bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1764: Targeting nucleotide exchange to inhibit Gq/11 driver mutations in uveal melanoma
Authors: Onken Michael D. , Makepeace Carol M. , Kaltenbronn Kevin M. , Kanai Stanley M. , Todd Tyson D. , Wang Shiqi , Broekelmann Thomas J. , Rao Prabakar Kumar , Cooper John A. , Blumer Kendall J. 
Published: August 2019

Abstract
Constitutively activating mutations in the G-protein alpha subunits GNAQ(Gαq) and GNA11(Gα11) act as oncogenic drivers in over 90% of uveal (eye) melanoma (UM) tumors. We show that constitutively active Gαq and Gα11 can be targeted in UM cells by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP guanine nucleotide exchange allosterically to trap constitutively active Gαq/11 in inactive GDP-bound Gαβγ heterotrimers. FR inhibits second messenger signaling, arrests proliferation and reinstates melanocytic differentiation in UM cells driven by constitutively active Gαq or Gα11. At higher doses, FR also induces apoptosis. The re-differentiation and anti-proliferative effects of FR are not seen in UM cells that lack mutations in Gαq or Gα11. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, and this re-differentiation can be blocked with an EZH2 inhibitor. The effector system regulating PRC2 downstream of constitutively active Gαq/11 in UM is currently under investigation. Preliminary data from human primary tumor samples suggest that targeting constitutively active Gαq/11 with FR could provide an important therapeutic approach for UM.
Citation Format: Michael D. Onken, Carol M. Makepeace, Kevin M. Kaltenbronn, Stanley M. Kanai, Tyson D. Todd, Shiqi Wang, Thomas J. Broekelmann, Prabakar Kumar Rao, John A. Cooper, Kendall J. Blumer. Targeting nucleotide exchange to inhibit Gq/11 driver mutations in uveal melanoma [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 1764.
Abstract 177: Sulfiredoxin promotes the invasion of human colorectal cancer cells through the activation of fascin
Authors: Jiang Hong , Ying Qi , Evers B. Mark , Wei Qiou 
Published: August 2019

Abstract
Sulfiredoxin (Srx) is multifunction enzyme with a primary antioxidant role of reducing the overoxidized inactive form of peroxiredoxins (Prxs). In contrast to the well-studied biochemical function, the biological significance of Srx in human diseases including cancer has not been well studied. Our previous studies show that it plays an important role in tumorigenesis and malignant progression of human skin, lung and colorectal cancers. Fascin homologue 1 (FSCN1) is an actin-binding protein that is critical for cancer cell invasion and metastasis. The purpose of this study is to understand the molecular mechanism of Srx on the invasion and metastasis of human colorectal cancer cells through the regulation of FSCN1. The effects of Srx on the migration and invasion of human colon cancer HCT116 cells were evaluated by wound healing and matrigel invasion assay, respectively. Actin stress fiber was visualized by F-actin fluorescence staining. Western blotting and reverse transcription & real-time PCR were used to examine the protein and RNA levels of FSCN1 in HCT116 cells. The effect of Srx on FSCN1 promoter and 3’ UTR were determined using luciferase reporter construct. We demonstrated that (1) knockdown of Srx suppressed HCT116 colony formation and cell invasion in the matrigel invasion assay; (2) knockdown of Srx inhibited FSCN1 expression in HCT116 cells at both RNA and protein level; (3) the inhibition is the result of decreased FSCN1 mRNA stability; (5) Srx stabilizes FSCN1 mRNA 3’ UTR mediated reporter expression; (4) knockdown of Srx reduced actin stress-fiber formation; (5) Srx and Prx4 synchronically regulates FASN1 expression. Therefore, we concluded that Srx promotes the invasion and metastasis of human colon cancer cells through the upregulation of FSCN1.
Citation Format: Hong Jiang, Qi Ying, B. Mark Evers, Qiou Wei. Sulfiredoxin promotes the invasion of human colorectal cancer cells through the activation of fascin [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 177.
Abstract 1770: RSK2 is required for TRAF6 phosphorylation-mediated colon inflammation
Authors: Yao Ke , Lee Sung-Young , Peng Cong , Lim Do Young , Yamamoto Hiroyuki , Ryu Joohyun , Lim Tae-Gyu , Chen Hanyong , Ma Wei-Ya , Bode Ann M. , Dong Zigang 
Published: August 2019

Abstract
Inflammation is a complex biological host reaction to tissue damage, infection and trauma. Extensive study of the inflammatory response has led to the identification of several protein kinases that are essential for signaling and could be potential therapeutic targets. The RSK family of kinases has multiple cellular functions. In our study, we found that RSK2 is a mediator for inflammation signaling and interacts with TRAF6. In vitro kinase assay results indicated that RSK2 strongly phosphorylates TRAF6 at serines 46, 47 and 48. Ectopic over-expression of TRAF6 or knocking down RSK2 expression confirmed that RSK2 is a positive regulator of TRAF6 K63 ubiquitination. TRAF6 is also required for RSK2 ubiquitination. TRAF6 bridges the TNF receptor superfamily and intracellular signaling for the induction of pro-inflammatory cytokines. We developed a colon inflammation model using RSK2 wild type (WT) and knockout (KO) mice. As expected, F4/80 and CD3 infiltration were significantly upregulated in WT mice compared to RSK2 KO mice. Furthermore, inflammation signaling, including Ikkα/β, p38 and JNKs, was dramatically up-regulated in WT mice. Colon tissue immunoprecipitation results further confirmed that TRAF6 K63 ubiquitination was lower in RSK2 KO mice. Overall, these results indicate that phosphorylation of TRAF6 (S46, 47, 48) by RSK2 is required for TRAF6 K63 ubiquitination and inflammation signaling.
Citation Format: Ke Yao, Sung-Young Lee, Cong Peng, Do Young Lim, Hiroyuki Yamamoto, Joohyun Ryu, Tae-Gyu Lim, Hanyong Chen, Wei-Ya Ma, Ann M. Bode, Zigang Dong. RSK2 is required for TRAF6 phosphorylation-mediated colon inflammation [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 1770.
Abstract 1776: An investigation of the effects of the atypical protein kinase C-ζinhibitor ζ-Stat on clear cell carcinoma ovarian cancer proliferation and invasion
Authors: Smalley Tracess , Patel Rekha , Acevedo-Duncan Mildred 
Published: August 2019

Abstract
Ovarian cancer is the most lethal gynecological cancer diagnosis. There is no efficient screening process for ovarian cancers and the average stage of diagnosis is stage III. The most common ovarian cancer diagnosis is epithelial ovarian carcinomas, which constitute for 85-90% of prognosis; of this percent, clear cell ovarian carcinoma (CCOC) represents 5% of incidence. CCOC presents unique pathological features, has poor prognosis and has a high reoccurrence rate after treatment. An overexpression of atypical protein kinase C isoforms (PKC-ζ and PKC-ι/λ) has been observed in various malignant cells lines and are linked to pathways for cellular proliferation and invasion. In this investigation, ovarian cell lines (TOV21G and ES-2) were treated with the atypical PKC-ζ inhibitor ζ-Stat and assayed to determine the effects on proliferation and cellular invasion. These assays included cell counting, WST-1 assay, Western Blot and endpoint polymerase chain reaction. Mouse xenograft experiments were also performed to determine the effects of ζ-Stat on TOV21G xenograft tumor growth in vivo. Our data showed that ζ-Stat decreased the proliferation and cell viability of clear cell carcinoma ovarian cancer cells. In addition, it knocked down the protein expression of PKC-ζ, as well as the protein and mRNA levels of RhoA (Ras homolog Family Member A). Our results also showed that tumor growth in athymic female mice was decreased when treated with ζ-Stat and that mouse body weight was maintained. This suggests that PKC-ζ is a novel target in the carcinogenesis of CCOC and its inhibition by way of ζ-Stat decreased the rate of proliferation, tumor growth and expression of invasive protein pathways.
Citation Format: Tracess Smalley, Rekha Patel, Mildred Acevedo-Duncan. An investigation of the effects of the atypical protein kinase C-ζinhibitor ζ-Stat on clear cell carcinoma ovarian cancer proliferation and invasion [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 1776.
Abstract 1777: Correlation between different C-KIT exon mutation and clinical outcome to Imatinib Mesylate treatment in patients with gastro-intestinal stromal tumors (GIST)
Authors: Bahnnasy Abeer A. , Khorshid Ola , Abdellateif Mona S. , Zakaria Ghada Y. , Allahloubi Nasr M. , Nassar Auhood , Zekri Abdel-Rahman N. 
Published: August 2019

Abstract
Aim: C-KIT exon mutations were assessed in patients with gastrointestinal stromal tumor (GIST) in relation to patients’ characteristics, response to treatment and survival rates.
Methods: C-KIT mutations were assessed in the representative formalin fixed paraffinembedded tissues (FFPETs) of 89 patients with GIST compared to 35 normal control (NC) subjects using the Real Time PCR (Rt-PCR) and immunohistochemistry (IHC).
Results: C-KIT mutations were detected in 61/89 (68.5%) patients, compared to none of the NC subjects (P=&lt;0.001). Most mutations were detected in exon 11 (50.8%), followed by exon 9 (24.5%), exon 13 (19.6%), exon 7 (4.1%), and exon 12 (only 1%). C-KIT protein expression was detected in 69 (77.5%) patients compared to none of the NC subjects (p=&lt;0.001). Significant measure of agreement was detected between C-KIT expression by IHC and and RT-PCR (K=0.774, p=0.0001).
The presence of C-KIT mutations associated significantly with large tumor size (P=0.01), High mitotic rate, lymph nodes metastasis and high tumor risk (p=0.001, for all). Patients with exon 11 mutations 26/31 (83.9%) had a better response to treatment compared to those with exon nine 7 (46.7%) and exon 13 mutation 1/12 (8.3%; P=0.001). Exon 11 mutations associated significantly with better PFS and OS compared to those with exon 9 and 13 mutations (P= 0.001, P= 0.0001; respectively). On univariate analysis, Exon 13 mutations was the most significantly associated with reduced PFS (P=0.0001), whereas advanced disease stage, absence of adequate safety margins and the site of exon mutation associated significantly with reduced OS. (P=0.012, P=0.05 and P=0.005; respectively.
Conclusion: GIST patients with C-KIT exon 11 mutations have a better response to imatinib treatment (predictive value), better OS and lower risk of disease progression than those with exon 9 and 13 mutations. Our specified mutations in exons 9& 13 mutations could be used as an independent prognostic factor for GIST patients.
Citation Format: Abeer A. Bahnnasy, Ola Khorshid, Mona S. Abdellateif, Ghada Y. Zakaria, Nasr M. Allahloubi, Auhood Nassar, Abdel-Rahman N. Zekri. Correlation between different C-KIT exon mutation and clinical outcome to Imatinib Mesylate treatment in patients with gastro-intestinal stromal tumors (GIST) [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 1777.
Abstract 1784: High expression of PTK-7 regulates the growth and invasion of triple-negative breast cancer cells
Authors: Bollu Lakshmi Reddy 
Published: August 2019

Abstract
Background: Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with poor prognosis. Due to the frequent distant metastasis and lack of successful targeted therapies, the overall survival rate for the patients with TNBC is significantly lower than estrogen receptor positive and HER2 positive breast cancers. To identify potential druggable targets, previously, we performed a gene expression analysis and identified protein kinases that are highly expressed in ER-negative breast cancers. Through these studies, we discovered that the expression of pseudo kinase-7 (PTK-7) is highly elevated in TNBCs and correlated with p53 mutation status and disease progression. We hypothesize that high expression of PTK-7 is required for the growth and invasiveness of TNBC cells.
Experimental design and methods: In this study, we analyzed the expression status of PTK-7 in TNBC and the association of PTK-7 expression with p53 status and disease prognosis using publicly available datasets. Protein levels of PTK-7 were determined through western blotting analysis. The association of p53 and PTK-7 expression was determined using Oncomine analysis. Using specific siRNAs against PTK-7, we determined whether PTK-7 is required for the growth of TNBC cells. The role of PTK-7 in migration and invasion of TNBC cells was determined using Boyden trans-well assays.
Results: Analysis of publicly available datasets reveals that PTK-7 expression is elevated in TNBCs compared with normal breast and ER-positive breast cancers. High PTK-7 expression was found to be associated with p53 mutations. Knockdown of PTK-7 using siRNA significantly reduced the growth of TNBC cells in vitro. In vitrotrans-well migration and invasion studies also demonstrated that knockdown of PTK-7 significantly reduced the migration and invasion of TNBC cells. In contrast knockdown of PTK-7 did not affect the growth and invasiveness non-TNBC cells.
Conclusion: Our results suggest that the expression of PTK-7, a critical regulator of growth and invasion of TNBCs. These results suggest that PTK-7 is a promising target for the treatment of women with TNBC. This work was supported by Susan G Komen Promise Grant (PB), SAB Komen grant (PB) and Young Foundation grant (PB).
Citation Format: Lakshmi Reddy Bollu. High expression of PTK-7 regulates the growth and invasion of triple-negative breast 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 1784.
Abstract 1791: RADIL regulates RAS downstream signaling
Authors: Choi Byeong Hyeok , Kou Ziyue , Philips Mark R. , Dai Wei 
Published: August 2019

Abstract
RAS proteins regulate a variety of cellular processes including cell survival, proliferation, and differentiation. RAS genes are among the most frequently mutated oncogenes in human malignancies. To date, there are no successful anti-cancer drugs in the clinic that target RAS proteins or their pathways. Therefore, it is imperative to identify and characterize new components that regulate RAS activity or mediates its downstream signaling. Recently, we identified a series of proteins that are associated with HRAS using a combination of immunoprecipitation and mass spectrometry. We first focused on RADIL, a gene product with Ras-Association (RA) and DIL domains. RADIL is known to be a downstream effector of RAP1, inhibiting RhoA signaling in the regulation of cell survival, adhesion, and migration. We demonstrated that RADIL interacted with all three isoforms of RAS, including H, N, and KRAS. Interestingly, constitutively active HRAS (HRASG12V) was strongly associated with RADIL whereas dominant negative HRAS (HRASS17N) displayed a compromised association with RADIL, suggesting that RADIL may be required for RAS activation. We also found that Radil Knockout cells had weakened ERK phosphorylation whereas induced expression of RADIL promoted ERK phosphorylation, suggesting that RADIL is required for the RAS-MEK-ERK signaling cascade in vitro. Taken together, our current studies strongly suggest that RADIL may be important for regulating RAS signaling.
Citation Format: Byeong Hyeok Choi, Ziyue Kou, Mark R. Philips, Wei Dai. RADIL regulates RAS downstream signaling [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 1791.
Abstract 1821: LINC00346 regulates c-Myc transcriptional activity through CTCF in pancreatic cancer
Authors: Peng Wan-Xin , Mo Yin-Yuan 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC), a most challenging malignant disease, is estimated to become the second leading cause of cancer-related deaths in the United States between the year 2020 and 2030. Although the aberrant activation of KRAS has been demonstrated as the driving force of PDAC progression, the contribution of other molecules, especially long non-coding RNAs (lncRNAs), to PDAC progression remain largely unknown. In the present study, we interrogated the pancreatic adenocarcinoma dataset of the Cancer Genome Atlas (TCGA) consisting of 186 cases. Among 2,730 lncRNAs analyzed, LINC00346 revealed the highest alterations among these lncRNAs with 11% frequency at the RNA level. In addition, its upregulation was significantly associated with overall survival (OS) and disease-free survival (DFS), respectively. To determine the biological function of LINC00346 in pancreatic cancer, we next performed loss-of-function assay in pancreatic cancer cell lines MIA PaCa-2 and BxPC-3 by CRISPR/Cpf1 technology using dual gRNA approach. The results showed that knockout (KO) of LINC00346 impaired pancreatic cancer cell proliferation, tumorigenesis, migration and invasion ability, while these phenotypes were restored by LINC00346 re-expression in KO cells (i.e., rescue experiment). Mechanistically, LINC00346 functions as a positive regulator of c-Myc. Further characterizations demonstrated that LINC00346 transcriptionally activates c-Myc expression by interaction with CTCF. Together, these results suggest that LINC00346 contributes to PDAC pathogenesis by activating c-Myc, and thus, LINC00346 may serve as a potential target for pancreatic cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Wan-Xin Peng, Yin-Yuan Mo. LINC00346 regulates c-Myc transcriptional activity through CTCF in pancreatic 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 1821.
Abstract 1823: SNORD78 promotes prostate cancer progression and regulates AR expression and signaling
Authors: Lombard Alan P. , Liu Chengfei , Armstrong Cameron M. , D'Abronzo Leandro S. , Lou Wei , Evans Christopher P. , Gao Allen C. 
Published: August 2019

Abstract
While small nucleolar RNAs (snoRNAs) have long been thought of as housekeeping genes, emerging evidence now suggests that snoRNAs are involved in more than previously thought and also in the development of disease. In cancer, it is understood that snoRNA expression and function can be altered, but little is known regarding the role of snoRNAs in these diseases. SNORD78 is a C/D box snoRNA which has been shown to be overexpressed in prostate cancer and associated with disease progression. However, there are no studies functionally characterizing SNORD78 in prostate cancer. In this study we sought to understand the functional contribution of SNORD78 in prostate cancer progression. Oncomine was used to assess SNORD78 expression in clinical prostate cancer samples. LNCaP and C4-2B prostate cancer cell lines were used. We used siRNAs to inhibit SNORD78 expression and cell viability assays to assess cell growth. ELISAs were used to assess PSA secretion and cell death. Western blots and quantitative PCR were used to assess cell death (PARP-cleavage) and AR expression and signaling. We found that SNORD78 expression was up-regulated in prostate tumors and associated with metastatic progression. Cell viability assays demonstrated that inhibition of SNORD78 expression resulted in a drastic reduction in prostate cancer cell growth and lower secretion of PSA into the media. Cell death ELISAs and western blots for cleaved-PARP showed that SNORD78 inhibition induced robust apoptosis in both LNCaP and C4-2B cells. As the androgen receptor (AR) is the primary target for prostate cancer therapy, we tested whether SNORD78 regulated AR expression and signaling. Inhibition of SNORD78 in both LNCaP and C4-2B cells resulted in reduced AR mRNA and protein levels. We also found that SNORD78 knockdown led to decreased levels of PSA and NKX3.1, suggesting that AR downstream signaling was inhibited. Our findings suggest that SNORD78 promotes prostate cancer cell viability and disease progression. We also demonstrate that SNORD78 regulates the AR and may be involved in promoting AR signaling needed for prostate cancer cell survival. Collectively, these data suggest that SNORD78 plays a critical role in prostate cancer progression and may represent a novel therapeutic target.
Citation Format: Alan P. Lombard, Chengfei Liu, Cameron M. Armstrong, Leandro S. D'Abronzo, Wei Lou, Christopher P. Evans, Allen C. Gao. SNORD78 promotes prostate cancer progression and regulates AR expression and signaling [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 1823.
Abstract 1824: Long noncoding RNA NR_027340 promotes head and neck cancer cell proliferation and glycolysis via PFKP
Authors: Yang Yifan , Wang Ru , Feng Ling , Shi Qian , Tan Chen , Fang Jugao 
Published: August 2019

Abstract
Introduction: Long noncoding RNAs (lncRNAs) play crucial roles in various cancers. Recent study has indicated that lncRNA NR_027340 was significantly upregulated in head and neck cancer (HNC). However, its multifaceted roles in HNC are unclear. Here we demonstrate the role of lncRNA NR_027340 in HNC cell proliferation and glycolysis.
Methods: qRT-PCR was used to detect lncRNA NR_027340 expression in HNC tissues, and the correlations between lncRNA NR_027340 and clinicopathologic features were then analyzed. RNA pull-down and mass spectrometry analysis were carried out to explore the lncRNA NR_027340-bound proteins. RNA immunoprecipitation (RIP) was used to confirm the association between lncRNA and relevant proteins. lncRNA NR_027340 knockout cell lines were generated using the CRISPR/Cas9. Colony formation, cell cycle analysis and flow cytometry were used to measure the proliferation of HNC cells. The production of lactate was observed to evaluate the glycolysis of HNC cells.
Results: We found lncRNA NR_027340 was significantly up-regulated in HNCs and the elevated lncRNA NR_027340 was correlated with poor clinical prognosis. Mechanistically, we identified PFKP as the protein partner of lncRNA NR_027340 in the cytoplasm. In addition, we found that both lncRNA NR_027340 and PFKP depletion reduced the cell proliferation and glycolysis in vitro. The ingenuity pathway analysis and Western blot assay indicated that lncRNA NR_027340 targeted PFKP to regulate cell proliferation and glycolysis in HNC.
Conclusion: These findings reveal a functional role for lncRNA NR_027340 in altering glycolysis and promoting proliferation in HNC cells, suggesting that lncRNA NR_027340 might serve as a prognostic and diagnostic indicator as well as a potential therapeutic target.
Citation Format: Yifan Yang, Ru Wang, Ling Feng, Qian Shi, Chen Tan, Jugao Fang. Long noncoding RNA NR_027340 promotes head and neck cancer cell proliferation and glycolysis via PFKP [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 1824.