bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2390: LncRNA PAINT promotes prostate cancer progression through modulation of genes involved in epithelial-mesenchymal transition and apoptosis
Authors: Ganapathy Kavya , Hasan Md Faqrul , Sun Jiao , Khatib Ayman , Andl Thomas , Soulakova Julia , Coppola Domenico , Zhang Wei , Chakrabarti Ratna 
Published: July 2021

Abstract
Long non-coding RNAs (LncRNAs) play regulatory roles in cellular processes and their aberrant expression may drive cancer progression. Here we report the function of a LncRNA PAINT (Prostate Cancer-Associated Intergenic Non-Coding Transcript) in promoting prostate cancer (PCa) progression. Upregulation of PAINT expression was noted in the advanced stage and metastatic PCa patient tissues and correlated with poor survival. Inhibition of PAINT decreased cell proliferation, S-phase progression, increased expression of apoptotic markers, and improved sensitivity to docetaxel and Aurora kinase inhibitor VX-680. Inhibition of PAINT also decreased cell migration and reduced expression of mesenchymal markers, Slug, and Vimentin. Ectopic expression of PAINT suppressed E-cadherin, increased S-phase progression, and cell migration. PAINT expression in PCa cells also induced larger colony formation and higher expression of mesenchymal markers. Transcriptome profiling of PCa cells overexpressing PAINT showed differential expression of genes involved in epithelial-mesenchymal transition (EMT), apoptosis, and drug resistance which were further validated by qRT-PCR analysis. Additionally, GO enrichment and KEGG pathway analysis revealed altered expression of multiple pathways including p53 signaling and drug metabolism pathways indicating that PAINT may promote an oncogenic environment by simultaneously regulating various biological processes in PCa. In summary, our findings establish the role of PAINT as an oncogene in PCa and indicate the clinical significance of PAINT as a diagnostic marker and a possible therapeutic target for aggressive PCa.
Citation Format: Kavya Ganapathy, Md Faqrul Hasan, Jiao Sun, Ayman Khatib, Thomas Andl, Julia Soulakova, Domenico Coppola, Wei Zhang, Ratna Chakrabarti. LncRNA PAINT promotes prostate cancer progression through modulation of genes involved in epithelial-mesenchymal transition and apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2390.
Abstract 2393: The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique
Authors: Ray Roslyn M. , Lang Lu , Pokharel Sheela P. , O'Meally Denis , Scott Tristan A. , Chen Chun-Wei , Morris Kevin V. 
Published: July 2021

Abstract
Long non-coding RNAs (LncRNAs) have been found to play important roles in maintaining and promoting cellular proliferation in cancerous cells. One such lncRNA, LINC00963 has been found to promote cellular proliferation, migration and tumorigenesis in prostate, ovarian, breast and non-small cell lung (NSCLC) cancer. In this study, we aim to identify important functional regions of this lncRNA with a view to identify unique regions for targeted drug therapy. In order to achieve this, we sought to investigate this lncRNA in the A549 NSCLC cell line. We found that LINC00963 was highly expressed and when targeted with either siRNAs or antisense oligonucleotides, cells rapidly undergo apoptosis. Using cell death as a proxy for loss-of-function, we characterized LINC00963 at the genomic level using a CRIPSRScan approach. CRISPRScan is a novel way of determining lncRNA functional domains through the introduction of local mutations. These mutations could potentially disrupt lncRNA function, which for LINC00963 would lead to apoptosis of the cell. We created a unique lentivirus library comprised of 1784 single guide RNAs spanning the length of LINC00963 in order to precisely identify regions of functional importance. Upon transduction in a stably expressing Cas9-A549 cell line, we collected cellular fractions over time, and using high-throughput sequencing (NextSeq, Illumina), evaluated the depletion of these sgRNAs as a proxy for their importance in LINC00963 function. The identification of these key genomic regions that may render LINC00963 non-functional may offer new lncRNA target sites for anti-cancer therapies in the future. Additionally, the utilization of an in-depth CRISPR-Cas9 approach to determine important lncRNA domains provides a novel and precise way in which to evaluate lncRNA function.
Citation Format: Roslyn M. Ray, Lu Lang, Sheela P. Pokharel, Denis O'Meally, Tristan A. Scott, Chun-Wei Chen, Kevin V. Morris. The systematic evaluation of the oncogenic lncRNA LINC00963 using a CRISPRScan technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2393.
Abstract 2397: Significance of the combination of biguanides and fatty acid β-oxidation inhibitors in triple-negative breast cancer
Authors: Park Junhyoung , Jung Kwang Hwa , Jia Dongya , Yang Sukjin , Sakthivel Dharaniya , Tiwari Abha , Onuchic José N. , Kaipparettu Benny Abraham 
Published: July 2021

Abstract
Compared to hormone receptor (HR) positive breast cancer (BC), basal or triple-negative BC (TNBC) suffers a poor prognosis, attributed to the limited understanding of its driver signaling pathways. Although TNBC exhibits unique characteristics, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are essential to reduce its severity. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a dominant metabolic pathway in TNBC. We have also reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC, via autophosphorylation of Src at Y419. However, single drug therapy using FAO inhibitors or Src inhibitors did not show a significant therapeutic advantage in TNBC. Biguanide such as metformin is one of the most widely administered anti-diabetic agents. Recently increasing evidence demonstrates that biguanide therapy can have an anticancer effect in various cancer types, including BC. Phenformin, a biguanide derivative similar to metformin, has greater potency than metformin. Both biguanides can suppress mitochondrial electron transport chain (ETC) function because of its inhibitory effect on ETC complex I activity. However, biguanides also lead to the activation of AMPK, which plays a vital role in insulin signaling and energy-sensing. Notably, AMPK is an upstream regulator of the FAO pathway because it can phosphorylate ACC and activate FAO. Considering the dependency of TNBC on mitochondrial FAO and the role of AMPK in the activation of FAO, our computational modeling predicted that the combined targeting of both ‘arms' of the pathway could provide a significant advantage to the anticancer effect in TNBC. Thus, we have used the combination of biguanides and FAO inhibitors to target both ETC and FAO respectively. Pharmacological and genetic approaches with multiple in vitro and in vivo analysis using TNBC cell lines and PDX models suggest that the combination of biguanides and FAO inhibitors can provide significant advantage in TNBC therapy. Further studies also show that the combination of biguanides with Src inhibitors can provide a better therapeutic option to target metastatic TNBC. We are currently evaluating these findings' translational significance as a cost-effective approach to managing non-targetable TNBCs.
Citation Format: Junhyoung Park, Kwang Hwa Jung, Dongya Jia, Sukjin Yang, Dharaniya Sakthivel, Abha Tiwari, José N. Onuchic, Benny Abraham Kaipparettu. Significance of the combination of biguanides and fatty acid β-oxidation inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2397.
Abstract 2402: Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression
Authors: Chang Ching-Wen , Chen Yu-Syuan , Lo Jeng-Fan , Wang Xin Wei 
Published: July 2021

Abstract
Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor to drive hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation, meanwhile; sequentially developed fatty liver, NASH, and cirrhosis/HCC in a Diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 mRNA expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that plays a key mechanism involved in the NASH-dependent HCC development. Overall, we established a new mouse model developing NASH-dependent HCC and provided a promising approach for improving the treatment.
Citation Format: Ching-Wen Chang, Yu-Syuan Chen, Jeng-Fan Lo, Xin Wei Wang. Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2402.
Abstract 2409: The regulation of mitochondria metabolism is correlated with gemcitabine resistance in MIA-PaCa-2 cell line
Authors: Fujiwara-Tani Rina , Kishi Shingo , Mori Shiori , Kuniyasu Hiroki 
Published: July 2021

Abstract
We established gemcitabine (GEM)-resistant pancreatic ductal adenocarcinoma (PDAC) cell line, MIA-G cells from MIA-PaCa-2 (MIA-P) cells by continuous low-dose GEM treatment. MIA-G cells was also resistant to 5-fluorouracil in comparison with MIA-P. Metabolic flux analysis showed that oxygen consumption rate (OCR) in MIA-G cells was higher than MIA-P cells, however, OCR was suppressed by GEM treatment only in MIA-G cells. In MIA-P cells, GEM treatment generated elevation of mitochondrial membrane potential and mitochondrial ROS, but not MIA-G cells. In MIA-G cells, expression of mitochondrial transcription factor A was also decreased. Moreover, glutamine uptake and glutamine peroxidase level were elevated in MIA-G cells. These findings suggest that suppression of OXPHOS contributes to GEM resistance through reduction of ROS production.
Citation Format: Rina Fujiwara-Tani, Shingo Kishi, Shiori Mori, Hiroki Kuniyasu. The regulation of mitochondria metabolism is correlated with gemcitabine resistance in MIA-PaCa-2 cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2409.
Abstract 2412: Decursin inhibits tumor progression in head and neck squamous cell cancer by down regulating CXCR7 expression
Authors: Joo Mina , Kim Solbi , Kim Nayoung , Lee Myung-Won , Jeon Heung Jin , Ryu Hyewon , Song Ik-Chan , Kim Jin-Man , Lee Hyo Jin 
Published: July 2021

Abstract
Background: CX chemokine receptor 7 (CXCR7) is frequently overexpressed in a variety of tumors and plays a significant role in tumor growth and metastasis. Thus, inhibition of CXCR7 is an important potential anticancer treatment strategy. Decursin, a derivative from Angelica gigas Nakai has been reported to have anti-tumor activity in various cancers. However, little is known about its anti-tumor activity and underlying mechanisms of action in head and neck squamous cell cancer (HNSCC).
Methods: CXCR7-overexpressing HNSCC cell lines were established in vitro. The effects of decursin on cell growth, motility, migration, and invasion were investigated using CCK-8, wound healing, and transwell assays. In addition, the mechanism by which decusin shows antitumor activity was investigated.
Results: Overexpression of CXCR7 significantly increased cell proliferation, migration, invasion, and cell motility compared with control cells. Treatment with decursin decreased membrane expression of CXCR7 in a concentration dependent manner and significantly inhibited tumor progression by suppressing cell growth, migration, invasion, and motility. Decursin was found to induce G0/G1 cell cycle arrest and regulate cell cycle-related proteins such as Cyclin A and CDK2 in HNSCC cells. In addition, decursin inhibited CXCR7-induced STAT3/c-MYC activation.
Conclusion: These results demonstrate that CXCR7 promotes cancer progression through the STAT3/c-Myc pathway in HNSCC and that decursin is a natural product that may target CXCR7 for HNSCC treatment.
Citation Format: Mina Joo, Solbi Kim, Nayoung Kim, Myung-Won Lee, Heung Jin Jeon, Hyewon Ryu, Ik-Chan Song, Jin-Man Kim, Hyo Jin Lee. Decursin inhibits tumor progression in head and neck squamous cell cancer by down regulating CXCR7 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2412.
Abstract 2415: The role of GTSF1 as a regulator of retrotransposons and its impact on carcinogenesis
Authors: Villarreal Amelia Martínez , Gantchev Jennifer , Litvinov Ivan 
Published: July 2021

Abstract
Hypomethylation of repetitive sequences is a common feature reported in cancer, particularly of retrotransposon elements. Retrotransposon elements can be deleterious due to their potential as insertional mutagens, so cells have deployed several control mechanisms to silence them through methylation of DNA. These methylation pathways are different between somatic and germline cells. In germline cells, the piRNA pathway is the main process responsible for silencing the retrotransposon LINE-1. GTSF1 is germline cell specific and an important part of this pathway. Along with PIWI proteins in the piRNA pathway, GTSF1 processes small RNA molecules and identifies active retrotransposons, recruiting the DNA methylation machinery to those sites. Aberrant expression of GTSF1 has been reported in cancer, particularly on lymphomas. We performed a Bayesian Analysis and Markov Chain Monte Carlo Method with GTSF1 levels of expression reported on The Cancer Genome Atlas (TCGA), which confirmed high levels of mRNA in lymphomas. Nonetheless, the role of GTSF1 in retrotransposon control in cancer and in carcinogenesis remains unknown. To address this issue, we have performed shRNA mediated knockdown in head and neck squamous cell carcinoma and cutaneous T-cell lymphoma cell lines, and we have overexpressed the cDNA of GTSF1 in immortalized keratinocytes. We evaluated the impact of the knockdown and overexpression on cell biology, retrotransposons, and genomic instability. Overall, GTSF1 expression seems to affect LINE-1 retrotransposon protein expression and function. Also, we are assessing the impact on genomic instability and methylation profiles. The aberrant expression of this gene poses an excellent clinical opportunity for targeted therapy development. Its germline cell restricted expression will potentially result in less secondary effects than current available therapies.
Citation Format: Amelia Martínez Villarreal, Jennifer Gantchev, Ivan Litvinov. The role of GTSF1 as a regulator of retrotransposons and its impact on carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2415.
Abstract 2416: Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation
Authors: Li Licen , Bao Jiaolin , Wang Haitao , Lei Haipeng , Cheng Peng , Zeng Jianming , Hao Wenhui , Zhang Xu , Xu Xiaoling , Yu Chundong , Deng Chu-Xia , Chen Qiang 
Published: July 2021

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains largely unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms.
Methods: The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used in vivo metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target.
Results: We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, via upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression.
Conclusions: These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression via Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.
Citation Format: Licen Li, Jiaolin Bao, Haitao Wang, Haipeng Lei, Peng Cheng, Jianming Zeng, Wenhui Hao, Xu Zhang, Xiaoling Xu, Chundong Yu, Chu-Xia Deng, Qiang Chen. Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2416.
Abstract 2418: PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression
Authors: Miller Karina , Degan Seamus , Wang Yanqing , Ku Sheng-Yu , Goodrich David W. , Gelman Irwin H. 
Published: July 2021

Abstract
Background: The loss of PTEN function, one of the most frequent mutations in prostate cancer (CaP), is presumed to drive disease progression through AKT activation. However, two transgenic mouse CaP models, Pten/RbPE:-/- and Akap12-/-;RbPE:-/-, exhibited different CaP and metastasis development even though both shared Rb loss plus Akt activation, based on increased relative AKTpoS473 levels.
Experimental Procedures: We analyzed whether PI3K-p110 and/or AKT isoform reliance, using isoform-specific RNAi or small molecule inhibitors, played a role in the different CaP outcomes.
Findings: In comparison to Akap12/Rb-null high-grade prostatic intraepithelial neoplasias, Pten/Rb-null adenocarcinomas had increased protein and activation levels of AKT2 and decreased relative levels of Smad4, a known CaP metastasis suppressor. Comparison of isogenic PTEN +/- pairs of human or mouse CaP cell lines indicated that PTEN-deficiency correlated with dependence on both p110β and AKT2 for survival or oncogenic growth/invasiveness, whereas PTEN expression correlated with greater dependence on AKT1 plus p110α. Inhibition of AKT2 in PTEN-null CaP cells induced higher SMAD4 levels and decreased chemotaxis and Matrigel invasiveness. Given that PTEN likely regulates non-redundant roles of the AKT isoforms during CaP progression, we sought to characterize AKT isoform substrates by phosphoproteomics analysis. Specifically, after endogenous kinases were inactivated in mouse Pten/Rb-null adenocarcinoma cell lysates using 5'-fluorosulfonylbenzoyl-5'-adenosine (FSBA), dialyzed samples were subjected to in vitro kinase reactions using enzymatically-active, full-length baculovirus-expressed AKT1, AKT2 or AKT3, or as a negative control, a heat-inactivated mixture of all three isoforms. Tryptic peptides isolated on TiO2 beads were subjected to LC-MS/MS. Data will be shown on the role of AKT isoform-shared vs. -preferred substrates in specific parameters of CaP progression controlled by PTEN.
Conclusion: Our data suggest that in the context of RB1 loss, PTEN controls a signaling plasticity and drug sensitivity through specific pairings of PI3K-p110 and AKT isoforms.
Citation Format: Karina Miller, Seamus Degan, Yanqing Wang, Sheng-Yu Ku, David W. Goodrich, Irwin H. Gelman. PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2418.