bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5715: Gene body methylation and expression of SHOX2 gene are potent prognostic markers for survival in intermediate grade gliomas and renal cancers
Authors: Zhang Yu-An , Zhou Yunyun , Luo Xin , Xiao Guanghua , Gazdar Adi F. 
Published: July 2017

Abstract
Background: Previous data indicated that low level of promoter methylation of the SHOX2 gene was a prognostic marker for worse progression-free survival for non-small cell lung cancer.
Purpose: (a) to determine the relationship between SHOX2 gene methylation and expression; b) to determine whether SHOX2 gene methylation and expression were prognostic markers for other cancers.
Methods: We examined multiple methylation and expression datasets available from The Cancer Genome Atlas (TCGA) and other previously published studies. Data from a total of more than 1000 intermediate grade gliomas and 1100 renal cancer cases were examined, along with smaller number of corresponding non-malignant tissues. We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression model analyses.
Results: SHOX2 gene contains three CpG islands encompassing the promoter region and body. Methylation of various regions of SHOX2 gene body was significantly positively correlated with its expression in gliomas and renal cancer. Aberrantly high methylation and expression of SHOX2 gene, which were significantly higher than the corresponding nonmalignant tissues, were identified in subsets of gliomas and renal cancers. Survival analysis of patients indicated that the methylation and expression of SHOX2 gene in gliomas and renal cancer (both clear cell and papillary cell carcinomas) were highly potent markers for poor survival. We further investigated the combination of SHOX2 with other known clinically relevant glioma markers (IDH genotype status, TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of glioma patients with significantly favorable survival outcomes, especially in the subgroup (i.e., IDH wild-type) associated with worse prognosis for each individual marker. Multivariate analysis demonstrated that SHOX2 was a potent independent survival marker for gliomas.
Conclusion: Gene body methylation and expression of SHOX2 gene are tightly positively correlated and are potent new markers for overall survival prognosis for intermediate grade gliomas and renal cancer. The combination of IDH or other relevant prognostic markers with SHOX2 identified intermediate grade glioma subsets with improved survival outcomes.
Citation Format: Yu-An Zhang, Yunyun Zhou, Xin Luo, Guanghua Xiao, Adi F. Gazdar. Gene body methylation and expression of SHOX2 gene are potent prognostic markers for survival in intermediate grade gliomas and renal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5715. doi:10.1158/1538-7445.AM2017-5715
Abstract 5717: PKR promotes EphA2 and other proteins degradation and is predictor of survival in lung cancer
Authors: Pataer Apar , Shao Ruping , Ozpolat Bulent , Fang Bingliang , Swisher Stephen G. 
Published: July 2017

Abstract
Relative expression of PKR and EphA2 was a significant predictor of survival in non-small cell lung cancer. To study the PKR-regulated protein, we evaluated expression of 149 proteins in lung cancer cells by reverse-phase protein assay (RPPA) after induction of PKR. Expression of several proteins (EphA2, IRS1, Chk1 and c-Raf and paxillin) was inhibited by PKR. In validating the downregulated proteins by western blot analysis, we observed that PKR reduced EphA2, IRS1, Chk1 and paxillin protein expression. We next investigated the involvement of the proteasomes and lysosomes in PKR-induced protein degradation. Human lung cancer H1299 and A549 cells were transfected with Ad-PKR for 48 h in the presence or absence of the proteasome inhibitor MG132 or lysosome inhibitor (3MA: 3-methyladenine). We observed that MG132 prevented PKR-induced IRS1 and Chk1 degradation, but not PKR-induced EphA2 and paxillin degradation in these cells. However, we found that 3MA prevented PKR-induced EphA2 and paxillin degradation in these cells. These data suggest that PKR is involved in proteasome as well as lysosome function. To study the involvement of autophagy pathway in PKR mediated protein degradation, we evaluated proteins which known involved in autophagy by Western blotting after induction of PKR on these cancer cells. We observed slightly decrease of LC-3, ATG5 and Beclin1 in these cancer cells after induction of PKR. Our data suggest that PKR may directly involve in in lysosome function.
Citation Format: Apar Pataer, Ruping Shao, Bulent Ozpolat, Bingliang Fang, Stephen G. Swisher. PKR promotes EphA2 and other proteins degradation and is predictor of survival in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5717. doi:10.1158/1538-7445.AM2017-5717
Abstract 5727: A functional polymorphism in DTX1 gene of Notch pathway predicts the prognosis of surgically resected non-small cell lung cancer
Authors: Lee Shin Yup , Lee Janghyuck , Shin Kyung Min , Son Ji Woong , Park Jae Yong 
Published: July 2017

Abstract
Notch signaling pathway has been implicated in the prognosis of non-small cell lung cancer (NSCLC). This study was conducted to determine the association between single nucleotide polymorphisms (SNPs) in the Notch pathway genes and survival outcomes of surgically resected NSCLC. Among the 64 SNPs analyzed in the discovery set, 8 SNPs were significantly associated with overall survival (OS) or disease-free survival (DFS). Among the 8 SNPs, the association was consistently observed only for DTX1 rs1732786A&gt;G in the validation sets. In combined analysis, the rs1732786A&gt;G was significantly associated with better OS and DFS (adjusted HR aHR for OS, 0.81; 95% CI, 0.68-0.95; P = 0.01; aHR for DFS, 0.82; 95% CI, 0.72-0.94; P = 0.003; under codominant model). To verify the functional relevance of the rs1732786A&gt;G in DTX1 promoter region, we conducted dual-luciferase reporter assays. The G allele showed significantly higher luciferase activity than the A allele (P &lt; 0.005) in lung cancer cell lines. The relative expression level of DTX1 mRNA was significantly lower in tumor tissues than in nonmalignant lung tissue (P = 0.003). Moreover, the level of DTX1 mRNA expression in tumor tissue increased as the number of G allele increased (P trend = 0.02). Higher levels of DTX1 mRNA expression were significantly correlated with a better OS and DFS (P = 0.03 and P = 0.002). Our results suggest that the DTX1 rs1732786 A&gt;G polymorphism may affect DTX1 expression and may be a useful marker for predicting the prognosis of patients with early stage NSCLC.
Citation Format: Shin Yup Lee, Janghyuck Lee, Kyung Min Shin, Ji Woong Son, Jae Yong Park. A functional polymorphism in DTX1 gene of Notch pathway predicts the prognosis of surgically resected non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5727. doi:10.1158/1538-7445.AM2017-5727
Abstract 5732: PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer
Authors: Blom Sami , Mäki-Teeri Petra , Erickson Andrew , Paavolainen Lassi , Mirtti Tuomas , Rannikko Antti , Potdar Swapnil , Östling Päivi , Weerden Wytske van , Kallioniemi Olli , Pellinen Teijo 
Published: July 2017

Abstract
Activation of PI3K/Akt pathway is associated with adverse outcome and aggressive disease in many cancers. In prostate cancer (PCa), the activity of this pathway has been shown to promote disease progression and metastasis. However, it is still controversial how PI3K/Akt regulates androgen receptor (AR), a central signaling molecule in prostate pathophysiology, and whether it has an active role in hormone naïve non-metastatic PCa. Here, we show using immunohistochemistry (IHC) and advanced quantitative multiplexed IHC that the expression of phosphorylated-Akt(S473) and AR are highly correlated in clinical PCa, even at the cellular level. Furthermore, we found that high expression of p-Akt(S473) predicts poor clinical outcome in two independent hormone-naïve non-metastatic PCa cohorts. To study whether PI3K/Akt regulates AR expression, we performed an in vitro drug screen with 32 PI3K/Akt/mTOR inhibitors in PC346C, an AR expressing cell line derived from a hormone-naïve primary tumor of prostate. We observed a strong correlation between p-Akt(S473) and AR also in vitro in individual cells independent of the inhibitor used. Although both PI3K and Akt specific inhibition reduced cell viability, the response in nuclear expression of AR was highly dependent on the target of inhibition: Akt specific inhibition reduced AR nuclear expression and resulted in large, spindle-shaped cells, whereas PI3K specific inhibition increased AR nuclear expression and resulted in smaller, round-shaped cells. These data suggest that PI3K and Akt have different roles in sustaining AR activity in PCa as perturbations of the two components leads to differential responses in terms of AR nuclear expression and cell morphology. In conclusion, activated Akt associates with AR expression and predicts poor clinical outcome in hormone-naïve non-metastatic PCa. Furthermore, the differing roles of PI3K and Akt in AR regulation warrants for further studies as it may have implications in the design of PCa therapy targeting PI3K/Akt, especially when the inhibitors are administered in combination with anti-androgens.
Citation Format: Sami Blom, Petra Mäki-Teeri, Andrew Erickson, Lassi Paavolainen, Tuomas Mirtti, Antti Rannikko, Swapnil Potdar, Päivi Östling, Wytske van Weerden, Olli Kallioniemi, Teijo Pellinen. PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5732. doi:10.1158/1538-7445.AM2017-5732
Abstract 5734: The influence of body mass index on overall survival following surgical resection of non-small cell lung cancer
Authors: Liu Xi , Sepesi Boris , Gold Kathryn A. , Correa Arlene M. , Heymach John V. , Vaporciyan Ara A. , Roszik Jason , Dmitrovsky Ethan 
Published: July 2017

Abstract
Prior work implicated an association between increased body mass index (BMI) and lower risk of mortality from lung cancer. The aim of our study was to comprehensively evaluate the influence of BMI on long-term overall survival in surgical patients with non-small cell lung cancer. This study investigated 1935 patients who underwent surgical resection for lung cancer at MD Anderson Cancer Center (from 2000 - 2014). Study variables included both patient and treatment related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with overall survival. By univariate analysis, significant predictors of better survival were higher BMI, pathologic tumor stage (stage I versus stages II, III, or IV), type of surgery (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female gender, and adenocarcinoma histology (versus squamous) (all p &lt; 0.05). Patients considered morbidly obese (BMI ≥ 35) had a trend towards better outcomes than those classified as obese (BMI ≥ 30 and &lt;35) (p = 0.05), overweight (BMI ≥25 and &lt;30) (p = 0.13), or healthy weight (BMI &lt; 25) (p = 0.37) (HR 0.727, 0.848, 0.926, and 1, respectively). By multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis showed significantly better overall survival (p = 0.008) in patients with BMI ≥ 30 as compared to BMI &lt; 25. For exploratory analysis of expressed mRNAs associated with obesity in lung cancer, the association between obesity-related species (LEP, LEPR, PCSK1, POMC, MC4R, BMIQ1, BMIQ2, BMIQ3, UCP2, BMIQ5, BMIQ6, INSIG2, FTO, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, SH2B1, MTCH2 and NPC1) and survival was explored using The Cancer Genome Atlas (TCGA). Kaplan Meier analyses demonstrated significantly improved overall survival in lung cancer patients with higher Uncoupling Protein 2 (UCP2) expression, as will be presented. In summary, this large, single center series, after controlling for disease stage and other variables found higher BMI was associated with improved overall survival following surgical resection of non-small cell lung cancer. Studies are underway to elucidate the underlying mechanisms responsible for this association between BMI and lung cancer survival.
Citation Format: Xi Liu, Boris Sepesi, Kathryn A. Gold, Arlene M. Correa, John V. Heymach, Ara A. Vaporciyan, Jason Roszik, Ethan Dmitrovsky. The influence of body mass index on overall survival following surgical resection of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5734. doi:10.1158/1538-7445.AM2017-5734
Abstract 5736: Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer
Authors: Tsuji Takahiro , Ozasa Hiroaki , Sakamori Yuichi , Nomizo Takashi , Funazo Tomoko , Yasuda Yuto , Yoshida Hironori , Nagai Hiroki , Kim Young Hak 
Published: July 2017

Abstract
Activation of c-MET through hepatocyte growth factor (HGF) increases tumorigenesis, induces resistance, and is associated with poor prognosis in various solid tumors. We previously reported that lung cancer cell lines had increased expression of c-MET due to gene amplification-induced cytotoxic drug resistance, and that resistant cells paracrine HGF and promote its resistance. However, the clinical significance of sHGF in patients with advanced or recurrent NSCLC, especially in patients treated with cytotoxic chemotherapy, is yet to be identified. Here, we present sHGF may be useful to predict tumor response and PFS in patients with advanced NSCLC. A total of 81 patients with 101 treatment regimens were investigated; 53 patients received first-line therapy and 48 patients received second-line therapy during the observation period. sHGF levels were evaluated using ELISA at 4 time-points: at pre-treatment, at response-evaluation (1-2 months after treatment initiation), at the best tumor response, and at the disease progression. As a control biomarker, serum carcinoembryonic antigen (CEA) was also evaluated. sHGF at response-evaluation in patients with progressive disease was higher compared with that of disease controls in both first-line and second-line treatment (median value (MV): under the limited of detection (LOD) vs. 0.40; P=0.0086 and MV: under the LOD vs. 0.41; P=0.0035, respectively). Positive-sHGF at response-evaluation predicts poor progression-free survival (PFS) compared with negative-sHGF in both first-line (median, 153.5 vs. 288.0; P=0.047) and second-line treatment (87.0 vs. 219.5; P=0.014). Lung adenocarcinoma subgroup analysis showed that in patients receiving second cytotoxic chemotherapy, there were no significant differences in PFS or HR between patients with low-CEA compared with those with high-CEA, but positive-sHGF at pre-treatment or at response-evaluation predicts poor PFS (35 vs. 132; P=0.0045, 50 vs. 215; P=0.0047, respectively). Simple and repeatable markers for activation of the HGF/c-MET pathway would provide rationale for future research investigating the merit of sHGF as a potential clinical biomarker to indicate administration of MET inhibitors.
Citation Format: Takahiro Tsuji, Hiroaki Ozasa, Yuichi Sakamori, Takashi Nomizo, Tomoko Funazo, Yuto Yasuda, Hironori Yoshida, Hiroki Nagai, Young Hak Kim. Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5736. doi:10.1158/1538-7445.AM2017-5736
Abstract 5739: Nicotine promotes stemness-related properties and cell migration/metastasis through IGF-1R regulation in triple negative breast cancer
Authors: Kuo Yung-Che , Chu Jan-Show , Lee Kha-Liang , Drew Victor James , Zhuang Wei-Zhan , Chen Chi-Long , Ho Yuan-Soon , Huang Yen-Hua 
Published: July 2017

Abstract
Purpose: To determine the role of insulin-like growth factor (IGF)-I receptor (IGF-IR) in alpha 9 nicotinic acetylcholine receptor (α9-nAChR)-induced stemness-related properties and to assess the therapeutic potential for preventing early tumor relapse and metastasis of TNBCs.
Experimental Design: Expression levels of stemness-related genes, α9-nAChR and IGF-IR in tissues (n = 67) were analyzed by real-time Q-PCR and the correlation of different gene levels were calculated by the Pearson correlation analysis. The effects of either α9-nAChR activation or IGF-1R transactivation on stemness expression in TNBC were examined using ALDEFLUOR assay with flow cytometry, RNA interference, wound closure/migration/invasion assay, and animal models. The α9-nAChR, OCT4 and IGF-1R protein, p-IGF-1R in tissues were detected by immunohistochemical staining.
Results: A high positive correlation between the gene expression levels of OCT4/NANOG/CD24/CD44 and α9-nAChR/IGF-IR in human breast cancer tissues was observed. Nicotine induced α9-nAChR activation trans-activates an IGF-IR expression and a phosphorylation of STAT3, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of either α9-nAChR or IGF-IR activation by RNA interference significantly suppressed the nicotine-induced stemness-related properties and cell metastasis both in vitro and in vivo.
Conclusions: IGF-1R signal regulates the nicotine/α9-nAChR-induced stemness properties and cell metastasis therefore convene poor prognosis in TNBCs.
Citation Format: Yung-Che Kuo, Jan-Show Chu, Kha-Liang Lee, Victor James Drew, Wei-Zhan Zhuang, Chi-Long Chen, Yuan-Soon Ho, Yen-Hua Huang. Nicotine promotes stemness-related properties and cell migration/metastasis through IGF-1R regulation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5739. doi:10.1158/1538-7445.AM2017-5739
Abstract 5744: The role of atypical protein kinase C in colorectal cancer cell growth and proliferation
Authors: Islam S M Anisul , Duncan Mildred Acevedo 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the second most common cancer in the world and death from colorectal cancer accounts for 8% of all cancer deaths both in men and women in the United States. CRC is life threatening disease due to therapy resistant cancerous cells. The exact mechanisms of cell growth, survival, metastasis and inter & intracellular signaling pathways involved in colon cancer are still a major challenge for scientists. Hence, investigating the signaling pathways that lead to colon carcinogenesis may give insight into the therapeutic target. In this study, the role of atypical Protein kinase C (aPKC) on colon cancer was identified by using four inhibitors of that particular protein class: 1) ACPD (2-acetyl-1,3-cyclopentanedione and 2) DNDA (3,4-diamino-2,7 naphthalenedisulfonic acid) are non-specific inhibitors of aPKCs; 3) ζ-Stat (8-hydroxy-1, 3, 6-naphthalenetrisulfonic acid) is a specific inhibitor of PKC-ζ; and 4) ICA-I (4, 5-amino-4-carbamoylimidazol-1-yl-2, 3-dihydroxycyclopentyl) methyl dihydrogen phosphate) is a specific inhibitor of PKC-ι. The cell lines tested were HT-29 colon cancer and CCD18CO normal colon epithelial. Although PKC-ι is an oncogene in many cancers, we found that the PKC-ζ was responsible for the abnormal growth and proliferation in HT-29 colon cancer cells. Additionally, the inhibition of aPKCs did not bring any significant toxicity on CCD18CO normal colon cell line. These results suggest the potentiality of utilizing aPKC-ζ inhibitors to block colon cancer cell growth and proliferation.
Citation Format: S M Anisul Islam, Mildred Acevedo Duncan. The role of atypical protein kinase C in colorectal cancer cell growth and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5744. doi:10.1158/1538-7445.AM2017-5744
Abstract 5746: TRAF1 is required for solar UV-induced skin carcinogenesis
Authors: Yamamoto Hiroyuki , Ryu Joohyun , Min Eli , Oi Naomi , Bai Ruihua , Zykova Tatyana A. , Yu Dong Hoon , Malakhova Margarita , Moriyama Kenji , Bode Ann M. , Dong Zigang 
Published: July 2017

Abstract
Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a member of the TRAF protein family, which regulates the canonical and non-canonical NF-κB signaling cascades. Although aberrant TRAF1 expression in tumors is reported, the role of TRAF1 remains elusive. Here, we report that TRAF1 is required for skin carcinogenesis induced by chronic solar UV radiation. In vivo studies with solar UV exposure indicate that the deletion of TRAF1 results in the inhibition of AP-1 activity by down-regulating the induction of c-Fos and c-Jun by regulating ERK5 activity. Furthermore, we show that TRAF1 is required for solar UV-induced ERK5 activation. Mechanistic studies revealed that TRAF1 expression enhances the ubiquitination of ERK5 on K184, which is necessary for AP-1 activation. Altogether, our results suggest that TRAF1 mediates ERK5 activity by regulating the upstream effectors of ERK5 and also by modulating its ubiquitination status. Targeting TRAF1 function might lead to strategies for preventing and treating skin cancer.
Citation Format: Hiroyuki Yamamoto, Joohyun Ryu, Eli Min, Naomi Oi, Ruihua Bai, Tatyana A. Zykova, Dong Hoon Yu, Margarita Malakhova, Kenji Moriyama, Ann M. Bode, Zigang Dong. TRAF1 is required for solar UV-induced skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5746. doi:10.1158/1538-7445.AM2017-5746