transactivating capacity of a synthetic fly-human CIC-DUX4. Consistent with these findings, we performed a retrospective analysis of over 70 breakpoints described from CIC-DUX4 human derived tumors, which revealed that the C1 domain is structurally conserved within the context of the CIC-DUX4 fusion. To further understand the functional role of the C1 domain in human CIC-DUX4 we generated human CIC-DUX4 C1 domain and HMG-box deletion (alone or in combination) mutant constructs and performed a series of studies to test the functional impact on CIC-DUX4 protein levels, subcellular localization, and transcriptional activity. Through these analyses we have found that deletion of the C1 domain does not impact CIC-DUX4 oncoprotein expression or localization but does dramatically reduce target gene expression. In ongoing in vivo studies, we aim to evaluate the significance of the C1 domain in inducing CIC-DUX4 driven tumorigenesis. Collectively, our findings validate the functional importance of the C1 domain in human CIC-DUX4 and to our knowledge provide the first harmonized analysis of breakpoint locations in CIC-rearranged sarcoma.
Citation Format: Cuyler Luck, Kyle A. Jacobs, Ross A. Okimoto. The C1 domain of capicua has functional importance in human CIC-DUX4. [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 3721.
Abstract 3723: Identification and functional characterization of long noncoding RNAs that regulate TGF-&lt;&946;&gt;-Smad pathway as Smad co-factors
Authors: Kitagawa Masatoshi , Ota Kosuke , Ohhata Tatsuya , Sakai Satoshi 
Published: April 2023

Abstract
TGF-β-Smad pathway participates in various biological processes such as development, differentiation, growth regulation, and cancer progression including epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) also involved in carcinogenesis and cancer malignancies. To identify lncRNAs regulating TGF-β-Smad pathway, we comprehensively identified lncRNAs induced by TGF-β and found and reported a lncRNA ELIT-1 (EMT-associated lncRNA induced by TGF-β-1) which was induced by TGF-β and promoted EMT by facilitating TGF-β-Smad signaling. ELIT-1 bound to Smad and participated in expression of TGF-β target genes including Snail. Prognosis of lung adenocarcinoma and gastric cancer patients with high expression of ELIT-1 was poor suggesting that ELIT-1 may be useful as a novel prognostic and therapeutic target. Recently, we found that lincNMR (long intergenic noncoding RNA-nucleotide metabolism regulation) was induced via TGF-β-Smad pathway in various cell lines. Moreover, RNA-seq analysis using lincNMRs-depleted cells indicated that lincNMRs was involved in expression of APOBEC3B, a cytidine deaminase, promoting C to U mutation and highly expressed in various human cancers. Although, regulatory mechanisms of APOBEC3B expression have not been fully elucidated, we proved that lincNMRs bound to Smad and promoted the activity of APOBEC3B promoter. These data suggest that lincNMRs participate in APOBEC3B expression by collaborating with TGF-β-Smad pathway. Additionally, high expression of lincNMRs was positively correlated with high expression of APOBEC3B in various cancer cell lines. The high expression of APOBEC3B as well as lincNMR was significantly associated with their poor prognosis in liver and lung cancer patients, suggesting that lincNMR may contribute to tumor malignancy by enhanced expression of APOBEC3B via TGF-β-Smad pathway.
Citation Format: Masatoshi Kitagawa, Kosuke Ota, Tatsuya Ohhata, Satoshi Sakai. Identification and functional characterization of long noncoding RNAs that regulate TGF-&lt;&946;&gt;-Smad pathway as Smad co-factors. [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 3723.
Abstract 3725: ABI1 regulates STAT3 transcription through a DNA binding activity
Authors: Li Xiang , Arya Neeru , Porter Baylee A. , Kemraj Allysa P. , Dong Xuesen , Frueh Dominique , Bah Alaji , Kotula Leszek 
Published: April 2023

Abstract
Prostate cancer (PCa) is characterized by the complexity of oncogenic signaling and heterogeneity of transcriptional landscapes. Adaptor protein ABI1 is a tumor suppressor in PCa, as evidenced by its loss or downregulation in high-grade and metastatic tumors. STAT3 activation is a hallmark of high-risk prostate tumors. ABI1 loss is associated with STAT3 activation leading to transcriptional reprogramming and epithelial-mesenchymal-transition (EMT) of prostate cancer cells (Nath, Li et al. Cell Commun Signal. 2019). EMT changes involve several homeobox transcription factors. The fact that ABI1 contains a homeobox homology region (HHR) suggests the possibility that it plays a role in EMT by directly regulating transcriptional activity by DNA binding. To examine this hypothesis, we set out to analyze ABI1-DNA binding. Structural NMR studies and in-vitro protein-DNA binding assays confirmed ABI1 binding to DNA regulated by alternative spliced ABI1 Exon 4 region located on the C-terminus of ABI1 HHR. RNA-sequencing data and PCa cell lines qPCR assays reveal the alternative ABI1 Exon 4 spliced-in is enriched in high Gleason-scored PCa samples. ABI1 and STAT3 co-regulate their nuclear vs. cytoplasm localization, and the subsequent functional studies using PCa lines expressing wild type or HHR Exon 4 deletion mutant of ABI1 demonstrated that HHR regulates the STAT3 DNA binding patterns, STAT3 mediated chromatin structure programming as well as its transcription activities. We propose that ABI1 is a critical regulator of STAT3 activity during prostate cancer progression.
Citation Format: Xiang Li, Neeru Arya, Baylee A. Porter, Allysa P. Kemraj, Xuesen Dong, Dominique Frueh, Alaji Bah, Leszek Kotula. ABI1 regulates STAT3 transcription through a DNA binding 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 3725.
Abstract 3736: ZBTB46/FOXA2/HIF1A transcription activator complex promotes MCTP1-regulated neuroendocrine differentiation and epithelial-to-mesenchymal transition
Authors: Phan Vu Thuy Dung , Wen Yu-Ching , Chen Wei-Yu , Chen Wei-Hao , Jiang Kuo-Ching , Li Han-Ru , Tram Van Thi Ngoc , Chen Zi-Qing , Wang Wan-Hsin , Liu Yen-Nien 
Published: April 2023

Abstract
Androgen deprivation therapy (ADT)-induced neuroendocrine differentiation (NED) is a well-known lethal subtype of prostate cancer (PCa) with a median survival rate of less than one year. Despite the increasing research attention on this variant of PCa, the underlying mechanism orchestrating therapy-related neuroendocrine prostate cancer (NEPC) remains elusive. We found that ADT-induced hypoxia-associated ZBTB46/FOXA2/HIF1A signaling enhances the multiple C2 domain transmembrane protein 1 (MCTP1), which promotes NED and epithelial-to-mesenchymal transition (EMT) of PCa. Mechanistically, ZBTB46 physically interacts with the HIF1A/FOXA2 complex, in which ZBTB46 may be a co-activator of the hypoxia-related FOXA2 transcription factor. Interestingly, this ZBTB46/FOXA2/HIF1A complex accumulates after hypoxia and functions as a transcriptional activator of MCTP1. Hypoxia-upregulated MCTP1 subsequently leads to NED and the increase in EMT, whereas the opposite is true for the knockdown of MCTP1 in PCa cells. Consistent with previous results, MCTP1 is highly expressed in high-grade castration-resistance prostate cancer (CRPC) and small-cell PCa (SCPC) tissues and is associated with NE markers and ZBTB46/FOXA2/HIF1A abundance. In this study, we explored the direct interaction of ZBTB46 protein with hypoxia-related FOXA2/HIF1A complex in PCa cells under hypoxic conditions, which promote MCTP1-driven EMT and NED. Our finding suggests that MCTP1 could be used as a biomarker for diagnosing NEPC and as a therapeutic target in clinical applications.
Citation Format: Vu Thuy Dung Phan, Yu-Ching Wen, Wei-Yu Chen, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Van Thi Ngoc Tram, Zi-Qing Chen, Wan-Hsin Wang, Yen-Nien Liu. ZBTB46/FOXA2/HIF1A transcription activator complex promotes MCTP1-regulated neuroendocrine differentiation and epithelial-to-mesenchymal transition. [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 3736.
Abstract 3743: circPMS1 is a pro-metastatic circular RNA in melanoma
Authors: Mecozzi Nicol , Vera Olga , Karreth Florian 
Published: April 2023

Abstract
Deregulated gene expression is a major driver of melanoma metastasis, a process that results in the majority of melanoma-related deaths. Importantly, these alterations are not limited to protein-coding mRNAs, but also include noncoding RNAs. Despite many recent studies implicating circular RNAs (circRNAs) in cancer development, it is unknown if their deregulation contributes to melanoma metastasis. To identify circRNAs with putative roles in melanomagenesis, we performed RNA sequencing on a panel of melanoma and melanocyte cell lines. 21 differentially expressed circRNAs were validated by qPCR and Sanger sequencing of the backsplice junction. Further analyses of the ratio of the circular and cognate linear RNA transcripts and expression in a larger panel of cell lines identified circPMS1 as a circRNA that is upregulated in melanoma through enhanced backsplicing of the linear PMS1 mRNA. Using transposon-mediated delivery, we examined the effects of stable circPMS1 overexpression on melanoma cells. While proliferation and focus formation were not impacted, migration and invasion were enhanced by circPMS1. Moreover, tail vein injection of circPMS1 overexpressing melanoma cells increased lung metastasis. In addition to this transplant model, we generated the first genetically engineered mouse model of melanoma overexpressing a pro-tumorigenic circRNA. These mice are currently being analyzed. Mechanistically, we find that circularization is required for the pro-migratory effects of the circPMS1 overexpression construct. Additionally, circPMS1 harbors the canonical PMS1 start codon, a predicted ORF spanning over the backsplice junction, and a predicted IRES sequence. Indeed, inserting a flag-tag in the overexpression construct revealed circPMS1 to be translated into a truncated 25kD PMS1 protein as well as a 20kD protein likely arising from an in-frame downstream start codon. Importantly, these truncated circPMS1 proteins are endogenously expressed and increased in melanoma compared to melanocytes while the full-length PMS1 protein is evenly expressed. These findings suggest that circPMS1 promotes melanoma metastasis, at least in part, by coding for truncated circPMS1 proteins. Further work will establish the functions of the circPMS1-encoded proteins and their roles in driving melanoma progression and metastasis.
Citation Format: Nicol Mecozzi, Olga Vera, Florian Karreth. circPMS1 is a pro-metastatic circular RNA in melanoma. [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 3743.
Abstract 3751: Characterizing the role of the y chromosome-expressed long non-coding RNA linc-SPRY3 family in lung cancer radiation resistance
Authors: Westemeier-Rice Emily S. 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. A major issue for clinicians and patients alike is inherent resistance to radiation therapy. Recently, certain long non-coding RNAs (lnc-RNAs) have been shown to regulate pathways involved in resistances to lung cancer treatments. Our group recently published that a group of long non-coding RNAs, named the linc-SPRY3 family, play an important role in radiation therapy sensitivity. Originating from the Y-Chromosome, these long non-coding RNAs have been shown in vitro and in vivo to decrease the tumor burden after radiation. Interestingly, certain male Non-Small Cell Lung Cancer (NSCLC) cell lines have been shown to have complete loss of the Y-chromosome (LOY), showing a radiation resistant phenotype. To test this, the DYZ1 region of the Y-chromosome, where the linc-SPRY3 family is expressed, was artificially introduced into radiation resistant male NSCLC cell lines with LOY. Remarkably, by adding the DYZ1 region of the Y-chromosome into these cells, they became more sensitive to radiation and had increased apoptosis. Based on this preliminary data, we hypothesize the linc-SPRY3 family interacts with important pathways in the cell to increase sensitivity to DNA double strand breaks. Through RNA-Sequencing and other preliminary experiments, we found that the linc-SPRY3 family regulates the expression of Cell Division Cycle 6 (CDC6) and Cell Division Cycle 25A (CDC25A) genes. Preliminary data suggests these interactions play a role in influencing NSCLC ability to invade and metastasize. We are currently characterizing this family of linc-RNAs by flow cytometry, in vivo metastasis models, and fluorescent in situ hybridization. We will characterize the mechanism of the linc-SPRY3 family in radiation resistance through genetic modifications and further downstream analysis via the over-expression and knockdown of these linc-RNAs. The characterization of these linc-RNAs will be critical for the development of potential diagnostic or therapeutic therapies.
Citation Format: Emily S. Westemeier-Rice. Characterizing the role of the y chromosome-expressed long non-coding RNA linc-SPRY3 family in lung cancer radiation resistance. [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 3751.