bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3704: The essential role of an alternate mRNA translation initiation in the regulation of breast cancer cell metabolism
Authors: Rosenstock Hanna , Mitaishvili Erna , de la Parra Columba 
Published: April 2023

Abstract
Translational control and metabolic reprogramming are hallmarks of advanced cancers. Important genes involved in cancer progression express mRNAs that are selectively translated, including regulators of cancer cell metabolism.
Cancer cells acquire an altered metabolism, switching from oxidative phosphorylation (OXPHOS) to a glycolytic phenotype (Warburg effect), to increase reliance on alternate metabolic pathways to support growth, proliferation, and metastasis. Triple-negative breast cancer (TNBC), one of the most aggressive and highly metastatic subtypes with the poorest outcome, is characterized by elevated glycolysis and low OXPHOS. Still, the exact mechanism for this metabolic switch is largely unknown. Using a TNBC cell model it has been shown an alternate mechanism of cap-dependent but mTORC1/eIF4Eindependent mRNA translation by the eIF4G homolog, DAP5, which directly binds the cap-binding protein eIF3d. Our research indicates that this alternate translation initiation is essential in regulating several mRNAs involved in breast cancer metabolism. DAVID analysis from genome-wide transcriptomic and translatomic studies, metabolomic assays including Glycolysis Assay [Extracellular Acidification], Oxidative Phosphorylation, and Mitotracker Assay, as well as RT-PCR and western blot analysis was performed from well-characterized triple-negative aggressive breast cancer cell lines,4T1 and MDA-231, Non-silencing (Nsi) control and silencing DAP5 (shDAP5) samples.
Several mRNAs related to glucose metabolism decreased after silencing DAP5 and on the opposite, critical mRNAs associated with OXPHOS increased, independent of their steady-state mRNA abundance. Silencing DAP5 increased Oxidative Phosphorylation activity and decrease the glycolytic rate in TNBC breast cancer cells. Proteins correlated with aberrant glycolytic metabolism including the E-cadherin transcriptional repressors Snail (SNAI1) were reduced after silencing of DAP5. Our data indicates that the alternate mRNA translation initiation mechanism by DAP5 of specific mRNAs correlated to glycolysis and OXPHOS could play an essential role in the mechanism by which TNBC breast cancer cells orchestrate a metabolic switch required for malignant progression and metastasis.
Citation Format: Hanna Rosenstock, Erna Mitaishvili, Columba de la Parra. The essential role of an alternate mRNA translation initiation in the regulation of breast cancer cell metabolism. [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 3704.
Abstract 375: Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma
Authors: Thangaretnam Krishnapriya , Obaidul Islam MD , Lu Heng , Peng Dunfa , Bhat Nadeem Sidiq , Soutto Mohammed , Chen Zheng 
Published: April 2023

Abstract
Esophageal Adenocarcinoma (EAC) is the most common subtype of Esophageal Cancer in Western countries, and its incidence rate has increased over the past few decades. The overall five-year survival rate of EAC is less than 20%. Smoking is a major risk factor for EAC development. WEE1 kinase plays a crucial role in the cell cycle by regulating the G2/M checkpoint, providing a time frame for the cells to repair DNA damage. Thus, targeting WEE1 using an inhibitor could potentiate the effect of chemotherapeutic drugs. This study investigated how smoking induces WEE1 protein expression, promoting docetaxel resistance in EAC.
IHC staining for WEE1 in the normal esophagus and EAC tissue sections revealed significant over-expression of WEE1 protein in EAC. Nicotine, Nicotine derived Nitrosamine Ketone (NNK), and 2% cigarette smoke extract (CSE) treatment induced WEE1 expression with a concomitant increase in CDC2 phosphorylation (p-CDC2, Y15), a well-established read-out of WEE1 activity in EAC cells. In addition, we found that smoking upregulates WEE1 expression by decreasing miR-195-5p expression levels in EAC.
Based on the differential gene expression signatures in EAC cell lines FLO1 and OE33 following WEE1 knockdown, drug and small molecule induced gene expression signatures analysis, L1000 fireworks display (L1000FWD), predicted that docetaxel is one of the best drug candidates which can synergize with the WEE1 inhibitor MK1775. Smoking-induced docetaxel resistance in EAC cells measured by cell viability assay. Down-regulating WEE1 expression with siRNA or pharmacological inhibition using MK1775 significantly sensitized EAC cells to docetaxel treatment, as evidenced by a remarkable decrease in the IC50 value of docetaxel. Inhibition of WEE1 combined with docetaxel can be considered an ideal therapeutic strategy due to its superior anti-tumor efficacy compared to the standard single-agent treatment. In conclusion, our data provide a firm rationale for the clinical combination of docetaxel with MK1775 in EAC patients.
Citation Format: Krishnapriya Thangaretnam, Islam MD Obaidul, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Zheng Chen. Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal 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 375.
Abstract 3753: miR-567 modulates the progression of melanoma cells and functions of macrophages
Authors: Nguyen Mai-Huong Thi , Lin Chen-Huan , Huang Yu-Chi , Tsai Mu-Shiun , Chen Ming-Hong , Miyashita Azusa , Fukushima Satoshi , Ma Nianhan 
Published: April 2023

Abstract
Purpose: Target therapy and immunotherapy are advancements in the treatment of melanoma; unfortunately, a subset of patients does not benefit or produces drug resistance. Therefore, an alternative strategy should be investigated to further improve clinical benefits. Macrophages are the abundant immune cells related to the progression of melanoma and resistance to drugs. In this study, we explored the novel roles of miR-567 in the progression of melanoma and effects of macrophages.
Methods: miR-567 expression in nevus and melanoma tissues was analyzed by in situ hybridization. miR-567 was transfected into melanoma cells to investigate its biological effects through functional assays such as proliferation, colony formation, soft agar, and migration assays. In addition, miR-567-related signal transduction pathways in the melanoma cells were studied by western blot and next-generation sequencing analyses. Different phenotypes of macrophages polarized from THP-1 monocyte cells were used as in vitro model to investigate the effects of miR-567 on macrophages.
Results: Our results showed that miR-567 expression levels were decreased in melanoma cells compared to melanocyte cells. Consistently, expression of miR-567 was 0.403-fold lower in melanoma tissues (n=118) as compared to nevus tissues (n=40). In addition, the receiver operating characteristic presented that the area under the curve value of miR-567 is 0.9495. Importantly, higher expression of miR-567 enhanced the overall survival of melanoma patients. Overexpression of miR-567 significantly reduced proliferation, survival, anchorage-independent growth, migratory, and invasive abilities of melanoma cells and BRAF-inhibitor resistant cells. Furthermore, our results demonstrated that IGF1R, E2F1, and Cyclin B2 are direct targets of miR-567 and knockdown of these genes attenuated proliferation and survival of melanoma cells. Interestingly, introduction of miR-567 downregulated MAPK/ERK and PI3K/AKT pathways in melanoma cells and regulated multiple pathways related to immune response. Of note, overexpression of miR-567 reduced the promoting melanoma growth induced by M2 or melanoma-associated macrophages, indicating the involvement of miR-567 in regulation of macrophages.
Conclusion: miR-567 could be served not only as biomarkers but also as potential molecular target for prevention of melanoma progression.
Citation Format: Mai-Huong Thi Nguyen, Chen-Huan Lin, Yu-Chi Huang, Mu-Shiun Tsai, Ming-Hong Chen, Azusa Miyashita, Satoshi Fukushima, Nianhan Ma. miR-567 modulates the progression of melanoma cells and functions of macrophages. [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 3753.
Abstract 3757: miR-200 inhibits the activation of cancer-associated fibroblasts in lung tumor microenvironment
Authors: Cheon Inyoung , Lee Sieun 
Published: April 2023

Abstract
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and promote cancer progression and metastasis. CAFs are regulated by diverse processes including regulation by miRNAs. To identify miRNAs involved in the regulation of CAF activation, we profiled miRNA expression within mouse lung normal fibroblasts (LFs) and CAFs using the NanoString nCounter method. Among numerous miRNAs differentially expressed between CAFs and LFs, miR-200 was selected for further investigation, which is more highly downregulated in CAFs. Overexpression of miR-200 in CAFs suppressed the migration and invasion of lung cancer cells in co-culture systems and inhibited metastasis in a mouse model. In addition, we verified that lung cancer patients with high miR-200 levels showed a good prognosis than those with low miR-200 levels. Next, we tried to identify novel miR-200 targets based on RNA sequencing data, lung adenocarcinoma TCGA, and TargetScan. NRP2 was confirmed to be a target of miR-200 by 3΄-UTR assay. NRP2 knockdown by siRNAs in CAFs suppressed cancer cell invasion, and NRP2 addback in CAF-200 restored cancer cell invasion inhibited by miR-200. NRP2 functions as a co-receptor with VEGFR, thus, CAF-200 was less responsive to VEGF than control CAFs. Collectively, this study suggests that downregulation of miR-200 in CAFs promotes lung cancer progression in tumor microenvironment; therefore, miR-200 will be a good therapeutic target or a biomarker in lung adenocarcinoma.
Citation Format: Inyoung Cheon, Sieun Lee. miR-200 inhibits the activation of cancer-associated fibroblasts in lung tumor microenvironment. [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 3757.
Abstract 3784: miR-489 induces apoptosis and immunogenic cell death through targeting FOXM1 in triple negative breast cancer cells
Authors: Gupta Gourab , Titus Ryan , Patel Yogin , Sarvanan Shakthika , Chen Hexin 
Published: April 2023

Abstract
It has been well established that microRNAs (miRNAs) have an important role in cancer sustenance and progression. Our previous studies have established the role of miR-489 as a tumor suppressor miRNA in breast cancer. However, the multiple targets of this miRNA have diversified its mechanism from preventing tumor cell proliferation to promoting cell death pathways. In this study we have aimed to establish the role of miR-489 in cell cycle inhibition, leading to Endoplasmic Reticulum stress (ER stress) and ultimately immunogenic cell death (ICD). Firstly, we found that overexpression of miR-489 in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, BT 549, drastically reduced cell proliferation using colony formation assay and real-time cell analysis. Furthermore, studies like GO analysis, sequence analysis and cell cycle analysis demonstrated that miR-489 induces cell cycle arrest and apoptosis in TNBC by directly targeting FOXM1 and regulating other kinases like CDK1. It was also shown for the first time that miR-489 overexpression induces ER stress and the release of damage associated molecular patterns (DAMPs), consistent with hallmarks of ICD like Calreticulin exposure on cellular surface and ATP release, triggering phagocytosis. It was also established that miR-489-induced apoptosis lead to the elevation of cleaved caspase 3, which was responsible for the activation of PANX1 and the consequent release of ATP. In conclusion, we tried to mechanistically understand the role of miR-489 in cell cycle arrest leading to cellular stress. Stress induced apoptosis and consequent ICD was also a possible outcome and it turned out miR-489 overexpression without any other ICD inducer was good enough to trigger the release of DAMPs and elucidate an immunogenic response.
Citation Format: Gourab Gupta, Ryan Titus, Yogin Patel, Shakthika Sarvanan, Hexin Chen. miR-489 induces apoptosis and immunogenic cell death through targeting FOXM1 in triple negative breast 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 3784.
Abstract 3785: Telomerase RNA component lncRNA regulates hsa-miR-320 family and promotes prostate cancer metastasis
Authors: Mbeje Mandisa , Kandhavelu Jeyalakshmi , Penny Clement , Dlamini Zodwa , Marima Rahaba 
Published: April 2023

Abstract
Telomerase RNA component (TERC) is a long non-coding (lncRNA) associated with prostate cancer progression and has novel prognostic biomarker potential. Differential methylation patterns of lncRNAs affect their expression levels, leading to cancer. This study aimed to profile and elucidate differential lncRNA expression patterns in prostate cancer (PCa). A 384-well plate of PCa associated lncRNA gene array panel was used in castration resistant PC-3 PCa cells vs androgen-sensitive PCa LNCaP cells. Annotation and enrichment analysis of lncRNA differential gene expression was performed using a human lncRNA sets database, LncSEA. Furthermore, digital droplet PCR (ddPCR) was used to verify the PCR array results. Up or down-regulation of ±2 and p &lt;0.05 were considered significant. Decreased hsa-miR-320 gene family expression has been reported in various tumors including PCa. However, the precise mechanisms of hsa-miR-320 gene family in PCa remain to be elucidated. Thirty six of 84 lncRNAs were shown to be upregulated, while 14% of the lncRNA genes were downregulated. Notably, TERC lncRNA was upregulated in high metastatic PC-3 cells. Hypermethylation patterns of this lncRNA in high metastatic PC-3 cells was also shown by enrichment analysis. Furthermore, TERC lncRNA was demonstrated to regulate the hsa-miR-320 family, suggesting a correlation between TERC hypermethylation and downregulation of hsa-miR-320 gene family expression in PCa, as revealed by bioinformatics analysis. TERC lncRNA promotes PCa cell proliferation, migration, invasion and metastasis by sponging hsa-miR-320 family. This TERC/hsa-miR-320 interaction holds potential to understanding PCa prognostic mechanisms by lncRNAs and may also be targeted for novel therapeutics.
Citation Format: Mandisa Mbeje, Jeyalakshmi Kandhavelu, Clement Penny, Zodwa Dlamini, Rahaba Marima. Telomerase RNA component lncRNA regulates hsa-miR-320 family and promotes prostate cancer metastasis. [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 3785.
Abstract 3826: Potency of cardiac glycosides by structure in organotypic models of pancreatic and ampullary carcinomas
Authors: Hossan Md Shahadat , Lin Ethan , Stram Austin , Warner Jamie , Koeppel Luke , Riedl Ellie , Kratz Jeremy 
Published: April 2023

Abstract
Background: Organotypic models have emerged as an important preclinical model for developmental therapeutics in pancreatic and biliary cancer. Naturally derived cardiac glycoside in 2D monoculture exquisite potency, here we describe their activity in cancer and normal liver with patient-derived cancer organoids (PCOs).
Methods: PCOs of pancreatic and ampullary cancers and normal hepatic tissues were generated. Response was assayed with four structurally different cardiac glycoside (cerberin, neriifolin, digitoxin, digoxin; 72h). Response was characterized by growth inhibition (GI50) using 3D CellTiterGlo (CTG) and subclonal population response by high content imaging using normalized change in diameter (n=1038).
Results: Dose response revealed improved potency for cerberin and neriifolin, versus digoxin and digitoxin across models (see table). In a normal liver organoid model, there was no convergence in dose response observed when extended to 1uM of each cardiac glycoside. Ampullary PCO response was assayed using subclonal population analysis. Cerberin at 10nM achieved growth arrest across the population as assayed by median Δ diameter (growth +4.0±32.0, GΔ=0.94, p&lt;0.005). Neriifolin at 10nM had subclonal with residual growth representing 72% of overall population as assayed by Δ diameter (growth +18.3%, GΔ=0.65). Traditional cardiac glycosides of digoxin and digitoxin at 10nM had significant portions with residual growth (94.9% and 84.7%, respectively) as well as did not achieve meaningful effect (GΔ=-0.10 and GΔ=0.05, respectively).
Conclusions: CGs have varied potency for anticancer activity between different structural motifs. Cerberin induce population growth arrest in cancer models which differed from normal liver. This work requires dedicated mechanistic modeling to explain differences in anti-cancer activity that may confer sensitivity and in considering models of cardiac toxicity.
Potency of Cardiac Glycosides in Organoid Models. GI50 (nM) Ampullary GI50 (nM) Pancreatic GI50 (nM) Normal Liver Cerberin 7.4 7.20 71.0 (NC) Neriifolin 10.2 7.4 62.0 (NC) Digoxin 29.6 47.9 55.5 (NC) Digitoxin NC 40.0 85.5 (NC)
Citation Format: Md Shahadat Hossan, Ethan Lin, Austin Stram, Jamie Warner, Luke Koeppel, Ellie Riedl, Jeremy Kratz. Potency of cardiac glycosides by structure in organotypic models of pancreatic and ampullary carcinomas. [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 3826.
Abstract 3949: CYR61, a member of the CCN protein family, regulates IGF-1 in metastatic prostate cancer
Authors: Ortiz-Hernandez Greisha L. , Walker Mya , Woods-Burnham Leanne , Kittles Rick A. , Casiano Carlos A. , Neuhausen Susan L. 
Published: April 2023

Abstract
The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF-1). High serum levels of IGF-1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF-1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. This study is designated to specifically determine and characterize the molecular interaction between CYR61 and IGF-1 in metastatic PCa and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3 and downregulated in the docetaxel-resistant cell line PC3-DR. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF-1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. We also initiated studies to determine the co-localization of CYR61 and IGF-1 using immunofluorescence microscopy (IF). Based on the initial IF observations, we will proceed to examine if their interaction is primarily intra- or extra-cellular. For intracellular interactions, we will co-immunoprecipitate CYR61 with IGF-1 and for extracellular interactions, we will use the AVidity-based EXtracellular Interaction Screen (AVEXIS) system. Our goal is to establish the contribution of CYR61-IGF1 protein-protein interaction to PCa cell proliferation. Specifically, the correlation between PCa aggressiveness and circulating levels of CYR61 and IGF-1 is poorly studied. Their combined role may explain a proportion of aggressive PCa.
Citation Format: Greisha L. Ortiz-Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan L. Neuhausen. CYR61, a member of the CCN protein family, regulates IGF-1 in metastatic 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 3949.