bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 775: MicroRNA-1205 regulation of FRYL in neuroendocrine prostate cancer
Authors: Naidoo Michelle K. , Ogunwobi Olorunseun 
Published: August 2019

Abstract
High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs further leads to progression to neuroendocrine PCa (NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with low survival rates. The molecular mechanisms of progression to NEPC are, however, still unclear. Further understanding of molecular mechanisms of NEPC is critical to improving patient outcomes. The 8q24 chromosomal locus is a highly susceptible PCa region that carries high risk genetic variants associated with PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes microRNA-1205 (miR-1205). We have previously reported that miR-1205 is underexpressed in PCa tissues in comparison to normal prostate tissue, and is also underexpressed in vitro in CRPC cells in comparison to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC tumor xenografts in mice, and that miR-1205 directly targets the putative oncogene, Fry-like (FRYL). FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in NEPC. To test this hypothesis, we first examined miR-1205 expression levels in PCa tissues with Gleason scores ≥8 and &lt;8, using a cohort of histologically confirmed tissues. We observed that miR-1205 was underexpressed in tumors with Gleason scores ≥8 when compared to those with Gleason scores &lt;8, suggesting that miR-1205 underexpression is characteristic of high grade PCa. To examine miR-1205 regulation of FRYL specifically in NEPC, we analyzed RNA sequencing data from a cohort of histologically confirmed NEPC tissues and prostate adenocarcinoma tissues obtained from TCGA via cBioPortal. We observed increased FRYL mRNA expression in NEPC tissues when compared to prostate adenocarcinoma tissues, indicating a putative oncogenic role of FRYL in NEPC. In vitro data revealed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of induced NEPC differentiation using LNCaP cells when compared to undifferentiated LNCaP cells. In conclusion, these data suggest that miR-1205 regulation of FRYL may be a critical mechanism in NEPC. Further understanding this mechanism may provide novel insights into effective therapeutic strategies for NEPC.
Citation Format: Michelle K. Naidoo, Olorunseun Ogunwobi. MicroRNA-1205 regulation of FRYL in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 775.
Abstract 788: Identification and optimization of pro-apoptotic molecules targeting adenine nucleotide translocator 2 (hANT2) in tumor mitochondria
Authors: Buron Nelly , Pertuiset Claire , Loyant Roxane , Martel Cécile , Porceddu Mathieu , Borgne-Sanchez Annie 
Published: August 2019

Abstract
The mitochondrial protein ANT2 is one of the four isoforms of the ADP/ATP translocase and is expressed in highly proliferating cells. ANT2 plays a crucial role in the maintenance of transmembrane potential and mitochondrial integrity in tumor cells by importing glycolytic ATP into the mitochondrial matrix. Thus, this protein is required for tumor cell survival and displays anti-apoptotic function. Recently, ANT2 upregulation was shown to be involved in drug resistance process in various cancer types. Considering ANT2 role in tumor cell metabolism, we searched for ANT2-ligand small molecules. Ligands were first identified by virtual screening of chemical library on 3D model of human ANT2 and validated as ADP/ATP translocase inhibitors using our screening platform on isolated mitochondria. Compound specificity for ANT2 isoform was validated by cellular knock-down and pull-down experiments. ANT2-ligands optimization lead to the selection of MTL105 compound that induce characteristic intrinsic apoptotic cell death, specifically in tumor cell lines at sub-µM concentrations with no effect on healthy cells, suggesting a strong safety margin. According to the NCI60 compare analysis, this compound constitutes a first-in-class product in cancer therapy with this MoA and would be particularly interesting to overcome multidrug-resistant cancers.
Citation Format: Nelly Buron, Claire Pertuiset, Roxane Loyant, Cécile Martel, Mathieu Porceddu, Annie Borgne-Sanchez. Identification and optimization of pro-apoptotic molecules targeting adenine nucleotide translocator 2 (hANT2) in tumor mitochondria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 788.
Abstract 79: Overexpression of BQ323636.1 modulates tamoxifen resistance in ER positive breast cancer via IL-8-mediated signaling pathway
Authors: Shi Ling , Tsoi Ho , Dong Miao , Man Ellen Pui , Khoo Ui Soon 
Published: August 2019

Abstract
Background
Tamoxifen has been used as first-line adjuvant treatment for estrogen receptor positive (ER+) breast cancer; however, the development of acquired resistance compromises its efficacy. Previously, our group identified BQ323636.1(BQ), a novel splice variant of nuclear receptor repressor 2 (NCOR2), which confers tamoxifen resistance by enhancing ER transcriptional activity1, 2. We hypothesize that BQ may also modulate tamoxifen resistance via androgen receptor (AR) activity. The current study investigates the effect of BQ in modulating the activities of ER and AR in tamoxifen resistant breast cancer.
Methods
In silico search was employed to identify candidate genes that contained both the androgen responsive element (ARE) and estrogen responsive element (ERE) genome-wide. Expression of candidate genes were evaluated by RT-qPCR. Western blot was used to determine the protein expression. Stably transfected BQ overexpressing MCF7 cell line (MCF7-BQ) and control cell line (MCF7-His) were established. ELISA was employed to determine the amount of IL-8. Repertaxin was used to inhibit IL-8 mediated signaling pathway.
Results
There were 22 candidate genes identified by in silico search. qPCR confirmed that IL-8 gene contained both functional ERE and ARE in MCF-7 cells. Overexpression of BQ could enhance the expression of IL-8 at both mRNA and protein levels. ELISA assay confirmed that BQ overexpression could promote the secretion of IL-8 in breast cancer cells. Western blot analysis showed that BQ overexpression could not alter the expression of IL-8 receptor CXCR1. The treatment with repertaxin could recover the response of MCF7-BQ to tamoxifen.
Conclusions
Our results suggest that BQ323636.1 could up-regulate IL-8 to modulate tamoxifen resistance. Targeting IL-8 signaling may provide insights to overcome tamoxifen resistance in ER+ breast cancer.
References
1. Zhang L., Gong C., Lau S.L.Y., Yang N., Wong O.G.W., Cheung A.N.Y., Tsang J.W.H., Chan K.Y.K. and Khoo US. (2013) Cancer Research 73:246-255
2. Gong, C., Man, E. P., Tsoi, H., Lee, T. K., Lee, ⋯.. Khoo, U. (2018). BQ323636.1, a Novel Splice Variant toNCOR2, as a Predictor for Tamoxifen-Resistant Breast Cancer. Clinical Cancer Research,24(15), 3681-3691. doi:10.1158/1078-0432.ccr-17-2259
Citation Format: Ling Shi, Ho Tsoi, Miao Dong, Ellen Pui Man, Ui Soon Khoo. Overexpression of BQ323636.1 modulates tamoxifen resistance in ER positive breast cancer via IL-8-mediated signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 79.
Abstract 790: STAT3 control of mitochondrial RNA stability and translation is a vulnerability in tumors
Authors: Fernando Chamira D. , Garama Daniel J. , Gough Daniel J. 
Published: August 2019

Abstract
Signal Transducer and Activator of Transcription (STAT)3 is a critical signalling molecule and transcription factor activated downstream of cytokines and growth factors to regulate immune responses, metabolism, proliferation and cell death. Whilst the activity of STAT3 is crucial for sustenance of life, aberrant activity is observed in around 50% of all human cancers. However, recent evidence has shown non-transcriptional activities of STAT3 that are critical for tumor growth. Mitochondria are the central powerhouse of the cell and provide the biomolecules required for rapid cell proliferation. Recently we showed that a pool of STAT3 resides in mitochondria and enhances the activity of complex I, II and V of the electron transport chain (ETC) driving Ras-dependent malignant transformation. Whilst STAT3 can physically interact with complex I, its low abundance compared to complex I suggests that a direct protein-protein interaction is unlikely to dictate metabolic activity of the ETC.To elucidate mitochondrial activity of STAT3, we isolated STAT3 from mitochondrial fractions of Ras-driven lung adenocarcinoma (A549 cell line) and identified its interactome using mass spectrometry. We show that STAT3 forms a stable 400 kDa complex with the LRPPRC/SLIRP proteins which are key regulators of mitochondrial mRNA stability and translation. STAT3 loss significantly reduced steady state levels of polyadenylated mitochondrial RNA which is due to instability of the polyadenylated transcripts but not due to changes in mitochondrial DNA copy number, differences in mitochondrial transcription kinetics or mitochondrial RNA processing. Furthermore, in the absence of STAT3 there is defective delivery of these transcripts to the mitochondrial ribosomes resulting in delayed mitochondrial translational kinetics. We propose that the ability of STAT3 to regulate mitochondrial transcription and translation is the fundamental mechanism by which a small pool of STAT3 can regulate highly abundant key component proteins of the ETC. Importantly, this activity is required for tumor formation, but is dispensable in normal tissues which makes this activity of STAT3 an attractive therapeutic target that will diminish tumor growth whilst preserving the critical nuclear functions of STAT3.
Citation Format: Chamira D. Fernando, Daniel J. Garama, Daniel J. Gough. STAT3 control of mitochondrial RNA stability and translation is a vulnerability in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 790.
Abstract 795: GDF15, the putative mitokine factor, promotes tumor progression in thyroid cancer via STAT3 regulation
Authors: Kang Yea Eun , Chang Jae Won , Liu Lihua , Lee Kyoungmin , Lim Mi Ae , Jung Seung-Nam , Oh Chan , Won Ho-Ryun , Shong Minho , Koo Bon Seok 
Published: August 2019

Abstract
Purpose: As mitochondrial dysfunction is an integral component during the initial stages of tumorigenesis, mechanistic insight on the interaction between these two pathways may lead to novel therapeutic approaches. The aim of this study is to investigate the role of GDF15, the putative mitokine factor in thyroid tumorigenesis.
Methods: Expression levels of GDF15 was investigated using The Cancer Genome Atlas database. The role of GDF15 in tumor aggressiveness was investigated by analyzing the effects of knock-down of GDF15 on proliferation, migration, and invasion of thyroid cancer cells. Serum levels of GDF15 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression of GDF15 by IHC was investigated in PTC samples. To investigate the exact mechanism of GDF15 in thyroid cancer, both IPA analysis and GSEA analysis were performed using TCGA database and RNA seq data from Chungnam national university hospital.
Results: TCGA data revealed the higher expression of GDF15 in tumor samples compared to in paired non-tumor samples. Thyroid cancer cells with knock-down of GDF15 revealed the decrease of proliferation, migration, and invasion compared to control cells via regulation of STAT3. Higher serum levels of GDF15 were found in patients with thyroid cancer than in control participants, and were significantly associated with tumor stage, lymphovascular invasion, and recurrence. In addition, patients with high GDF15 expression by IHC revealed the aggressive phenotype compared to patients with low GDF15 expression.
Conclusions: GDF15 is a new biomarker for predicting tumor progression, and therapies targeting GDF15 may be effective for treating thyroid cancer.
Citation Format: Yea Eun Kang, Jae Won Chang, Lihua Liu, Kyoungmin Lee, Mi Ae Lim, Seung-Nam Jung, Chan Oh, Ho-Ryun Won, Minho Shong, Bon Seok Koo. GDF15, the putative mitokine factor, promotes tumor progression in thyroid cancer via STAT3 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 795.
Abstract 798: Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin
Authors: Wu Meng-Ju , Kim Mi Ran , Gampala Silpa , Zhang Yingsheng , Wang Yueyang , Yang Jer-Yen , Chang Chun-Ju 
Published: August 2019

Abstract
Mitochondria are dynamic organelles that have been linked to stem cell homeostasis. However, the mechanism involved in mitochondrial regulation of stem cell fate determination remain elusive. Here we discover that epithelial-mesenchymal transition (EMT), a key process in cancer progression, induces mitochondrial fusion through regulation of miR200c-PGC1a-MFN1 pathway. EMT-activated MFN1 forms a complex with PKCz and is required for PKCz-mediated NUMB phosphorylation and dissociation from the cortical membrane to direct asymmetric division of mammary stem cells, where fused mitochondria are tethered by MFN1-PKCz to the cortical membrane and asymmetrically segregated to the stem cell-like progeny with enhanced glutathione synthesis and reactive oxygen species scavenging capacities, allowing sustaining of a self-renewing stem cell pool. Suppression of MFN1 expression leads to equal distribution of the fragmented mitochondria in both progenies that undergo symmetric luminal cell differentiation. Together, this study elucidates a novel role of mitofusin in stem cell fate determination to mediate EMT-associated stemness and provides therapeutic implications for targeting EMT-induced tumor stem cell populations.
Citation Format: Meng-Ju Wu, Mi Ran Kim, Silpa Gampala, Yingsheng Zhang, Yueyang Wang, Jer-Yen Yang, Chun-Ju Chang. Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 798.
Abstract 806: Mitochondrial oncobioenergetic Index (MOBI) mediated by oxidative stress as a marker for progression from indolent to aggressive cancer
Authors: Vayalil Praveen Kumar 
Published: August 2019

Abstract
Cellular Metabolic profile is governed by the way which the mitochondria functions in a cell. Any change in mitochondrial function would alter the cellular metabolic profile. During the evolution of tumor from onset to aggressive cancer, the metabolic needs also differs as alterations in oncogenes, tumor suppressor genes, and changes in the epigenetics and microenvironment occurs at each stage of the tumorigenesis process. Therefore, we hypothesized that mitochondrial function will be stably and dynamically altered at each stage of the tumor development. Moreover, the ability mitochondria to withstand stress will also be different. We recently defined MOBI, which is a mathematical representation of oncobioenergetic profile of a cancer cell. MOBI increases significantly upon transformation into localized premalignant form and rapidly falls below the normal as they become aggressive. We also show that the MOBI of cancer cells at various stages of tumorigenesis after oxidative stress depend on their initial MOBI. Aggressive cancer cells completely lost their MOBI upon stress, even though some of the cancer cells had high initial reserve capacity. However, cells from pre-malignant cells had significantly higher MOBI than the normal epithelial cells. This study thus reveals that MOBI could be a potential biomarker to distinguish aggressive cancer from that of indolent disease and screening of compounds that specifically target the bioenergetics of cancer cells.
Citation Format: Praveen Kumar Vayalil. Mitochondrial oncobioenergetic Index (MOBI) mediated by oxidative stress as a marker for progression from indolent to aggressive cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 806.
Abstract 808: Aggregation alters the metabolism of serous ovarian cancer cells
Authors: Edwards Stephanie , Pyne Emily , Lui Lu , Guinan Jack , Frisard Madlyn , Schmelz Eva 
Published: August 2019

Abstract
Ovarian cancer is typically diagnosed at late stages with a poor prognosis due to high recurrence. Exfoliation from the primary tumor results in aggregation of ovarian cancer cells into spheroids in the peritoneal cavity, which may increase survival of cancer and metastasis to other tissues. We have previously reported metabolic changes in adherent ovarian cancer cells to rely more heavily on glycolysis. However, metabolic changes in cancer cell aggregates are poorly understood. In this study, we investigated differences in spheroid metabolism in normoxic and hypoxic conditions as compared to adherent cells. We examined late-stage and tumor-initiating murine ovarian cancer monolayers and spheroids. Using a Seahorse XF extracellular flux analyzer, we investigated changes in metabolism over time in the presence of mitochondrial inhibitors (oligomycin and rotenone) or uncouplers (FCCP). Data show a reduction in basal respiration, maximal oxygen consumption rate, and spare respiratory capacity of spheroids compared to adherent monolayers. This suggests a reduction in energetic demand and metabolic flexibility in spheroids, which may confer increased survival capabilities. The identification of these metabolic changes that may increase survival and metastasis of spheroids provide targets for treatment to control the ability of spheroids to survive in the peritoneal cavity.
Citation Format: Stephanie Edwards, Emily Pyne, Lu Lui, Jack Guinan, Madlyn Frisard, Eva Schmelz. Aggregation alters the metabolism of serous ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 808.
Abstract 809: Response of metabolic phenotype to chemotherapy agents in a simulated tumor microenvironment
Authors: Hoffman David L. , Rumble Julie M. 
Published: August 2019

Abstract
Chemotherapeutic agents inhibiting fatty acid oxidation can sensitize cells to the tumor microenvironment.
Chemotherapeutic agents (CA), while standard-of-care for treating numerous types of cancer are, by nature, poisonous. Studies have shown that treatment with certain CA, such as Irinotecan, leads to chemotherapy associated steatohepatitis (CASH) resulting from the inhibition of mitochondrial fatty acid oxidation (FAO). While inhibition of FAO may have harmful effects on the liver, it may have a different effect in the tumor microenvironment (TME). Within the TME exists a unique metabolic environment, consisting of low [O2], low pH and high concentrations of fatty acids. Occupying the TME are immunosuppressive myeloid derived suppressor cells (MDSCs), which aid in tumor growth by suppressing T cells, which would normally attack the tumor. It is thought that the MDSCs localized to the TME undergo an alteration in metabolic phenotype, allowing them to utilize the high concentrations of fatty acids found in the TME as their primary carbon source, becoming reliant on FAO. It is therefore hypothesized that normoxic MDSCs will alter their metabolic phenotype in response to a simulated TME to favor FAO. This altered metabolic phenotype will sensitize MDSCs to inhibition of FAO by SN-38, the active metabolite of Irinotecan. The response of metabolic phenotype to hypoxic conditions will also be examine in HCT116 colorectal carcinoma cells.
Note: This abstract was not presented at the meeting.
Citation Format: David L. Hoffman, Julie M. Rumble. Response of metabolic phenotype to chemotherapy agents in a simulated tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 809.
Abstract 815: Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer
Authors: Hsu Ping-Ching , Kadlubar Susan , Siegel Eric , Rogers Lora J. , Todorova Valentina K. , Su Joseph , Makhoul Issam 
Published: August 2019

Abstract
Neoadjuvant chemotherapy is given before surgery to patients with primarily unresectable, advanced-stage cancers to render the tumor resectable, and to facilitate breast conservation. Previously, we have reported a prospective phase II trial for women with stage IIA-B/IIIA-B-C breast cancer with improved pathologic complete response (pCR) when using bevacizumab in the neoadjuvant setting. Chemotherapy agents are given orally or intravenously during multiple cycles of systemic treatments. However, the effect of the treatment can only be evaluated upon the completion of therapy. Here, we aim to identify epigenetic signatures in blood for patients at baseline as non-invasive markers to predict their pCR from the treatment, and to determine if treatment-related changes in epigenetic profiles reflect responsiveness to therapy. We performed genome-wide DNA methylation profiling using blood-derived DNA, and found that pre-treatment methylation status of BRD9 was predictive of responsiveness to therapy. Post-treatment global methylation differences were also observed between responders and non-responders. Most differentially methylated CpGs were located in promoter CpG island regions for responders, but in the open sea region for non-responders. DNMT3B was hypomethylated while most of the other genes were hypermethylated after 4 cycles of treatment. Hypomethylation of DNMT3B could potentially lead to the increased methylation of oncogenes and genes responsible for cell growth and proliferation, facilitating responsiveness to the therapy. These results support the development of BRD9 as a biomarker for treatment selection before neoadjuvant therapy with bevacizumab, and indicate DNMT3B as a potential target to improve clinical response.
Citation Format: Ping-Ching Hsu, Susan Kadlubar, Eric Siegel, Lora J. Rogers, Valentina K. Todorova, Joseph Su, Issam Makhoul. Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 815.