bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5820: NF-κB signaling regulates miRNA expression in ovarian cancer
Authors: Kamdar Rahul D. , Harrington Brittney S. , Korrapati Soumya , Wong Nathan , House Carrie D. , Annunziata Christina M. 
Published: June 2022

Abstract
Epithelial ovarian cancer (EOC) remains the fifth leading cause of cancer related death in women worldwide, partly due to the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. Previous studies described the role of the NF-kB pathway in promoting TIC chemoresistance and survival through the action of key transcription factors (TFs) like RelA and RelB. These TFs serve as key master regulators of genes important for the inflammatory response, which also overlap with the regulation of targets associated with cancer promotion. We previously showed that RelA and RelB exert different effects in ovarian cancer cells, with RelB relatively more important for tumor initiation. In this study, we hypothesize that NF-kB signaling regulates the expression of several microRNAs (miRNAs) differentially through RelA and RelB to promote TIC survival and proliferation. miRNAs comprise a subset of small, noncoding RNAs that regulate gene expression and present potential therapeutic targets for clinical use. Inducible shRNA stably was expressed in OV90 EOC cells to knockdown RelA or RelB; cells were subsequently analyzed by miR-seq to identify differentially expressed miRNAs in cells grown in TIC vs adherent (adh) conditions. To validate the miR-seq findings, we performed qPCR assays of the candidate miRNAs differentially expressed in TIC or adh conditions with RelA or RelB knocked down. We confirmed the decreased expression of oncogenic miRNAs hsa-miR-105-5p and hsa-miR-452-5p, while also confirming the increased expression of tumor suppressive miRNA hsa-miR-34a-5p observed in the miR-seq using OV90 cells. Ongoing work will validate these expression changes in additional cell lines and conduct functional assays to characterize the effect of mimicking or inhibiting these miRNAs of interest. The identification of miRNAs differentially expressed in TICs under the control of RelA or RelB will provide key insights in designing treatments against them to prevent disease relapse in patients with EOC.
Citation Format: Rahul D. Kamdar, Brittney S. Harrington, Soumya Korrapati, Nathan Wong, Carrie D. House, Christina M. Annunziata. NF-κB signaling regulates miRNA expression in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5820.
Abstract 5823: Studying the role of microRNAs that target stem cell genes in the emergence of tumor heterogeneity in development of human colorectal cancers
Authors: Stark Victoria A. , Facey Caroline O. B. , Opdenaker Lynn M. , Boman Bruce M. 
Published: June 2022

Abstract
We investigated miRNAs that are implicated to target genes that encode different stem cell markers (SC) during tumorigenesis of colorectal cancer (CRC), one of the leading causes of cancer deaths in the US. One reason behind the lack of efficacy in cancer drug therapeutics is due to the development of tumor heterogeneity. We hypothesize that different miRNAs target different SC genes, which leads to the emergence of multiple cancer SC (CSC) subpopulations and tumor heterogeneity. Flow cytometry helped evaluate the expression of multiple SC markers including ALDH1, CD166, LGR5, and LRIG1 in the HT29 CRC cell line. CSC sub-populations were isolated using fluorescence activated cell sorting (FACS) and the expression of miRNAs in each CSC subpopulation was measured using NanoString profiling. The differential expression of miRNAs between CSC subpopulations helped rank the different levels of miRNA upregulation in each of the CSC subpopulations. The mRNAs predicted to be targeted by the most significantly upregulated miRNAs were identified using bioinformatics analysis via NanoString and mRNAs were classified according to their predicted function by David functional annotation analysis. Altogether, our results indicate that multiple CSC subpopulations exist in the HT29 cell-line, and we identified unique miRNA signatures for each CSC subpopulation. Moreover, the mRNAs predicted to be targeted by the miRNAs in each CSC subpopulation were found to have different functional classifications. We conclude that multiple CSC subpopulations emerge in HT29 cells due to the expression of unique miRNAs that target different SC genes (and their co-expressed genes), resulting in the emergence of multiple CSC subpopulations and tumor heterogeneity.
Citation Format: Victoria A. Stark, Caroline O. B. Facey, Lynn M. Opdenaker, Bruce M. Boman. Studying the role of microRNAs that target stem cell genes in the emergence of tumor heterogeneity in development of human colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5823.
Abstract 5828: Functional role of long non-coding RNA YTHDF3-AS1 in breast cancer
Authors: Bera Alakesh , Radhakrishnan Surya , Russ Eric , Biswas Diya , Subramanian Madhan , Pollard Harvey B. , Hu Hai , Shriver Craig D. , Biswas Roopa , Srivastava Meera 
Published: June 2022

Abstract
Breast cancer (BrCa) is the most common form of cancer in women worldwide, impacting nearly 2.1 million women each year. Importantly, current treatment options for metastatic breast cancer fail to elicit an anti-tumor response, leading to a 5-year survival rate below 30%. While most classes of therapy focus on inhibiting or targeting specific proteins, long non-coding RNAs (lncRNAs) offer a unique, relatively untapped, source of potential therapeutic targets. Ongoing experiments are evaluating the regulatory role of the lncRNA YTHDF3-AS1 (ENSG00000270673), which has the potential to develop into a novel therapeutic intervention of BrCa. Through genome-wide analysis, we found that YTHDF3-AS1 expression correlates with essential developmental regulatory genes such as CA3, VPS28, EXOSC4, and TM2D2 and according to pathway analysis is likely linked with the Wnt pathway. Additionally, TCGA data reveals that over 5% of patients with BrCa have an increased copy number of YTHDF3-AS1. Although the role of YTHDF3-AS1 has yet to be explored, YTHDF3 expression was recently shown to be a critical driver of breast cancer metastasis. Of note, YTHDF3-AS1 is upstream of the protein-coding region, but within the promoter region of the YTHDF3 gene. Mechanistically, this allows the lncRNA YTHDF3-AS1 to potentially upregulate the expression of the protein-coding YTHDF3 gene, as two known functions of antisense lncRNAs describe the ability to 1) induce nearby gene expression through binding to the promoter region and 2) stabilize the RNA product of the nearby gene through binding to the 5’UTR. Interestingly, this manner of relationship between antisense (or "divergent") lncRNAs and their protein-coding partner was shown to be highly prevalent in pluripotent stem cells, with the downregulation of both the antisense and protein-coding transcripts following differentiation. Together, our preliminary analysis and previous literature suggest that the lncRNA YTHDF3-AS1 may contribute to the upregulation of YTHDF3, which is a known metastatic promoting protein. Our current study aims to determine the functional role of YTHDF3-AS1 in BrCa oncogenesis, with an emphasis on the mechanistic actions of this lncRNA for the development of future therapeutic approaches.
Citation Format: Alakesh Bera, Surya Radhakrishnan, Eric Russ, Diya Biswas, Madhan Subramanian, Harvey B. Pollard, Hai Hu, Craig D. Shriver, Roopa Biswas, Meera Srivastava. Functional role of long non-coding RNA YTHDF3-AS1 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5828.
Abstract 5833: Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells
Authors: Cheng Ya-Yun , Prosser Denise , Velikokhatnaya Liudmila , Lokshin Anna 
Published: June 2022

Abstract
Ovarian cancer is the fifth leading cause of cancer-related death in women and mainly develops in older women. High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer and recently has been shown to arise from the distal end of the fallopian tube. About 96% of HGSC cases were found to contain mutations in TP53 and missense mutation was the most frequent type. It is known that TP53 mutation is an early event occurred in HGSC and may drive tumorigenesis. Different TP53 mutations have been reported to promote cell survival, metastatic potential or tumorigenicity. However, the roles of TP53 mutations and the underlying molecular mechanisms have not been satisfactorily understood in HGSC. In order to functionally characterize TP53 mutations in a systematic approach, primary human fallopian tube secretory epithelial cells (FTSECs) from normal fallopian tube specimens were used. We isolated and transduced FTSECs with hTERT for extending cell lifespan. Afterwards, both overexpression and knock down experiments were performed. According to the IARC TP53 Database, we selected four TP53 hotspot mutations found in ovarian cancer patients for further investigation. The mutant TP53, including R175H, Y220C, R273C, and R273H, were expressed in FTSECs. Meanwhile, knock down was achieved by introducing shRNAs targeting TP53. The transduced cells were subjected to RNA sequencing experiments to identify the significantly influenced genes and signaling pathways. The candidate genes and pathways will be validated in FTSECs and a panel of ovarian cancer cell lines. Functional assays, such as cell viability assay, migration/invasion assay, and metabolism assay, will be performed to study the effects of TP53 mutations. The results can provide further understanding of TP53 mutations and the downstream signaling in HGSC tumorigenesis.
Citation Format: Ya-Yun Cheng, Denise Prosser, Liudmila Velikokhatnaya, Anna Lokshin. Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5833.
Abstract 5836: SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cell metabolism
Authors: Zhang Wei , Huang Xin , Li yueming , Gong yingxuan , Li xiuzhi 
Published: June 2022

Abstract
Structural maintenance of chromosomes 4 (SMC4), one subunit of condensin complexes, is a key structural component of mitotic chromosomes. Accumulating evidence has suggested that SMC4 regulates prostate carcinogenesis. However, its roles on regulation of prostate cancer development remain unclear. Our previous studies showed that the expression of SMC4 is increased in highly lung-metastatic prostate cancer cells, RM1-LM, an organ-specific metastasis cell line that we developed. To investigate the function of SMC4, SMC4 gene was knockdown in RM1-LM cells by CRISPR/Cas9 system. Knockdown of SMC4 significantly diminished the cancer cell growth in RM1-LM. In addition, transwell assay results showed that SMC4 knockdown in RM1-LM suppressed the cell migration and invasion. Furthermore, we observed that SMC4 protein is important in the non-dividing phase of the cell cycle. In particular, cell cycle flow cytometry analysis indicated that SMC4 knockdown leaded to cell arrest in S phase. Finally, RM1-LM cells showed increased lung metastases compared with RM1-SMC4+/- cells in a murine model. The H&E and IHC results confirmed that RM1-LM cells induced greater number of lung metastases and colonization than RM1-SMC4+/-cells, suggesting the loss of SMC4 suppressed prostate cancer metastasis. The interactome of SMC4 was uncovered through IP-MS and revealed that SMC4 may interacted with GLUT1, a key protein in glycolysis pathway. The ATP rate assay and Glycolysis rate assay illustrated a significantly metabolic switch existing in RM1-SMC4+/-cells compared with their parental cells. Collectively, our study suggested that the interaction between SMC4 and GLUT1, confirmed by Co-IP, promotes prostate cancer cells metastasis via modifying the cell metabolism. This work was supported by NSFC projects 81802949, 81773146, 81972766, 81972420, 82173336; Shenzhen Science and Technology Commission Project JCYJ20190809161811237, JCYJ2021032410424040; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018);and College students' innovative entrepreneurial training program (S202114325028)
Citation Format: Wei Zhang, Xin Huang, yueming Li, yingxuan Gong, xiuzhi Li. SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5836.
Abstract 5840: The characteristics of TP53 germline mutations analyzed in a large-scale cohort of Chinese glioma patients
Authors: Hong Xinyu , Zhao Ximeng , Guo Zeshang , Yang Xiaochen , Guo Bella , Zhang Xiang , Ma Tonghui 
Published: June 2022

Abstract
Backgrounds:TP53 germline mutation is well known to be the cause of Li-Fraumeni syndrome (LFS), a rare autosomal dominant cancer syndrome, characterized by predisposition of breast cancer, soft tissue carcinoma, osteosarcoma, brain cancer and etc. LFS has been reported in cases or small-scale cohorts for decades, while the characteristics of TP53 germline mutations carried by glioma patients were still less studied due to rarity. We performed large-scale retrospective research to identify TP53 germline mutations in Chinese glioma patients, which would extend the genetic knowledge of LFS related glioma.
Methods:We enrolled 3325 glioma patients in this study (female=1423, male=1902). Next-generation sequencing panel targeting 825 genes was performed to identify TP53 germline mutations. Mutations were annotated pathogenic or likely pathogenic according to ACMG guidelines or referring to the literatures.
Results:After annotation, 20 pathogenic or likely pathogenic germline mutations (PGMs) in TP53 were found in 3325 glioma patients. There was no statistical significance of gender ratio between all glioma patients and mutation carriers (female=6, male=14, p=0.25). The highest incidence rate of PGMs occurred in glioblastoma (n=16, 80.0%), followed by anaplastic astrocytoma (n=2, 10.0%), oligodendroglioma (n=1, 0.5%) and diffuse midline glioma (n=1, 0.5%). Significant difference of onset age between TP53 mutation carriers and non-carriers was pronounced (22.90YO vs 43.35YO avg, p&lt;0.0001). Furthermore, the carrier rate of PGMs was prone to decrease with increasing onset age (table 1).
Conclusions:This research indicated that TP53 PGMs were prone to occur in younger glioma patients, suggesting the importance of TP53 germline mutations being screened. It might be able to assist with early detection and treatment of glioma.
The carrier rate of TP53 PGMs in each onset age intervals onset age glioma patient number PGM carrier number carrier rate 0-18 444 10 2.25% 19-30 263 4 1.52% 31-45 826 4 0.48% 46-55 717 1 0.14% 56-65 687 1 0.15% 66-75 337 0 0.00% 76+ 51 0 0.00%
Citation Format: Xinyu Hong, Ximeng Zhao, Zeshang Guo, Xiaochen Yang, Bella Guo, Xiang Zhang, Tonghui Ma. The characteristics of TP53 germline mutations analyzed in a large-scale cohort of Chinese glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5840.
Abstract 5847: Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity
Authors: Ben-Yishay Rakefet Ruth , Herman Naama , Noy Vered , Mor Eyal , Mansur Aiham , Ishay-Ronen Dana 
Published: June 2022

Abstract
Background: Epithelial-mesenchymal transition (EMT) in breast cancer drives tumor invasion, metastasis and drug resistance. BRCA1 mutation carriers have a high risk for developing aggressive basal-like triple-negative breast cancers with EMT characteristics. It has been described that normal mammary epithelium of BRCA1-mutation carriers is comprised of aberrant luminal progenitor cell population resembling basal-like breast cancer cells. Yet, the role of BRCA1 in regulating epithelial cell plasticity in normal mammary gland remains largely obscure. Aim: Here, we used patient-derived normal and cancer organoid cultures from BRCA1-mutation carriers and noncarriers, to examine the effect of the BRCA1 mutation background on epithelial cell plasticity and the susceptibility to EMT.
Methods and results: Mammary organoids were established from normal or cancer mammary tissues obtained from consenting patients undergoing lumpectomy or mastectomy. Isolated cells were plated in adherent basement membrane extract (BME) drops and overlaid with optimized organoid culture medium. EMT regulation in breast cancer is usually studied using cell lines and murine models. To determine the possibility to study EMT on patient-derived organoids, organoid culture media was optimized and established organoids were exposed to TGFβ to induce EMT. Morphological and phenotypic alterations were characterized using immunolabeling and visualization with confocal microscopy. Breast cancer organoids induced with TGFβ demonstrated EMT-like changes including the downregulation of E-Cadherin and upregulation of N-Cadherin. Moreover, breast cancer organoids showed typical cytoskeleton rearrangements. Here, the transformation from cortical actin into stress fibers formed in dedifferentiated mesenchymal cells, was visualized with actin staining. However, normal mammary organoids behaved differently. The cytoskeleton of BRCA-wild type (noncarriers) normal mammary organoids was not affected by the treatment. Curiously, normal mammary organoids derived from BRCA1-mutation carriers demonstrated EMT like changes upon exposure to TGFβ. To further determine mechanisms facilitating cell plasticity in BRCA1-mutation carriers, single cell RNA sequencing analysis on BRACA1-mutation carriers and noncarriers derived organoids is ongoing.
Conclusion: The results suggest that BRCA1 germline mutation predisposes normal mammary epithelium dedifferentiation due to increased susceptibility to EMT.
Citation Format: Rakefet Ruth Ben-Yishay, Naama Herman, Vered Noy, Eyal Mor, Aiham Mansur, Dana Ishay-Ronen. Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5847.
Abstract 5849: Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection
Authors: Bhat Nadeem S. , Soutto Mohammed , Zhang Xing , Chen Zheng , Zhu Shoumin , Lu Heng , Peng Dunfa , Xu Zekuan , El-Rifai Wael 
Published: June 2022

Abstract
Background: Gastric cancer is considered the 5th most common form of cancer and 4th leading cause of cancer-related deaths worldwide. Due to the late stage of diagnosis, gastric cancer carries poor prognosis and poor overall survival. Infection with H. pylori is the strongest known risk factor. Fibroblast Growth Factor Receptor 4 (FGFR4) belongs to a family of highly conserved tyrosine kinases. This study investigated the molecular mechanism of FGFR4 regulation in response to H. pylori infection.
Methods and Results: Among all the FGFRs, FGFR4 mRNA expression level was the most significantly elevated in human gastric cancer samples as compared to normal samples, using Real-time qPCR. These results were confirmed using the TCGA and Geo database analysis, confirming that FGFR4 is highly expressed in gastric cancer. Using western blot, we found that FGFR4 is significantly expressed in dysplasia and adenocarcinoma lesions in the TFF1-KO gastric cancer mouse model. Following infection with H. pylori in in-vitro (J166, 7.13) and in-vivo (PMSS1) models, we detected a significant increase in the expression of FGFR4 at the protein and mRNA levels. We also detected activation of STAT3 in human gastric cell lines and mice gastric tissues. Furthermore, analysis of FGFR4 promoter revealed several putative binding sites for STAT3. To confirm that FGFR4 expression is dependent upon STAT3 activation, we performed ChIP assay and confirmed direct functional binding of STAT3 on FGFR4 promoter. Using the FGF19, the ligand for FGFR4, we found that FGF19-FGFR4 axis played a vital role in activating STAT3 through an SRC-dependent mechanism and discovered that there is a feedforward activation loop between FGFR4 and STAT3. Functionally, we found that FGFR4 protected against H. pylori-induced DNA damage and cell death.
Conclusion: Our study established a feedforward activation loop between FGFR4 and STAT3 in response to H. pylori infection and FGFR4 could be a possible druggable moiety for future therapies in gastric cancer.
Citation Format: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Heng Lu, Dunfa Peng, Zekuan Xu, Wael El-Rifai. Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5849.
Abstract 5863: The ABID (Assessing the gut microbiota and Individual Diet) Study in the Navajo Nation
Authors: Pete Dornell , Phipps Amanda I. , Salama Nina R. , Lampe Johanna W. , Wu Michael C. 
Published: June 2022

Abstract
A substantial burden of stomach cancer continues to be observed in American Indians (AI) in the Southwestern United States. The Navajo Nation, the largest tribe in the Southwest, is experiencing higher incidence of stomach cancer compared to the general population in the region, possibly due to high prevalence of Helicobacter pylori (H. pylori) infection and other contributing factors, like diet. To learn about factors linked to stomach cancer, we initiated a cross-sectional study to determine the prevalence, virulence, and dietary correlates of H. pylori infection among Navajo adults. We hypothesized that H. pylori infections, particularly with the virulent cagA gene, would be highly prevalent in Navajo adults compared to other non-AI populations, and that diets high in salt, processed meats, and low in vegetables would be associated with prevalent H. pylori infection. Study recruitment occurred from January to October 2021 in two geographic areas of the Navajo Nation. Participants were recruited using online and offline platforms, including social media (Facebook, Instagram), study website (www.theabidstudy.com), newspapers, flyers, word of mouth, and community outreach events. Eligible, consenting study participants provided a stool sample, which was analyzed by droplet digital PCR assays for H. pylori 16S gene detection and cagA virulence gene typing. Participants also provided health and food information through two questionnaires.Preliminary data indicate that prevalence of H. pylori is high in the included regions of the Navajo Nation. The H. pylori prevalence (51.5%, 95% CI: 38.9-64.0) in this study is higher than the prevalence in the US population (35%). Moreover, the cagA virulence gene prevalence in the Navajo with H. pylori was 55.9% (95% CI: 37.9-72.8), which is comparable to the US prevalence of 50%. These early results point to a need of developing prevention strategies to reduce H. pylori infection in the Navajo Nation.
Citation Format: Dornell Pete, Amanda I. Phipps, Nina R. Salama, Johanna W. Lampe, Michael C. Wu. The ABID (Assessing the gut microbiota and Individual Diet) Study in the Navajo Nation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5863.