bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 716: Chakasaponin I from tea (Camellia sinensis) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant ovarian cancer cells
Authors: Chen Yi C.
Published: August 2019

Ovarian cancer has the highest rate of death among gynecological malignancy and ranks fifth in cancer deaths among women. Adverse side effects and acquired resistance to conventional chemotherapy based on platinum drive the exploration of other anticancer therapies,thus natural products have drawn greater attention for cancer treatment in recent years. Tea (Camellia sinensis) flower being an abundant agricultural by-product in China and Japan, has been studied for its bio-functional effects. A recent research showed that tea flower saponins (TFS) could induce anti-proliferative effect and cell cycle arrest in human ovarian cancer cells. In the present study, Chakasaponin I, one of the major constituents in TFS, whose main structure is oleanane-type triterpene, showed strong growth inhibitory effects on cisplatin-resistant OVCAR-3 cells at 3 μM by MTS assay. Such inhibitory effects might result from the induction of apoptosis. Western blot assay, Hoechst 33342 staining assay, and flow cytometry analysis were used to examine the effects of Chakasaponin I on apoptosis. The results showed that Chakasaponin I treatment dose-dependently activated the pro-apoptotic proteins (Bad and Bax) and therefore induced apoptosis might by the intrinsic apoptotic pathway.

Citation Format: Yi C. Chen. Chakasaponin I from tea (Camellia sinensis) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant 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 716.
Abstract 719: Combination of atypical protein kinase-C inhibitor and 5-fluorouracil retards the proliferation of colorectal cancer cells
Authors: Islam S M Anisul , Dey Avijit , Acevedo-Duncan Mildred
Published: August 2019

Colorectal cancer (CRC) is the third most common malignancy and considered as the fourth most common cause of cancer-related death worldwide. Although the number of CRC survivors with stage II and III are increasing, more than 50% of patients are diagnosed with stage III or beyond where the distant disease progression has already occurred. Surgical removal of cancerous tissue coupled with chemotherapeutic intervention is the main treatment of metastatic CRC and only hope of enhanced survival. The treatment of metastatic CRC considered palliative for many years aiming for an improved life, with little hope of a cure, highlighting the need for developing novel targeted therapy for CRC. Dysregulation of kinases has been shown to be pivotal of the various pathological process including cancer. Human protein kinases constitute a complicated system with intricate internal and external interaction which stimulates various cellular processes such as cell growth, metabolism, survival, and apoptosis. In this study, a combination of atypical protein kinase c (aPKC) inhibitor (ICA-I, PKC-ι inhibitor or ζ-Stat, PKC-ζ inhibitor) and 5-FU was used to examine the effect of aPKC and thymidylate synthase on CRC cells viability. The cell lines tested were LoVo and RKO CRC cells. Our findings showed that the combination of aPKC inhibitor and 5-FU significantly reduced the viability and induce apoptosis of CRC cells. These data suggest that the simultaneous knockdown of upstream aPKC protein and downstream DNA replication would be a useful approach to combat CRC and to improve overall patients’ survival rate. These results indicate the possibility of utilizing aPKC as the potential therapeutic targets in addition to blocking DNA synthesis in metastatic CRC.

Citation Format: S M Anisul Islam, Avijit Dey, Mildred Acevedo-Duncan. Combination of atypical protein kinase-C inhibitor and 5-fluorouracil retards the proliferation of colorectal 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 719.
Abstract 728: Genomic alterations in lung adenocarcinoma precursor lesions
Authors: Asiedu Michael K. , Reed Nanette R. , Aubry Marie Christine , Roden Anja C. , Wigle Dennis A.
Published: August 2019

Background: Adenocarcinoma of the lung is the most common type of non-small cell lung cancer and is the subtype found in approximately 50% of all lung cancer cases. Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are thought to be precursor lesions of invasive disease. It has been hypothesized that there is a step-wise progression to lung adenocarcinoma, but little is known about genomic alterations in these precursor lesions.

Methods: Genomic analysis including whole genome and exome sequencing, and SNP array analysis were performed on 9 AIS and 18 MIA pathologically confirmed samples to identify single nucleotide variants (SNVs), structural variations and copy number variations. Mutation significance and signature analysis were determined by MutSig and NMF analyses. Altered pathways were determined by Ingenuity variant effect pathway analysis.

Results: The tumor mutation burden (TMB) for AIS and MIA ranged from 0.8 to 23.1 mut/Mb with a median of 3.0mut/Mb and a mean of 5.1mut/Mb. Highly mutated genes identified in AIS and MIA were RPL10, NBPF1, KRAS, GPR52, CAMK2A, ATOX1, STK11, TP53, MET and EGFR. Genes with recurrent mutations included SPTA1, USH2A, CACNA1E, EGFR, KRAS, MUC16, MUC17, OTOG, RYR2, COL20A1, CSMD3, RFX6 and XIRP2, which implicated pathways involving the EGFR-KRAS-TP53-MAPK axis. Somatic mutations were characterized by a C>T, T>C transitions and C>A transversion signature. There were comparable structural variations in the AIS cases compared to MIA.

Conclusion: In contrast to hypothesized models of tumor progression, AIS and MIA can harbor significant genomic alterations and tumor mutation burden, which suggests an intriguing concept of immunotherapeutic options for either treatment or chemoprevention. Deregulation of EGFR-KRAS-TP53-MAPK pathway indicates a role in early events of carcinogenesis.

Citation Format: Michael K. Asiedu, Nanette R. Reed, Marie Christine Aubry, Anja C. Roden, Dennis A. Wigle. Genomic alterations in lung adenocarcinoma precursor lesions [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 728.
Abstract 734: Large-scale radiogenomic profiling of patient derived xenografts (PDX)
Authors: Gopal Priyanka , Bera Titas , Peacock Craig , Abazeed Mohamed
Published: August 2019

The determinants of clinical failure after radiotherapy remains poorly understood. Although cancer derived cells grown in vitro have served as a valuable resource to identify tumor cell intrinsic determinants of radiation sensitivity, their propensity to undergo genetic selection due to non-native culture conditions reduces intratumoral heterogeneity and alters transcriptomic fidelity. We show that patient-derived xenografts (PDX) models recapitulate the genetic and transcriptomic features of the primary tumors from which they are derived. We extend this characterization to an extensive collection of PDXs derived from multiple cancer types. We propose our “10,000 mice” PDX effort, which seeks to profile up to 500 PDX across 20 cancer types with multiple single fraction doses of radiation (2, 4, 6, 8, 10 Gy). We establish the feasibility of our approach using a 3x1x1 experimental design (3 mice per PDX per dose of radiation). Initial treatment responses following single doses radiation revealed that tumors exhibit significant variation in their response to radiation. Responses in PDX correlated with clinical outcomes, mainly in patients treated with radiation or chemoradiation alone. We compare pre- and post-irradiation PDX and deoncstruct the phylogenetic architecture of tumors before and after treatment selection. We show that in a substantial proportion of the tumors profiled to date, treatment resistance is regulated by subclonal outgrowths. Taken together, our results demonstrate the feasibility of high-content profiling of PDX to identify determinants of radiation sensitivity.

Note: This abstract was not presented at the meeting.

Citation Format: Priyanka Gopal, Titas Bera, Craig Peacock, Mohamed Abazeed. Large-scale radiogenomic profiling of patient derived xenografts (PDX) [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 734.
Abstract 756: Whole exome sequencing identifies frequent mutations of PTPRB and KDR in secondary angiosarcoma
Authors: Gayden Tenzin , Dickson Brendan C. , Nikbakht Hamid , Fiset Pierre-Olivier , Jay Nicolas De , Nadaf Javad , Burk David L. , Berghuis Albert , Gladdy Rebecca , Wunder Jay , Turcotte Robert , Majewski Jacek , Jabado Nada
Published: August 2019

Angiosarcoma is an uncommon malignant vascular tumor that can occur anywhere on the body, with a predilection for the skin or soft tissues of the scalp and face.

By whole exome sequencing, we identified recurrent somatic mutations in PTPRB, which encodes an endothelial-specific phosphatase that negatively regulates angiogenesis, in three secondary angiosarcoma tumors (3/10). In addition, four tumors harbored missense variants in the KDR gene, including three germline substitutions. Neither the PTPRB nor the KDR alterations were found in the 5 primary tumors studied. Copy number analysis derived from the exome and methylation data revealed frequent MYC amplification in the majority of secondary angiosarcoma tumors (9/10).

Altogether, our data provide a comprehensive overview of genetic and epigenetic landscapes of angiosarcoma, and demonstrate that aberrant angiogenesis associated with PTPRB and KDR mutations may contribute to the pathogenesis of angiosarcoma.

Citation Format: Tenzin Gayden, Brendan C. Dickson, Hamid Nikbakht, Pierre-Olivier Fiset, Nicolas De Jay, Javad Nadaf, David L. Burk, Albert Berghuis, Rebecca Gladdy, Jay Wunder, Robert Turcotte, Jacek Majewski, Nada Jabado. Whole exome sequencing identifies frequent mutations of PTPRB and KDR in secondary angiosarcoma [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 756.
Abstract 757: MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway
Authors: Akagi Ichiro , Ishibashi Osamu , Ogawa Yota , Takizawa Toshihiro
Published: August 2019

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is frequently activated in various human cancers and plays essential roles in their development and progression. Accumulating evidence suggests thatdysregulated expression of microRNAs (miRNAs) is closely associated with cancer progression and metastasis. Here, we focused on miRNAs that could regulate genes related to the PI3K/AKT pathway inesophageal squamous cell carcinoma (ESCC).To identify upregulated miRNAs and their possible target genes in ESCC, we performed microarraybased integrative analyses of miRNA and mRNA expression levels in three human ESCC cell lines and a normal esophageal epithelial cell line. The miRNA microarray analysis revealed that miR-31-5p, miR-141-3p, miR-200b-3p, miR-200c-3p, and miR-205-5p were expressed at higher levels in the ESCC cell linesthan the normal esophageal epithelial cell line. Bioinformatical analyses of mRNA microarray data identified several AKT/PI3K pathway-related genes as candidate targets of these miRNAs, which include tumor suppressors such as DNA-damage-inducible transcript 4 and pleckstrin homology domain leucine-rich repeat protein phosphatase-2 (PHLPP2). To validate the targets of relevant miRNAs experimentally, synthetic mimics of the miRNAs were transfected into the esophageal epithelial cell line. Here, we report that miR-141-3p suppress the expression of PHLPP2, a negative regulators of the AKT/PI3K pathway, as a target in ESCC.

Note: This abstract was not presented at the meeting.

Citation Format: Ichiro Akagi, Osamu Ishibashi, Yota Ogawa, Toshihiro Takizawa. MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT 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 757.
Abstract 759: microRNA 26a-5p inhibited stemness and enhanced the chemosensitivity of non-small cell lung cancer
Authors: Son Jiwoong , Kwon Sun Jung , Jeong In Beom , Kim Ji Hye
Published: August 2019

Only a subpopulation of cells which have the ability to regulate self-renewal and differentiation of cancer cells, are able to tumorigenic capacity. This subpopulation of cells is called cancer stem cells (CSC). Cancer stem cells are also identified in lung cancer and exhibits resistance to chemotherapy, radiotherapy and targeted therapy. Therefore, the technology to control CSCs is a good strategy to overcome resistance to cancer therapy. Epithelial-mesenchymal transition (EMT) has been linked with the generation of cancer stem cells (CSCs). Recent evidence proposes that EMT-related transcriptomic alterations correlate with the acquisition of CSC phenotype. In previous study, we investigated the miRNA profiles of mesenchymal-like lung cancer cell lines to evaluate the relationship beween EMT and miRNA in non-small cell lung cancer (NSCLC). miR-26a-5p is down-regulated in mesenchymal like lung cancer cell lines. These findings suggested miR-26a-5p may be involved in cancer stemness of lung cancer cells. To test that miR-26a-5p has a role in stemness of lung cancer, we performed colony formation assay, sphere formation assay and fluorescence activated cell sorting. RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. To verify that miR-26a-5p regulates POLR3G, we performed qRT-PCR, western blot and luciferase assays. Cell proliferation assay was performed to evaluate miR-26a-5p’s role of chemosensitizer. The overexpression of miR-26a-5p induced a marked reduction of the colony formation and sphere formation in non-small lung cancer cell lines. Overexpression of miR-26a-5p lead to reduction of CD133+ cells. Co-treatment with miR-26-5p and Paclitaxel treatment showed a significant reduction of growth. miR-26a-5p regulated the expression of POLR3G at the mRNA and protein levels. These data demonstrate for the first time that miR-26a-5p suppresses lung cancer stemness by repressing POLR3G expression. This provides new insight into a potential approach for the treatment of lung cancer by regulating cancer stemness.

Citation Format: Jiwoong Son, Sun Jung Kwon, In Beom Jeong, Ji Hye Kim. microRNA 26a-5p inhibited stemness and enhanced the chemosensitivity of non-small cell lung 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 759.
Abstract 763: The regulation of miR-125b1-peroxiredoxin like 2A anti-oxidative activity in oral squamous cell carcinoma
Authors: Chen Yi-Fen , Wei Yun-Yen , Yang Cheng-Chieh , Chang Kuo-Wei , Lin Shu-Chun
Published: August 2019

Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common cancer worldwide. MicroRNAs are small non-coding RNAs that are involved in the modulation of biological/pathological properties. Peroxiredoxin like 2A (PRXL2A) has been reported to be an antioxidant protein that protects cells from oxidative stress. Our previous study identified an association between PRXL2A up-regulation in OSCC and a worse patient prognosis. The miR-125 family of genes drive pluripotent regulation across a wide variety of cancers. In this study, we identify the oncogene eligibility of PRXL2A and clarify miR-125b as its upstream regulator. Down-regulation of miR-125b can be observed in OSCC tumors. Lower miR-125b expression in tumors results in a worse patient prognosis at the relatively early stage. Reporter assays were able to validate that PRXL2A is a direct target of miR-125b. Exogenous miR-125b expression in OSCC cells results in increased oxidative stress and drug sensitivity, and suppressor activity that is paralleled by the knockout of PRXL2A gene. The suppressor activity of miR-125b is able to be rescued by PRXL2A, which suggests the existence of a miR-125b-PRXL2A regulatory axis that is part of OSCC pathogenesis. Nuclear factor erythroid-2-related factor was found to be a downstream effector of the miR-125b-PRXL2A cascade. As a whole, this study has pinpointed novel clues demonstrating that down-regulation of miR-125b suppressor underlies up-regulation of PRXL2A in OSCC, and this then protects the affected tumor cells from oxidative stress resulting in a worse prognosis.

Citation Format: Yi-Fen Chen, Yun-Yen Wei, Cheng-Chieh Yang, Kuo-Wei Chang, Shu-Chun Lin. The regulation of miR-125b1-peroxiredoxin like 2A anti-oxidative activity in oral squamous cell carcinoma [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 763.
Abstract 764: MicroRNA-1205 contributes to the risk of castration-resistant prostate cancer
Authors: Wen Wen , Wang Yicun , Zhang Yue , Cui Xuelian , Liu Xiaoguang M. , Liu Runhua
Published: August 2019

Although death rates for prostate cancer are down about 50% as a result of improvements in early detection and treatment, it is still the second leading cause of death (26,120 cases) for American men. However, the genetic mechanism underlying the development and progression of prostate cancer remains poorly understood. It is therefore important to identify the genetic risk factors for prostate cancer. Genome-wide association studies (GWAS) showed evidence for an association of prostate cancer risk with independent genetic variants on chromosome 8q24, conferring prostate cancer susceptibility at this locus. Nevertheless, at the locus with these genetic variants, no specific gene has been identified as responsible for the risk of prostate cancer. At 8q24.21, there is a long-range interaction of these genetic variants with c-MYC or long non-coding RNAs (lncRNAs) in a tissue-specific manner, including prostate, suggesting master genetic factors at 8q24.21 that contribute to this genetic risk. The chromosome 8q24.21 locus, which contains the proto-oncogene c-MYC, long non-coding RNA PVT1, and microRNAs (miRs), is the most commonly amplified region in human prostate cancer. Here, the copy numbers and expressions of miRs-1204~1208 were investigated using quantitative PCR for prostate cancer cell lines and primary tumors. The data revealed that copy numbers and expression of miR-1205 were increased in both castration-resistant prostate cancer cell lines and primary tumors. In castration-resistant prostate cancer specimens, the copy number at the miR-1205 locus correlated with expression of miR-1205. Furthermore, functional analysis with a miR-1205 mimic, a miR-1205 inhibitor, and CRISPR/Cas9 knockout revealed that, in human prostate cancer cells, miR-1205 promoted cell proliferation and cell cycle progression but not apoptosis. In these cells, miR-1205 downregulated expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) gene and targeted a site in its 3’-untranslated region to downregulate its transcriptional activity. Thus, by targeting EGLN3, miR-1205 has an oncogenic role and may contribute to the genetic risk of castration-resistant prostate cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Wen Wen, Yicun Wang, Yue Zhang, Xuelian Cui, Xiaoguang M. Liu, Runhua Liu. MicroRNA-1205 contributes to the risk of castration-resistant 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 764.
Abstract 766: Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung cancer
Authors: Koyama Nobuyuki , Ishikawa Yuichi , Iwai Yuki , Aoshiba Kazutetsu , Nakamura Hiroyuki , Hagiwara Koichi
Published: August 2019

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of polycomb repressive complexes, promotes tumor progression and metastasis. Expression levels of EZH2 are associated with clinical outcomes in a variety of tumors. High expression levels of EZH2 have been reported in cell lines and tissues of small cell lung cancer (SCLC), which is characterized by its invasiveness and metastatic potentials. Epithelial-mesenchymal transition (EMT) is well recognized to contribute to aggressiveness of SCLC, and microRNA (miRNA) is known to be associated with both EMT and the biological characteristics of SCLC. The aim of this study was to identify a novel miRNA defining EZH2-assciated EMT and tumor aggressiveness in SCLC. Immunohistochemistry and quantitative PCR showed that EZH2 expressions levels were decreased in three types of SCLC cell lines and tumor tissues from 34 patients with SCLC. Small interfering RNA (siRNA) against EZH2 suppressed its expression and EMT in SBC3 and SBC5 cell lines, both of which had high EZH2 expression levels as SCLC cell lines. Comprehensive miRNA expression analysis was used to compare changes of miRNA expression between EZH2 siRNA-transfected cells and mock-transfected cells. As a result, miR-4448 expression was significantly decreased in

SBC3 and SBC5 cells transfected with EZH2 siRNA. Cell growth assay and cell invasion assay revealed that overexpression of miR-4448 inhibited cellular proliferation and invasion potential. Furthermore, we confirmed that overexpression of miR-4448 abrogated EMT and decreased EZH2 expression. In conclusion, EZH2 and miR-4448 mutually suppressed these expressions and functions, which was associated with tumor progression via EMT in SCLC. The findings of this study suggest that miR-4448 may play a crucial role in the biological characteristics of SCLC.

Citation Format: Nobuyuki Koyama, Yuichi Ishikawa, Yuki Iwai, Kazutetsu Aoshiba, Hiroyuki Nakamura, Koichi Hagiwara. Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung 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 766.
Abstract 769: Mechanistic role of miR-29 in pancreatic ductal adenocarcinoma progression
Authors: Dey Shatovisha , Kwon Jason J. , Liu Sheng , Factoria Tricia , Hodge Gabriel A. , Wan Jun , Kota Janaiah
Published: August 2019

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a 5-year survival rate of 8% (Kota et al., 2017, Cancer Lett.). Lack of curative treatment for PDAC warrants better understanding of its mechanisms. Our previous work demonstrated that miR-29 is commonly downregulated in PDAC, while its restoration exhibits tumor-suppressive effects (Kwon et al., 2016, Oncotarget; Kwon et al., 2015, Sci Rep.). To understand these mechanisms, first we performed siRNA mediated knockdown of several miR-29 promoter binding transcription factors, including MYC, which play a role in PDAC. Our results indicate MYC represses miR-29 expression, and MYC nuclear localization negatively correlates with miR-29 in pancreatic cancer cells (PCCs). Next, to identify global miR-29 targets associated with PDAC, we conducted RNAseq on two miR-29 overexpressing PCC lines. This identified 41 overlapping miR-29 targets downregulated in both datasets. Gene ontology and survival correlation analyses identified seven most prominent targets (LOXL2, MYBL2, TRIB2, HGK, NRAS, CD276 and CLDN1). Ectopic expression of miR-29 significantly altered protein levels of these genes, confirming a translational suppression mechanism mediated by miR-29. RNAi mediated silencing of these targets significantly reduced the migratory ability of the PCCs. Our top target LOXL2 is involved in regulation of EMT/migration and extracellular matrix (ECM) remodeling. Luciferase reporter assay verified LOXL2 as a direct miR-29 target in PDAC. Immunohistochemical analyses in clinical specimens from PDAC patients and KPC mice pancreatic tissues showed higher LOXL2 expression in regions of pancreatic intraepithelial neoplasia (PanIN) lesions as compared to non-cancerous areas. This increased LOXL2 level was accompanied by concomitant reduction in miR-29 expression. Thus, our current study provides insight into new miR-29 mediated regulatory pathways in PDAC and reveals the association of miR-29-LOXL2 axis in the disease progression. Together, our data suggest miR-29 to play a critical role in mechanisms of PDAC progression and could serve as a potential therapeutic target for the disease.

Citation Format: Shatovisha Dey, Jason J. Kwon, Sheng Liu, Tricia Factoria, Gabriel A. Hodge, Jun Wan, Janaiah Kota. Mechanistic role of miR-29 in pancreatic ductal adenocarcinoma progression [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 769.
Abstract 771: CMTM6-mediated maintenance of sarcoma malignancy
Authors: Nishiyama Yuko , Tsuchiya Naoto
Published: August 2019

Sarcomas are malignant bone and soft tissue tumors that have highly aggressive and metastatic features. To reveal molecular networks associated with sarcomas, comprehensive expression profiles were generated using clinical samples. We identified miR-451a, showing different levels according to the prognosis of Ewing’s sarcoma (EWS) patients. High expression of miR-451a was also associated with good prognoses of patients with other types of sarcomas, suggesting repression of malignant properties across histological subtypes. Although miR-451a did not affect cell proliferation, it strongly repressed migration of EWS cells. Using gene expression analysis, we identified that CMTM6, encoding a chemokine-like membrane protein, was a target of miR-451a. Depletion of CMTM6 suppressed cell migration and induced changes in the expression of genes encoding plasma membrane and secretory proteins. Interestingly, we found high levels of CMTM6 mRNA under low-glucose culture conditions. Unexpectedly, under the same conditions, high extracellular miR-451a levels were observed; this suggested that the glucose level might be a modulator of the miR-451a-CMTM6 axis. Our data suggest that the malignant properties of sarcoma are influenced by the nutrient status of the tumor microenvironment.

Citation Format: Yuko Nishiyama, Naoto Tsuchiya. CMTM6-mediated maintenance of sarcoma malignancy [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 771.
Abstract 775: MicroRNA-1205 regulation of FRYL in neuroendocrine prostate cancer
Authors: Naidoo Michelle K. , Ogunwobi Olorunseun
Published: August 2019

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 <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 <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

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

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

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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

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

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

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

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

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.