bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1281: Oncoprotein YB-1 modulation of Lyn-MAPK-NF-kB pathway, a potential therapeutic strategy combined with sorafenib for advanced stage HCC
Authors: Pazzi Ana G. Ayala , Karkoutly Omar , Ezell Kristopher , Lopez Samantha , Doxtater Kyle D. , George Elias , Dhevan Vijian , Tripathi Manish K. 
Published: April 2023

Abstract
The Y-Box Binding protein 1 (YB-1) is a 324 amino acid-long member of the Cold Shock Domain (CSD) protein superfamily. YB-1 interacts with micro RNAs and non-coding RNAs in the cytoplasm, acting as a regulator of mRNA translation. YB-1 translocation into the nucleus is circadian clock-dependent and leads to the upregulation of cyclin gene expression, among others. Another mechanism of nuclear translocation of YB-1 is mediated by phosphorylation of the Ser 102 residue in the CSD. The YB-1 oncoprotein acts as a transcription factor when bound to DNA, modulating the transcription of genes that regulate biological processes such as Multidrug Resistance Mutation 1 (MDR1). YB-1 is linked to poor prognosis in breast, prostate, and liver cancer. Despite advances in biomedicine, the incidence and mortality of hepatocellular carcinoma (HCC) remain high. Sorafenib, a tyrosine kinase Inhibitor (TKI), is the first-line treatment for advanced HCC. Sorafenib also inhibits downstream activation of NF-kB by inhibition of Lyn phosphorylation (Y397). However, it was observed in many patients that its sorafenib’s effectiveness is hampered by drug resistance, but the mechanism is still unclear. We have found that SK-HEP-1 HCC cells transfected with a YB-X-1 overexpression plasmid subsequently developed into a stable YB-1 overexpression cell line (SK-HEP-1+YB-1) displayed increased invasion, migration, proliferation, and colony formation property as compared to the vector control (SKHEP1+Vec). The SK-HEP-1+YB-1 cell line also showed increased IC50 for sorafenib and elevated phosphorylation of Lyn (Y397) and further activated NF-kB (S165/S176) phosphorylation. This indicates YB-1 may cause increased Sorafenib resistance in HCC by activating tyrosine kinases (TK), such as lyn, and simultaneous activation of NF-kB. The combination of YB-1 inhibition and sorafenib might provide a novel therapeutic strategy and improve the survival of patients with advanced-stage HCC.
Citation Format: Ana G. Ayala Pazzi, Omar Karkoutly, Kristopher Ezell, Samantha Lopez, Kyle D. Doxtater, Elias George, Vijian Dhevan, Manish K. Tripathi. Oncoprotein YB-1 modulation of Lyn-MAPK-NF-kB pathway, a potential therapeutic strategy combined with sorafenib for advanced stage HCC [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 1281.
Abstract 1292: CX3CR1 surface expression and phenotypic plasticity in metastasis-initiating cells
Authors: Zhang Jieyi , Oyende Yetunde , Lynch Jennifer , Meucci Olimpia , Fatatis Alessandro 
Published: April 2023

Abstract
Metastasis-initiating cells (MICs) display stem cell-like features and cause metastatic recurrences leading to patients' demise. We found that prostate and breast cancer cells with high surface expression of the chemokine receptor CX3CR1 (CX3CR1high) account for ~5-7% of the whole population and are endowed with metastasis-initiating ability and exhibits stemness features, including expression of pluripotency genes Nanog and Oct4a. Notably, impairing CX3CR1 signaling hinders metastatic initiation and progression in mouse models of human disease. We also found that cancer cells lacking surface CX3CR1 expression (CX3CR1low) can re-acquire CX3CR1-associated features over time by undergoing phenotypic plasticity. Accordingly, when grafted as pure CX3CR1low populations these cells could generate disseminated tumors in mice, implying that MICs can emerge from cancer cells lacking stemness features. In vitro studies by flow cytometry show that cell surface re-exposure of CX3CR1 by CX3CR1low cells begins within 2 days post-sorting, with the whole population reaching phenotypic equilibrium at 12-16 days post-sorting. Further mechanistic studies revealed that both CX3CR1 protein trafficking and transcriptional regulation play a role in phenotypic plasticity. Additionally, disseminated tumors in mice harbor higher percentages of CX3CR1high cells than in vitro cultures, suggesting that the tissue microenvironment of target organs promotes phenotypic plasticity. These findings nominate CX3CR1 as a novel marker of MICs and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation and progression.
Citation Format: Jieyi Zhang, Yetunde Oyende, Jennifer Lynch, Olimpia Meucci, Alessandro Fatatis. CX3CR1 surface expression and phenotypic plasticity in metastasis-initiating 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 1292.
Abstract 1362: Impact of chemotherapy on functional and biochemical characteristics of cancer-associated fibroblasts​
Authors: Xia Zihan , De Wever Olivier 
Published: April 2023

Abstract
Cancer-associated fibroblasts (CAFs), as the major components of the tumor microenvironment (TME), have been extensively explored and are known to be involved in tumor biology, including growth, energy metabolism, immune regulation, invasion and metastasis. A large number of preclinical studies describe the functional and biochemical impact of commonly used chemotherapeutics, such as paclitaxel and oxaliplatinum, on cancer cells, but their effect on the phenotypical and biochemical changes of CAFs and their reciprocal impact on tumor progression are lacking.
In our study, we used patient-derived breast and colorectal CAF to evaluate dose-response effects of paclitaxel and oxaliplatinum, respectively first-line chemotherapeutics in breast and colorectal cancer. We evaluated the damage responses of CAF and investigated changes in morphology, cell death, woundhealing migration, type I collagen contraction and invasion, cytokine and chemokine release, differential protein expression, and metabolic activity. In response to paracrine signals emerging from chemotherapy-treated CAF we investigated the impact on functional activity of macrophages, neutrophils and cancer cells. Our project could help us better understand and modulate the activity of CAFs, which might provide novel targets for the clinical treatment of cancer.
Citation Format: Zihan Xia, Olivier De Wever. Impact of chemotherapy on functional and biochemical characteristics of cancer-associated fibroblasts​ [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 1362.
Abstract 1422: Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma
Authors: Sircar Anuvrat , Singh Satishkumar , Young Ken H. , Epperla Narendranath , Sehgal Lalit 
Published: April 2023

Abstract
Cell cycle dysregulation and significant enrichment of E2F1 target genes are hallmarks of MCL, and the inability to directly target E2F1-dependent processes is a clinical hindrance. Despite several treatment options, mantle cell lymphoma is associated with poor clinical outcomes and the development of resistance. We identified Fibroblast Growth Factor Receptor-1 is upregulated in relapsed mantle cell lymphoma patients and high FGFR-1 expression in MCL correlates with poor overall and progression-free survival. Genetic ablation of FGFR1 in MCL cells induced cell cycle arrest, and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. Functionally, FGFR1 loss upregulates the expression of the cell-cycle dependent Kinase inhibitor 1C (CDKN1C) through epigenetic repression via EZH2. CDKN1C binds to E2F1 and regulates the transactivation of its target genes, including CDK1. CDK1 further stabilizes MYC and positively regulates the expression of EZH2, activating the feed-forward loop to promote cell survival. Conversely, losing FGFR1 disrupts this feed-forward loop in malignant cells. This is the first report establishing FGFR1 as a novel therapeutic target and providing a rationale to target FGFR1 to treat Mantle cell lymphoma and disrupt the feed-forward loops contributing to the survival of malignant cells.
Citation Format: Anuvrat Sircar, Satishkumar Singh, Ken H. Young, Narendranath Epperla, Lalit Sehgal. Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma [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 1422.
Abstract 1446: The elevated expression of INSM1 is correlated with EZH2 in neuroendocrine prostate cancer
Authors: Li Lin , Cheng Siyuan , Yu Xiuping 
Published: April 2023

Abstract
Background: Neuroendocrine prostate cancer (NEPCa) is the most aggressive and non-targetable prostate cancer (PCa). It is well accepted that NEPCa arises from prostate adenocarcinoma (AdPCa) via trans-differentiation. NEPCa tumors exhibit a similar mutation burden but a different transcriptome profile from AdPCa. This suggests that the acquisition of the NE phenotype is driven by epigenetic, transcriptional reprogramming but not genetic alterations. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is an epigenetic regulator and upregulated in NEPCa. The upregulation of EZH2 in PCa has been considered to be correlated with therapy-induced plasticity and NE differentiation. Insulinoma-associated 1 (INSM1), is a zinc-finger transcription factor, which is predominantly expressed in neuroendocrine (NE) cells and important for the NE developmental pathways. INSM1 has been considered as a biomarker for multiple types of NE tumors, like pancreatic, lung, and prostate. Also, the increase level of INSM1 is associated with NE differentiation in PCa. Analysis of PCa transcriptomic profiles suggests that EZH2 and INSM1 have positive correlation in PCa and function together in NEPCa.
Methods: To study the expression of INSM1 and EZH2, we did immunofluorescence (IF), immunohistochemistry (IHC), Western blot and RT-qPCR in prostate cancer cell lines, mouse tissues, and human patients samples. The bioinformatics analysis was done using the publicly available RNA-Seq data obtained from the cBioportal, the Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia websites (CCLE).
Results and Conclusion: Our IHC results confirmed that INSM1 is highly expressed in NEPCa rather that AdPCa in both human and mouse tissues. By IF, we further found that INSM1 also expresses in PCa amphicrine cells. Additionally, we found that the expression of INSM1 is positively associated with EZH2 expression in PCa. These data indicates that INSM1 may act as a marker for not only NE cells but also amphicrine cells in PCa. Also the correlation between INSM1 and EZH2 further indicates the importance of INSM1 in NEPCa. Our further study will focus on how INSM1 functions and whether there’s a direct regulation between INSM1 and EZH2.
Acknowledgement: This work was supported by NIH R01 CA226285, and the Feist-Weiller Cancer Center (FWCC).
Citation Format: Lin Li, Siyuan Cheng, Xiuping Yu. The elevated expression of INSM1 is correlated with EZH2 in 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 1446.
Abstract 1450: Global changes in RBPs and mRNA interactions during prostate cancer progression
Authors: Dwead Abdulrahman M. , Al-Mathkour Marwah M. , Cinar Bekir 
Published: April 2023

Abstract
Prostate cancer (PC) is a leading cause of cancer in men in the United States and worldwide, disproportionately affecting men of African ancestry. The etiology and molecular mechanism contributing to lethal human PC remain poorly understood. RNA binding proteins (RBPs) controlled all aspects of RNA biogenesis, and dysregulated RBPs are linked to human diseases, including cancer. However, the global changes in RBP-mRNA interactions during PC progression are unknown. Here, we have investigated the patterns of RBPs and polyA-mRNA interaction in the castration-sensitive LNCaP and castration-resistant C4-2 PC cell lines. Our enhanced-RNA interactome capture assay combined with mass spectroscopy (MS) revealed that LNCaP and C4-2 cells showed distinct RBP-mRNA interaction patterns in steady-state and androgen-treated conditions. Also, we have studied the interaction between Yes-associated protein 1 (YAP1) and nucleophosmin (NPM1) RBP. Androgen increased NPM1 and mRNA interaction, and NPM1 is part of the YAP1 multiprotein complex, as revealed by MS-based proteomics approaches. Our proximity ligation assay showed that androgen hormone signaling regulated the interaction between YAP1 and NPM1. Besides, our GST-pulldown demonstrated that NPM1 binds the proline-rich region domain of YAP1, whereas the WW/SH3 domain of YAP1 mediates the interaction in C4-2 cells. Genetic silencing of NPM1 reduced PC cell growth in culture. Furthermore, the upregulation of NPM1 correlates with prostate adenocarcinoma and metastasis. These observations suggest that changes in RBP and RNA interaction patterns may play a critical role in PC progression and recurrence.
Citation Format: Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Bekir Cinar. Global changes in RBPs and mRNA interactions during 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 1450.
Abstract 1489: Overexpression of ribosomal L22-like1 (RPL22L1) enhances cancer stem cell properties and promotes tumor progression in hepatocellular carcinoma (HCC)
Authors: Huang JinLin , Guo Zhenyang , Luo Jie , Liu Beilei , Gong Lanqi , Fang Xiaona , Kwong Dora Lai-wan , Guan Xinyuan 
Published: April 2023

Abstract
The abnormality of ribosomal biogenesis is found to be involved in carcinogenesis and progression in various types of cancer. RPL22L1 gene is a highly homologous paralog of RPL22, both of which belong to the L22E family of ribosomal proteins and take part in encoding a cytoplasmic ribosomal protein that is a component of the 60S subunit of ribosomes. Our previous work has established a CRISPR/Cas9 genome-wide knockout screening profile and developed a two-component mixture model to identify cancer-specific essential genes in 436 cancer cell lines. Bioinformatics analysis reveals that RPL22L1 acts as a feature gene to predict cancer-specific essential genes in human cancer. Previous studies suggest that RPL22L1 is correlated with tumor progression and adverse prognosis in several cancer types, while its role in hepatocellular carcinoma (HCC) is unknown. In the present study, we found that RPL22L1 is highly expressed in embryonic stem cells (ES) and liver progenitor cells, which were acquired from a vitro hepatic differentiation model originating from ES cells. Hence, we hypothesized that RPL22L1 enhances cancer stem cell properties in HCC. Functional assays showed that RPL22L1 would promote sphere formation in vitro. qRT-PCR and Western Blotting results indicated that RPL22L1 could promote stemness-related gene expressions such as CD133, CD44, and SOX9 in HCC cell lines. Overexpression of RPL22L1 increased aldehyde dehydrogenase (ALDH) activity, which was decreased when RPL22L1 was silenced with short hairpin RNA (shRNA). Extreme limiting dilution assay showed that RPL22L1 overexpression stimulated self-renewal ability in immunodeficient mice. Furthermore, higher RPL22L1 expression can also promote cell proliferation and epithelial-mesenchymal-transition, as well as drug resistance to 5-Fluorouracil (5-FU) and cisplatin (CDDP). Silver nitrate staining demonstrated that RPL22L1 overexpression correlated with a larger size and number of nucleoli. The expression of RPL22L1 was also associated with adverse prognosis in HCC clinical samples. In conclusion, our study reveals aberrant ribosomal protein activity in HCC and the role of RPL22L1 in promoting HCC tumor progression.
Citation Format: JinLin Huang, Zhenyang Guo, Jie Luo, Beilei Liu, Lanqi Gong, Xiaona Fang, Dora Lai-wan Kwong, Xinyuan Guan. Overexpression of ribosomal L22-like1 (RPL22L1) enhances cancer stem cell properties and promotes tumor progression in hepatocellular carcinoma (HCC) [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 1489.
Abstract 1491: Delineating the oncogenic mechanisms of NAT10 in hepatocellular carcinoma
Authors: Patrasso Emmely A. , Raikundalia Sweta P. , Arango Daniel 
Published: April 2023

Abstract
Protein synthesis is often dysregulated in cancer, highlighting the regulatory mechanisms of translation as potential targets for cancer treatment. With more than 140 chemical modifications of RNA, the epitranscriptome is a central mechanism in regulating protein synthesis. Remarkably, the epitranscriptome is often altered in cancerous tumors and under stress conditions such as reactive oxygen species (ROS) and anti-tumor therapies. For instance, N-acetyltransferase 10 (NAT10), the enzyme responsible for acetylating cytidines (N4-acetylcytidine or ac4C) in RNA, is highly overexpressed in cancers such as Hepatocellular Carcinoma (HCC). Of significant relevance to cancer, NAT10 is considered an oncogenic driver in fatty acid-induced HCC. Hence, this project aims to characterize the underlying oncogenic mechanisms of the NAT10/ac4C axis. Our data indicate that NAT10 and RNA acetylation levels are altered in response to fatty acids, ROS, and chemotherapeutic drugs. Likewise, we observed altered subcellular localization of NAT10 and ac4C in response to ROS and chemotherapeutic drugs. Building on our previous findings that NAT10-catalyzed ac4C promotes translation efficiency, our model stipulates that subcellular redistribution of the RNA acetyltransferase complexes enhances cell cycle progression, cancer cell proliferation, and cellular resilience by fine-tuning the translation of cancer driver genes. Collectively, our findings advance our understanding of how NAT10 promotes cancer growth while providing the mechanistic basis to target NAT10 for therapeutic purposes.
Citation Format: Emmely A. Patrasso, Sweta P. Raikundalia, Daniel Arango. Delineating the oncogenic mechanisms of NAT10 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 1491.
Abstract 1566: DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency
Authors: Halazonetis Thanos D. , Petropoulos Michalis , Rossetti Giacomo G. , Karamichali Angeliki , Freudenmann Alena , Iacovino Luca , Dionellis Vasilis , Sotiriou Sotirios K. 
Published: April 2023

Abstract
An important advance in cancer therapy in the last decade has been the development of poly ADP-ribose polymerase (PARP) inhibitors for the treatment of select ovarian and breast cancers. The clinical benefit stems from the synthetic lethality of PARP inhibitors with homologous recombination (HR) deficiency, which deficiency is prevalent in the cancer types listed above. The current model to explain the synthetic lethality is based on the observation that PARP inhibitors trap PARPs on DNA: the trapped PARPs block progression of the replisome, leading to the formation of DNA double-strand breaks (DSBs), which require HR for repair.
Here, we propose a novel mechanism to explain the synthetic lethality between PARP inhibitors and HR deficiencies. We show that PARP1 functions together with the proteins TIMELESS and TIPIN to protect the replisome from transcription-replication conflicts (TRCs). In the absence of any one of these proteins, TRCs evolved into DNA DSBs that required HR for repair, explaining the observed synthetic lethality. In further support of this model, when we inhibited transcription elongation, which prevents the emergence of transcription-replication conflicts, then the HR-deficient cancer cells became resistant to PARP inhibitors.
We further observed that trapping of PARPs on DNA was not required for the synthetic lethality with HR deficiency, since we could observe strong synthetic lethality simply by depleting PARP1 and PARP2 by siRNA. Rather, trapping of PARPs on DNA correlated with the ability of the various PARP inhibitors to inhibit PARP enzymatic activity in cells; the strongest trappers were also the most potent inhibitors of PARP1 in cells. In vitro, all PARP inhibitors tested were almost equipotent in their ability to inhibit the enzymatic activity of PARP1, meaning that the potency of PARP1 inhibitors in vitro did not reflect their inhibitory potency in cells.
Our model provides a new framework for understanding the mechanism of action of PARP inhibitors in the clinic and the mechanisms by which resistance can emerge.
Citation Format: Thanos D. Halazonetis, Michalis Petropoulos, Giacomo G. Rossetti, Angeliki Karamichali, Alena Freudenmann, Luca Iacovino, Vasilis Dionellis, Sotirios K. Sotiriou. DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency [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 1566.