bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4686: Core transcriptional regulatory circuitry FOXA1-MAX-SP1 promotes malignancy of hepatocellular carcinoma
Authors: Peng Li , Yuan Xiaoqing , Chen Zhen , Zhang Chaoyang , Tian Duanqing , Yin Dong , Lin De-Chen 
Published: September 2020

Abstract
Background: Super-enhancers (SEs) are large clusters of transcriptionally active enhancers. Functionally, they are capable of driving the expression of key genes that control cell identity, which are also particularly important for tumor biology. This study is aimed at probing the biological function and mechanisms of the hyper-activation of the SEs associated core transcriptional regulatory circuitry (CRC) constituted by FOXA1-MAX-SP1 in hepatocellular carcinoma.
Results: ChIP-seq analysis of H3K27ac showed that the expression of three transcription factors FOXA1, MAX and SP1 is driven by super-enhancers in hepatocellular carcinoma cells. Notably, these three transcription factors also regulate large number of super-enhancers, whose characteristics fit the mathematical model of the core transcriptional regulatory circuitry (CRC). ChIP-seq analysis of FOXA1, MAX, SP1, H3K27ac, H3K4me1 and H3K4me3 confirmed the occupancy of FOXA1, MAX and SP1 at super-enhancers and promoters of some genes, including FOXA1, MAX and SP1. Also, FOXA1, MAX and SP1 have a positive correlation with each other in human hepatocellular carcinoma tissue. In addition, CCK8 assay showed that FOXA1, MAX and SP1 could promote cell growth of HCC cells. Relative open chromatin at FOXA1, MAX and SP1 genes mirrored their more active transcriptional state in HCC patients from TCGA ATAC-seq data. The mRNA expression of these three TFs were increased, which predict a worse prognosis of HCC patients.
Conclusion: FOXA1-MAX-SP1 regulate super-enhancers and may form a core transcriptional regulatory circuitry, so as to promote malignancy of hepatocellular carcinoma. They are potential therapeutic targets and prognostic biomarkers for hepatocellular carcinoma.
This work was supported by the National Natural Science Foundation of China (81802812 and 81972658), the Natural Science Foundation of Guangdong Province (2018A030313129 and 2019A1515012114).
Citation Format: Li Peng, Xiaoqing Yuan, Zhen Chen, Chaoyang Zhang, Duanqing Tian, Dong Yin, De-Chen Lin. Core transcriptional regulatory circuitry FOXA1-MAX-SP1 promotes malignancy of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4686.
Abstract 4721: Arid1a suppresses Akt/NRas-driven hepatocarcinogenesis in mice
Authors: Zhang Shanshan , Zhou Yufeng , Cao Di , Ren Qiannan , Zhang Meiyin , Mai Shijuan , Wang Huiyun 
Published: September 2020

Abstract
The SWI/SNF chromatin remodeling complexes are increasingly appreciated for their roles in carcinogenesis. Recent progress in human cancer genomic sequencing revealed that chromatin remodeling complexes are frequently targeted by cancer mutations, particularly in hepatocellular carcinomas (HCC). However, their precise role in HCC remains controversial and incompletely understood. AKT and NRAS are two major liver oncogenes that promote aberrant growth, metabolism and proliferation of hepatocytes, leading to initiation and development of HCC. Here, we investigated the role of Arid1a, one of the most mutated subunits of the SWI/SNF chromatin-remodeling complex across all human cancers, in hepatocarcinogenesis. To this end, we used Akt/NRas-driven mouse liver cancer model generated by hydrodynamic transfection (HDT). We found that overexpression of Arid1a strongly attenuated Akt/NRas-driven liver tumorigenesis and prolonged survival of animals. Conversely, knockdown of Arid1a accelerated Akt/NRas-driven liver cancer development and shortened survival in mice. We further showed that Arid1a antagonized activation of multiple molecular pathways downstream of Akt/NRas. Conclusion: Arid1a acts as a tumor suppressor in the Akt/NRas mouse HCC model. These new findings provide in vivo evidence for a tumor suppressive role of Arid1a-dependent chromatin remodeling in Akt/NRas-driven hepatocarinogenesis.
Citation Format: Shanshan Zhang, Yufeng Zhou, Di Cao, Qiannan Ren, Meiyin Zhang, Shijuan Mai, Huiyun Wang. Arid1a suppresses Akt/NRas-driven hepatocarcinogenesis in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4721.
Abstract 473: Preclinical model of radiation induced lymphopenia to identify abrogation strategies to enhance cancer therapy
Authors: Sharma Amrish , Neri Shinya , Venkatesulu Bhanu P. , Lin Steven H. 
Published: September 2020

Abstract
Radiation induced lymphopenia (RIL) is a common and yet often ignored side effect of radiation therapy that has been observed for over 100 years. Numerous studies have demonstrated the correlation between RIL and inferior overall survival outcomes in nearly all cancer types that are treated with radiation therapy. To assess the causative link between RIL and poor disease outcomes, as well as its impact on therapy response, we have developed a mouse model of RIL. Using cone beam CT based image-guided radiation targeting the mid-thorax, we showed that conventionally fractionated radiation of 2 Gy x 5 fractions caused severe and sustained lymphopenia in both C57BL/6 (Th1) and BALB/c (Th2). Increasing the radiation dose and radiation field resulted in more pronounced RIL. Enlarging the volume to include the spleen along with the thorax resulted in greater than 90% elimination of circulating lymphocytes (CD8/CD4/CD19/NK cells). However, radiation to the head resulted in only minimal lymphodepletion suggesting site specific susceptibility to the development of severe RIL. The severity of the lymphodepletion was also unperturbed by rate of blood flow as the administration of varying anesthetics that caused 5 fold differences in heart rate did not alter the severity of RIL. Functionally, RIL abrogated the immunotherapeutic effectiveness of anti-CTLA4 mAb as lymphopenic mice bearing CT26 tumors had complete lack of response to anti-CTLA4 treatment as compared to its control littermates. Similarly, animals treated with radiotherapy had nearly complete amelioration of radiotherapy effectiveness in the setting of severe RIL. However, exogenous administration of IL-15 super agonist (IL-15 SA) (IL-15 and IL-15Rα-Fc) therapy replenished cytotoxic CD8+ T killer cells and natural killer cells to control levels which restored the tumoricidal effect of radiation therapy. Taken together our study have generated the evidence for the causative link between RIL and poorer disease outcomes and presented a potential therapeutic strategy to overcome the adverse effect of RIL.
Citation Format: Amrish Sharma, Shinya Neri, Bhanu P. Venkatesulu, Steven H. Lin. Preclinical model of radiation induced lymphopenia to identify abrogation strategies to enhance cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 473.
Abstract 4743: Genetic characteristics of PanNETs, Rectal NETs, Thoracic NETs and its correlation with efficacy of chemotherapy
Authors: Chi Yihebali , Liu Weili , Zuo Lijie , Wang Yuehua , Cai Weijing , Shi Susheng , Ge Yanying , Li Rui , Song Lijie , Yang Yiqi , Liu Zheng , Dou Xiaowu , Zhao Hong 
Published: September 2020

Abstract
Background: Neuroendocrine tumors (NETs) are clinical heterogeneous. To date, no studies have focused on the genetic characteristics of NETs at different anatomical sites in the Chinese cohort. We aim to explore the genetic similarities or differences between NETs at different sites, and evaluate the predictive indicators of chemotherapy based on Temozolomide.
Methods: The patients were from a prospective clinical study STEM (from a single institute, NCT03204032, NCT03204019). This cohort included 47 patients with NETs, including 14 Pancreatic NETs (PanNETs), 11 Rectal NETs, 14 Thoracic NETs, and 8 Others. Whole exome sequencing (WES) was performed.
Results: A total of 76,057 somatic mutations were detected in 16,510 genes. The median tumor mutation burden (TMB) was 13.4, 10.5, 11.0 and 11.9 in PanNETs, Rectal NETs, Thoracic NETs and Others, respectively. After sequencing depth filtering, they were 3.5, 3.9, 3.3 and 3.6, respectively. Low intra-tumoral heterogeneity (ITH) was observed in NETs. The median ITH index was 2, 2.5, 2.5 and 2 in PanNETs, Rectal NETs, Thoracic NETs and Others, respectively; the median Shannon diversity index (SDI) was 0.23, 0.13, 0.23 and 0.24, respectively. The driver gene mutations varied in NETs at different sites. The recurrently mutated driver genes were MEN1, ATM, TSC2, PLXNB2, MUC6, AMER1 and USP9X for PanNETs; APC, APOB and FAT1 for Rectal NETs; KMT2B and CACNA1A for Thoracic NETs. Copy number analysis showed that copy number loss frequently occurred in all NETs. The median copy number variation burden (CNV burden) was 34.0, 10.9, 16.1 and 11.6 in PanNETs, Rectal NETs, Thoracic NETs and Others, respectively. The CNV burden of PanNETs was higher than others. Based on the results of CNVs, NETs at different sites could be distinguished by linear discriminant analysis (LDA). We analyzed the correlation between genetic characteristics and progression-free survival (PFS). As a result, NETs with higher TMB (&gt;10 /Mb, P=0.043) or higher CNV burden (&gt;20, P=0.047) showed statistically longer PFS. More patients should be included to find a correlation between genetic characteristics and PFS.
Conclusions: NETs at different sites harbored different somatic driver mutations, and copy number loss was widespread in NETs. NETs with higher TMB or higher CNV burden showed statistically longer PFS.
Citation Format: Yihebali Chi, Weili Liu, Lijie Zuo, Yuehua Wang, Weijing Cai, Susheng Shi, Yanying Ge, Rui Li, Lijie Song, Yiqi Yang, Zheng Liu, Xiaowu Dou, Hong Zhao. Genetic characteristics of PanNETs, Rectal NETs, Thoracic NETs and its correlation with efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4743.
Abstract 4747: Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma
Authors: Li Jun , Li Xinlin , Ye Qiancheng , Tian Yu , Kong Xiangxing , Liu Yue , Xu Xiaoming , Zhang Lina , Xiao Qian , Hu Yeting , Xu Rongzhen , Li Jingsong 
Published: September 2020

Abstract
AFP-producing gastrointestinal adenocarcinoma (APA-GI) is a rare type of cancer, typically with hepatoid differentiation, chemotherapy resistance and poor prognosis. As the mechanisms of its AFP production and hepatoid differentiation remain unclear, the present study aims to reveal the pathogenesis of APA-GI through genomic and transcriptomic profile analysis. We firstly performed 200 × whole exome sequencing of 29 APA-GI and 8 non-APA-GI cases from our hospital, but found no significant difference in single nucleotide variants (SNV) or insertion/deletion(indels). Additionally, there was no overlap gene when compared with the known genes harbored at 20q11.21-13.12 reported in gastric hepatoid adenocarcinoma. We then performed single-cell mRNA sequencing in one APA-GI, and observed several hepatoid differentiation markers in AFP positive cells including HNF4A and HNF1A. To further determine the specific alterations of APA-GI, we divided 339 gastric cancer patients from TCGA database into AFP-low group and AFP-high group by the level of AFP transcription through a dynamic grouping method named grid search. We performed a series differentially expressed genes detections within different grouping strategies and no significant SNV or indels difference was recognized. We identified hepatoid differentiation markers (i.e. HNF4A, HNF1A and ALB, et al) in AFP-high patients in mRNA level. As the difference of hepatoid differentiation markers only occurred in the mRNA level without DNA alteration, we hypothesized that it was probably caused by epigenetic regulation. We further compared these genes with an epigenetic regulators database named EpiFactors. Finally, it showed CCCTC-Binding Factor Like (CTCFL) was stably related with AFP producing within the grid search. In conclusion, comprehensive genomic analysis of APA-GI shows significant hepatoid differentiation at the transcriptomic level without disease-specific DNA alteration. The pathogenesis of APA-GI may be associated with other mechanisms like epigenetic regulation. Further study was needed to confirm the role of epigenetic regulators we detected in the present study in the development of APA-GI.
Citation Format: Jun Li, Xinlin Li, Qiancheng Ye, Yu Tian, Xiangxing Kong, Yue Liu, Xiaoming Xu, Lina Zhang, Qian Xiao, Yeting Hu, Rongzhen Xu, Jingsong Li. Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4747.
Abstract 4751: Brain and plasma choline compounds altered by cancer and cancer-induced cachexia
Authors: Bharti Santosh K. , Winnard Paul T. , Sharma Raj Kumar , Penet Marie-France , Krishnamachary Balaji , Bhujwalla Zaver M. 
Published: September 2020

Abstract
Introduction: Cancer-induced cachexia has lethal consequences. Cachexia results in lower tolerance to chemotherapy1. Cachectic patients experience a wide range of symptoms affecting the function of organs such as muscle, liver, brain, and heart, causing significant morbidity 2. An altered choline metabolism is one of the hallmarks of cancers. Here, for the first time, we identified changes in brain choline metabolism induced by cachexia-inducing pancreatic cancer xenografts and related these changes to plasma choline levels.
Methods: Panc1 or Pa04C cells were implanted in the flank of SCID mice. Snap frozen brains were powdered under liquid nitrogen, weighed, and dual phase extraction was performed3. All 1H MR spectra were acquired on a Bruker Avance III 750 MHz MR spectrometer. Mouse plasma choline was quantified using a fluorometric assay (Choline Assay Kit, BioAssay Systems). Brain and plasma studies were performed with normal mice (n=10), mice with cachexia-inducing Pa04C tumors (n=9) and mice with non cachexia-inducing Panc1 tumors (n=10).
Results and Discussion: Cachexia-inducing Pa04C tumors induced significant weight loss in mice compared to Panc1 tumor bearing mice or normal mice3. A significant decrease of brain choline was observed in Pa04C tumor bearing mice compared to control mice as well as Panc1 tumor bearing mice, whereas brain phosphocholine (PC) levels were significantly lower compared to normal mice. Brain glycerophosphocholine (GPC) was significantly lower in both tumor bearing groups compared to normal mice. We observed a significant decrease of plasma choline in Pa04C tumor bearing mice. Plasma choline in Panc1 tumor bearing mice also decreased but not as drastically. The changes in plasma choline levels most likely contributed to the reduction of brain choline, PC and GPC. Reduced plasma choline may represent a risk factor for cancer as choline deficiency is known to result in lymphocyte apoptosis and DNA damage 4 that may compromise the immune response. Normalization of plasma choline using metabolic supplements merits investigation in reducing cancer morbidity and the onset of cachexia.
Acknowledgement: This work was supported by NIH R35CA209960 and R01CA193365.
References
1. Argiles JM et al., Nature reviews Cancer. 14(11):754-762.
2. Inui A. 2002. CA Cancer J Clin. 52(2):72-91.
3. Winnard PT, Jr., et al., Cancer Res. 76(6):1441-1450.
4. da Costa KA, et al., The American journal of clinical nutrition. 84(1):88-94.
Citation Format: Santosh K. Bharti, Paul T. Winnard, Raj Kumar Sharma, Marie-France Penet, Balaji Krishnamachary, Zaver M. Bhujwalla. Brain and plasma choline compounds altered by cancer and cancer-induced cachexia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4751.
Abstract 4808: ONC201 decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, intregrated stress response and tumor cell death
Authors: Zhou Lanlan , Safran Howard P. , Glantz Michael J. , El-Deiry Wafik S. 
Published: September 2020

Abstract
Brain tumors are one of the most lethal cancers in children and young adults. We previously reported that first-in-class small-molecule imipridone ONC201 can antagonize dopamine receptor D2 (DRD2), inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce growth arrest or cell death in tumor cells. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant glioma patients. We hypothesized that ONC201 may synergize with radiotherapy and temozolomide in brain tumors. Glioblastoma (GBM: SNB19, T98G and U251), diffuse intrinsic pontine glioma (DIPG: SU-DIPG-IV and SU-DIPG-36) and atypical teratoid rhabdoid tumor (ATRT: BT-12, BT-16) cell lines were tested using cell viability or colony formation assays with ONC201 up to 20 μM alone or in combination with radiotherapy up to 8 Gy and temozolomide up to 100 μM. We observed synergy between ONC201 and radiation and temozolomide by multiple assays with the best combination index of 0.31 under the treatment of 0.625 μM ONC201, 25 μM TMZ and 4 Gy irradiation in cell viability assay. We observed induction of PKA substrate phosphorylation as a marker of DRD2 antagonism, induction of ATF4 as a marker of ISR activation, and multiple markers of cell death in treated brain tumor cells. Mitochondrial dysfunction induced by ONC201 was greatly reflected in reduction of maximal cell respiration in brain tumor cell lines. ClpXP is a proteolytic machine in mitochondria comprising of the protein chaperone ClpX and protease ClpP, a recently described binding target of ONC201. We have observed that ONC201 induced cytotoxicity depends on ClpP and knockdown of ClpP strongly protects multiple human cancer cell lines from ONC201-mediated (but not other drugs, e.g. temozolomide) cytotoxicity. The ClpX protein level decreased dramatically upon ONC201 treatment. We are exploring the potential interplay between ClpP, dopamine receptors, the ISR and TRAIL signaling pathways after single agent or combinatorial treatments. Our data suggests that ONC201 may be combined synergistically with temozolomide or radiation to address gliomas, along with potential pharmacodynamic biomarkers. The results implicate ClpX and ClpP in downstream cell death induction following ONC201 treatment of brain tumor cells.
Citation Format: Lanlan Zhou, Howard P. Safran, Michael J. Glantz, Wafik S. El-Deiry. ONC201 decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, intregrated stress response and tumor cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4808.
Abstract 4822: The 3'UTR of CAPZA1 functions separately and oppositely to its host gene in ESCC
Authors: Li Dan , Kang Nan , Li Zhangfu , Zhan Qimin 
Published: September 2020

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and highly prevalent in China. According to our previous study on whole-genome sequencing (WGS) and whole-exome sequencing (WES) of ESCC, we identified that CAPZA1 displayed copy number losses in the ESCC sequencing cohort. CAPZA1, which modulates the dynamic assembly of actin filament and cell motility, has been reported dysregulated expression in neuroblastoma, gastric cancer, liver cancer and breast cancer. However, the functional role and the underlying mechanism of CAPZA1 in ESCC have not been elucidated. Here, we identify the expression of CAPZA1 significantly decreased in cancer tissues than in normal tissues by immunohistochemical assay. Through gain and loss of function approaches, we found that CAPZA1 suppressed the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Moreover, we found that CAPZA1 promoted the expression of E-cadherin, while decreased the expression of Vimentin and Twist. Intriguingly, we demonstrated that the 3'UTR of CAPZA1 could function as an independent RNA molecule separately with a full length of 1487nt by RACE and Northern-blot assays. Furthermore, the RNA in situ hybridization assay was employed to validate that 3'UTR expression levels were significantly higher in cancer tissues than in normal tissues. Additionally, the 3'UTR promoted cell migratory and invasive capabilities, which is oppositely to its host gene CAPZA1. The 3'UTR performed oncogenic role by enhancing the combination of IGF2BPs proteins to c-myc mRNA and promoted the translation of c-myc. These findings offer a new dimension to the crosstalk between 3'UTR and its host gene, which may open new ways towards additional therapeutic strategies in the treatment of ESCC.
Citation Format: Dan Li, Nan Kang, Zhangfu Li, Qimin Zhan. The 3'UTR of CAPZA1 functions separately and oppositely to its host gene in ESCC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4822.
Abstract 4825: Super enhancer-associated lincRNA BCSL1 promotes the development of breast cancer
Authors: Yuan Xiaoqing , Peng Li , Chen Jianing , Cui Xiuying , Liu Yujie , Song Erwei 
Published: September 2020

Abstract
Long Intergenic non-coding RNAs (lincRNAs) expressed in tissue-specificity model are involved in a variety of tumor biological processes. Super enhancers (SEs) have been shown to drive the expression of genes including lincRNAs that control cell identity and the development of cancer. However, the role of super-enhancer-driven lincRNAs in luminal type breast cancer (BC) is poorly understood. Here we identified a lincRNA, BCSL1, was uniquely up-regulated in BC tumor tissues and cell lines. ChIP-sequencing and Hi-C analysis manifested that BCSL1 was directly regulated by the luminal subtype specific SEs in BC cells. Nuclear plasma separation assay and FISH test showed that BCSL1 slightly more located in the cytoplasm than the nucleus of MCF7 cells. Knocking down of BCSL1 significantly inhibited the proliferation, colony formation and apoptosis of BC cells, and the cell cycle switching from G1 stage to S stage. Overexpression of BCSL1 significantly increased their proliferation, colony formation and apoptosis. Mechanistically, RNA pulldown, Mass spectrometry and RNA-sequencing indicated BCSL1 may be involved in the development of luminal BC by participating in apoptosis-related pathways.In summary, we identified a lincRNA, BCSL1, that is uniquely increased in breast cancer. Increased expression of BCSL1 promotes the proliferation, colony formation and apoptosis of luminal breast cancer cells. BCSL1 might be developed as a biomarker of luminal breast cancer patients. This work was supported by the National Natural Science Foundation of China (81803636 and 81972658), the Natural Science Foundation of Guangdong Province (2018A0303130329).
Citation Format: Xiaoqing Yuan, Li Peng, Jianing Chen, Xiuying Cui, Yujie Liu, Erwei Song. Super enhancer-associated lincRNA BCSL1 promotes the development of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4825.