bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4390: Non-coding RNAs in EGFR therapy resistance in breast cancer
Authors: Borrero-García Luis D. , Castillo-Pichardo Linette , Redis Roxana S. , Calin George A. , Dharmawardhane Suranganie 
Published: May 2015

Abstract
The purpose of this study is to identify novel mechanisms of resistance to epidermal growth factor receptor (EGFR) targeted therapies. The initial success of EGFR targeted therapies such as gefitinib and lapatinib has been confounded by intrinsic or acquired therapy resistance. Emerging data, including our studies, show drug-induced dysregulation of non-coding RNAs (ncRNAs) that may downregulate multiple effectors of chemoresistance by transcriptional or post-transcriptional regulation. To investigate the role of ncRNAs in regulation of EGFR therapy resistance, we created syngeneic therapy sensitive and resistant breast cancer (BC) cell lines by exposing therapy sensitive SKBR3 and BT-474 cells to different concentrations of gefitinib or lapatinib. Differentially expressed ncRNAs in resistant and sensitive cells were identified from quantitative RT-PCR analysis and their targets detected by Western blot. A long ncRNA (lncRNA) that we have named Colon Cancer Associated Transcript 2 (CCAT2) (Ling et al., Genome Res. 2013, 23:1446-61) was downregulated in EGFR/HER2 therapy resistant BC cells. The microRNA miR -221/222 was upregulated in parallel with decreased CCAT2. Increased miR-221/222 and decreased miR-200 family have been associated with cancer malignancy and epithelial to mesenchymal transition (EMT), a hallmark of therapy resistance. Accordingly, miR-200a was downregulated in EGFR therapy resistant BC cells. miR-200 family plays an important role in suppression of EMT by downregulation of zinc finger E-box binding homeobox (Zeb)1/2 and β-catenin. Zeb 1/2 are negative regulators of E-cadherin, and β-catenin is a potent pro-cancer transcriptional activator in the absence of an E-cadherin axis. Results show upregulation of Zeb1, β-catenin and its transcriptional effector c-Myc, and stem cell-like marker CD44, while E-cadherin was downregulated in the E-cadherin positive BT-474 cells. We also found downregulation of miR-221/222 targets, PTEN and APAF1, in the SKBR3 resistant variants, which is consistent with the upregulation of miR-221/222 expression. In conclusion, this data suggest that downregulation of CCAT2 and miR-200 family, and upregulation of miR-221/222 contributes to EGFR targeted therapy resistance. Therefore, targeting these ncRNAs maybe a viable alternative to overcoming therapy resistance in BC.
Citation Format: Luis D. Borrero-García, Linette Castillo-Pichardo, Roxana S. Redis, George A. Calin, Suranganie Dharmawardhane. Non-coding RNAs in EGFR therapy resistance in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2014-4390
Abstract 4391: Multi-modal nanomedicine for glioblastoma
Authors: Ofek Paula , Calderon Marcelo , Sheikhi-Mehrabadi Fatemeh , Ferber Shiran , Haag Rainer , Satchi-Fainaro Ronit 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is an aggressive primary neoplasm of the brain that exhibit notable refractivity to standard treatment regimens. Recent large-scale molecular profiling has revealed deregulated molecular networks as potential targets for therapeutic development. MicroRNAs (miRNAs) are noncoding RNA molecules which act as post-transcriptional regulators of specific messenger RNA transcripts. miRNAs play major roles in normal developmental processes, and their deregulation significantly contributes to various aspects of carcinogenesis.
Nevertheless, in vivo delivery of small interfering RNA (siRNA) and miRNA remains a crucial challenge for their therapeutic success. siRNAs and miRNAs on their own are not taken-up by most mammalian cells in a way that preserves their activity. In order to circumvent these limitations, we developed a cationic carrier system, which can strongly improve its stability, intracellular trafficking and silencing efficacy. Polyglycerol (PG)-Amine, a water-soluble polyglycerol-based hyperbranched polymer accumulates in the tumor microenvironment due to the enhanced permeability and retention (EPR) effect, and therefore, represents an ideal nanocarrier for antitumor biological agents.
Using our novel nanocarrier, we have studied the expression targets and functional effects of miR-34a in several human glioblastoma cell lines and human tissue samples. miR-34a levels inversely correlated to their target gene levels measured in the same cell lines or tissue. Transient transfection of PG-NH2-miR-34a polyplex into glioblastoma cells strongly inhibited cell proliferation, cell cycle progression, and cell migration. Consequently, we performed an in vivo experiment and achieved a significant tumor growth inhibition effect following treatment with PG-NH2-miR-34a polyplex in a human glioblastoma mouse model.
We further characterized the synergistic effect of combining PG-NH2-miR-34a polyplex with chemotherapy and achieved promising results. Together, our findings show that PG-NH2 efficiently delivers anticancer miRNAs to glioblastoma cells and suppresses brain tumor growth. These results suggest that our polyplex could serve as a potential nanomedicine for glioblastoma.
Citation Format: Paula Ofek, Marcelo Calderon, Fatemeh Sheikhi-Mehrabadi, Shiran Ferber, Rainer Haag, Ronit Satchi-Fainaro. Multi-modal nanomedicine for glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4391. doi:10.1158/1538-7445.AM2014-4391
Abstract 4394: Genistein downregulates onco-miR-1260b and inhibits Wnt-signaling in renal cancer cells
Authors: Hirata Hiroshi , Ueno Koji , Tanaka Yuichiro , Tabatabai Z.Laura , Nakajima Koichi , Hinoda Yuji , Ishii Nobuhisa , Dahiya Rajvir 
Published: May 2015

Abstract
Introduction and Objective: Wnt signaling plays an important role in renal cancer and that is modulated by genistein in other cancers. Recently microRNAs have emerged as new regulators of gene expression. Thus we focused on microRNAs to examine the regulatory mechanism of genistein on the Wnt signaling pathway in RCC.
Methods: Initially we investigated the effect of genistein on Wnt signaling (TCF reporter assays) in renal cancer cells and using microarray identified candidate miRNAs whose expression was decreased by genistein. We performed functional analyses and investigated the relationship between miRNA expression and renal cancer patient outcomes. We also did 3′UTR luciferase assays to look at direct miRNA regulation of Wnt signaling related genes.
Results: Genistein promoted apoptosis while inhibiting RCC cell proliferation and invasion. Genistein also decreased TCF reporter activity in RCC cells. We found that miR-1260b was highly expressed and significantly down-regulated by genistein in RCC cells. The expression of miR-1260b was significantly higher in renal cancer tissues compared to normal and significantly related to over-all shorter survival. Additionally miR-1260b promoted renal cancer cell proliferation and invasion in RCC cells. The 3′UTR luciferase activity of target genes (sFRP1, Dkk2, Smad4) was significantly decreased and their protein expression significantly up-regulated in miR-1260b inhibitor transfected renal cancer cells.
Conclusions: Our data suggests that genistein inhibited Wnt signaling by regulating miR-1260b expression in renal cancer cells.
Source of Funding: Grants RO1CA138642, RO1CA130860, RO1CA160079, I01BX001123, VA Merit Review and VA Program Project (PI: R. Dahiya).
Citation Format: Hiroshi Hirata, Koji Ueno, Yuichiro Tanaka, Z.Laura Tabatabai, Koichi Nakajima, Yuji Hinoda, Nobuhisa Ishii, Rajvir Dahiya. Genistein downregulates onco-miR-1260b and inhibits Wnt-signaling in renal cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4394. doi:10.1158/1538-7445.AM2014-4394
Abstract 4398: MicroRNA-203 enhances radiosensitivity of human malignant glioma cells
Authors: Hwang Yeohyeon , Lee David J. , Choi Eun Jung , Cho Bong Jun , Kim In-Ah 
Published: May 2015

Abstract
Glioblastoma multiform (GBM) is the most common, lethal and aggressive type of primary brain tumor. Despite the improvement of surgical and chemo/radiotherapeutic techniques, the prognosis for GBM is still poor, with median survival of 9-12 months. The occurrence of radio-resistance is one of the major obstacles to treat the GBM. Aberrant expression of miRNAs has been demonstrated to be involved in the initiation, progression, and metastasis of cancers. miRNA expression profiling studies revealed that a number of miRNA were dysregulated in GBM. Here, we investigated the potential role of miR-203, which is one of the downregulated miRNAs, in the modulation of radio-sensitivity in GBM. Transiently overexpressed miR-203 sensitized U251 malignant glioma cells to radiation concurrent with the downregulation of AKT activity. Overexpression of miR-203 prolonged radiation-induced γH2AX foci formation and downregulation of DNA-dependent protein kinases, suppressed invasion, migration potential and vasculogenic mimicry formation. In contrast, antisense-mediated inhibition of miR-203 expression results in decreased radio-sensitivity and features of Epithelial-Mesenchymal Transition (EMT). Taken together, our findings suggest that the miR-203 could be a useful target for overcoming the radio-resistance of GBM.
Citation Format: Yeohyeon Hwang, David J. Lee, Eun Jung Choi, Bong Jun Cho, In-Ah Kim. MicroRNA-203 enhances radiosensitivity of human malignant glioma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4398. doi:10.1158/1538-7445.AM2014-4398
Abstract 4399: Somatic HIF2A mutations identified in a new syndrome with multiple paragangliomas and somatostatinomas associated with polycythemia
Authors: Yang Chunzhang , Pacak Karel , Zhuang Zhengping 
Published: May 2015

Abstract
Hypoxia inducible factors (HIFs) control the cellular response to hypoxia and when dysregulated, contribute to tumorigenesis. We identified somatic HIF2A mutations in patients with a new disease syndrome of multiple paragangliomas and somatostatinomas associated with polycythemia. Five different somatic mutations in HIF2A were identified. All of them have a single amino acid substitution in the evolutionarily conserved oxygen-dependent degradation (ODD) domain resulting in disrupting the HIF-2α hydroxylation by prolyl hydroxylase domain-2 containing protein (PHD2). Changes of HIF-2α hydroxylation resulted in the stabilization of HIF-2α and cellular psuedohypoxia, that trigger activation of hypoxia-related genes expression and, dysregulate hematopoiesis leading to tumorigenesis. These results show for the first time that the intrinsic HIF mutations are present in tumors.
Citation Format: Chunzhang Yang, Karel Pacak, Zhengping Zhuang. Somatic HIF2A mutations identified in a new syndrome with multiple paragangliomas and somatostatinomas associated with polycythemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4399. doi:10.1158/1538-7445.AM2014-4399
Abstract 4400: The let-7 microRNA binding site variant in the KRAS 3′-UTR is not associated with the risk of head and neck cancer
Authors: Dalay Nejat , Demokan Semra , Suoglu Yusufhan , Yilmazer Rasim , Ulusan Murat 
Published: May 2015

Abstract
The KRAS gene is activated by somatic mutations in many cancer types. However, KRAS mutations are relatively rare in squamous cell carcinomas. In squamous cell cancers of the head and neck (HNSCC) amplification of the KRAS gene has been shown to promote tumor growth. miRNAs are short non-coding RNAs which play an important role as regulators of gene expression. They bind to the 3′-untranslated regions (UTRs) of the mRNAs and prevent translation of their target genes. SNPs in the miRNA binding sites are associated with disease risk and prognosis. The let-7 family of miRNAs regulate multiple oncogenes including the KRAS gene and have been shown to play a critical role in different cancer types. A functional polymorphism in the KRAS gene, not included in the GWAS platforms has been identified by candidate gene approach and was found to be a genetic marker of cancer risk and increased susceptibility to the carcinogenic effects of tobacco smoke. The polymorphism is referred to as the LCS6 (let-7 complementary site 6) variant and disrupts the let-7 binding site leading to higher KRAS expression. Such an increase in KRAS expression associated with the variant allele may represent an alternative form of KRAS activation in HNSCC and could lead to impairment of the EGFR signaling. In this study we evaluated the frequency of the KRAS variant in 216 patients with head and neck cancer and 85 healthy individuals. DNA was extracted from whole blood prior to chemotherapy or radiotherapy. The variant allele was analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Genotype and allele frequencies were evaluated using the De-Finetti case control program. 13 % of the patients were heterozygous and 3 patients (1.5 %) were homozygous for the variant allele. The polymorphism was present in heterozygous form in 12 % of the controls. No homozygous individual was detected in the control group. The frequencies of the variant allele were 92 % and 94 % in the patients and controls, respectively. Our data indicate that the KRAS let-7 LCS6 variant allele is not associated with an increased risk of HNSCC.
Citation Format: Nejat Dalay, Semra Demokan, Yusufhan Suoglu, Rasim Yilmazer, Murat Ulusan. The let-7 microRNA binding site variant in the KRAS 3′-UTR is not associated with the risk of head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4400. doi:10.1158/1538-7445.AM2014-4400
Abstract 4405: AXL receptor tyrosine kinase is associated with the prognosis of patients with esophageal squamous cell carcinoma
Authors: Yang Pei-Wen , Hsieh Min-Shu , Huang Ya-Chuan , Chiang Tzu-Hsuan , Lee Jang-Ming 
Published: May 2015

Abstract
PURPOSE:
The AXL receptor tyrosine kinase has been suggested as a prognostic factor and a therapeutic target in esophageal adenocarcinoma. Whether AXL play some role in the prognosis of esophageal squamous cell carcinoma (ESCC) is unknown. We aim to investigate the association of AXL expression in tumor tissues with the prognosis of patients with ESCC.
PATIENTS AND METHODS:
The study was analyzed retrospectively. A total of 57 patients diagnosed with ESCC were enrolled in the study. AXL expression in esophageal timorous tissues was detected by immunnohistochemisty (IHC), and was correlated with the overall survival (OS) or progression-free survival (PFS) of patients by multivariate Cox regression analysis and Kaplan-Meier survival function.
RESULTS:
AXL could be detected in 38 patients (66.7%). Elevated expression of AXL was associated with increased risk of both death and recurrence (HR[95 % CI]=1.46 [1.05-2.04], Ptrend=0.026 in death and HR[95 % CI]=1.75[1.24-2.48], Ptrend=0.002 in recurrence). Patents expressing high levels of AXL (n=25, 43.9 %) exhibited a 2.15 fold increased risk of recurrence compared to those absence or with low level of AXL (HR[95 % CI]=2.15[1.08-4.28], P=0.029). Kaplan-Meier survival function demonstrated that the progression-free duration was significantly different among the patients expressing different levels of AXL (log-rank P=0.029).
CONCLUSION:
Expression of AXL in esophageal tumor tissues is a prognostic predictor of ESCC. The results revealed AXL could also be a therapeutic target of ESCC.
Citation Format: Pei-Wen Yang, Min-Shu Hsieh, Ya-Chuan Huang, Tzu-Hsuan Chiang, Jang-Ming Lee. AXL receptor tyrosine kinase is associated with the prognosis of patients with esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4405. doi:10.1158/1538-7445.AM2014-4405
Abstract 4408: Her2 C terminal PDZ binding domain interacting with DLG1 is required for radioresistance through induction of EMT and loss of epithelial polarity
Authors: Lin Dong , Zhang Xiaodi , Eldridge Angela , Fan Ming , Menaa Cheikh , Li Jianjian 
Published: May 2015

Abstract
The tyrosine kinase receptor HER2 (ErbB2/neu) is predominantly localized to the basolateral membrane of the epithelium and has been implicated in mammary tumorigenesis as well as in resistance to chemotherapy and radiation. Here we demonstrate that HER2 interacts with discs large 1 (DLG1) that is one of PDZ domain proteins expressed at the basolateral membrane of human breast epithelial cells and plays an important role in the establishment and maintenance of epithelial polarity in Drosophila. However, either loss of the last 6 C-terminal amino acids (HER2-Δ1250-1255) or a valine-to-alanine C-terminal substitution (HER2-V1255A) in HER2, abrogates the interaction with DLG1. In contrast, either PDZ domain 1 or 3 within Dlg1 is required for interaction with HER2. Moreover, HER2-Δ1250-1255- or HER2-V1255A-expressing MCF10A human breast epithelial cells show the reduction of mesenchymal-to-epithelial transition (EMT) proteins including vimentin and Snail. In addition, HER2-wt cells promotes EMT as shown by down-regulation of E-cadherin and upregulation of vimentin and Snail. Taken together, these results indicate that C-terminal PDZ binding domain in HER2 modulates biological functions of HER2. These results reveal new insight into the structure and function of HER2, which may guide the design and development of new anti-cancer targets to treat HER2-positive breast cancer.
Citation Format: Dong Lin, Xiaodi Zhang, Angela Eldridge, Ming Fan, Cheikh Menaa, Jianjian Li. Her2 C terminal PDZ binding domain interacting with DLG1 is required for radioresistance through induction of EMT and loss of epithelial polarity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4408. doi:10.1158/1538-7445.AM2014-4408
Abstract 442: RASA1 alteration promotes melanoma tumorigenesis
Authors: Sung Hyeran , Ding Li , Kanchi Krishna L. , Messina Jane L. , Sondak Vernon K. , James Mulé J. , Wilson Richard K. , Weber Jeffrey S. , Kim Minjung 
Published: May 2015

Abstract
Melanoma shows frequent Ras-Raf-MAPK pathway activation via frequent mutations in NRAS and BRAF. Novel mutations in other components of this pathway such as MEK1, MEK2, MAP3K5, and MAP3K9 have been reported recently by high-throughput sequencing efforts. In addition, NF1 (neurofibromatosis type 1), one of the Ras GTPase activating proteins (RasGAPs), has been shown to be mutated or suppressed in melanoma. However, importance of other RasGAPs has not been addressed in melanoma.
To obtain a comprehensive view of melanoma genomes, we conducted whole genome sequencing (WGS) of 15 metastatic melanomas and matched normal PBMC genomes from 13 melanoma patients. All melanoma genomes from these 13 patients contained at least one mutation in genes of Ras-Raf-MAPK pathway (MAPK1, MAP3K1, MAP4K2, MAP3K14, NRAS, and BRAF). Our whole genome analyses also identified two novel somatic missense mutations (p.Tyr472His and p.Leu481Phe) in or around the PH domain in RASA1 gene. RASA1 (RAS p21 protein activator (GTPase activating protein) 1, also called as p120RasGAP) is a GTPase activation protein that negatively regulates Ras by catalyzing the hydrolysis of active Ras-GTP to inactive Ras-GDP. In this study, we addressed possible roles of RASA1 in melanoma tumorigenesis. To determine RASA1 level in melanocytic lesions, immunohistochemical analysis of RASA1 on human melanoma tissue microarray (TMA) containing nevi (n=34), primary melanomas (n=63), lymph node metastasis (n=35), and distal metastasis (n=29) was performed. This analysis has shown the inverse correlation of RASA1 expression to melanoma progression. Functionally, ectopic expression of RASA1 mutant increased soft-agar colony formation and tumor growth while that of wild-type RASA1 decreased. shRNA-mediated knock down of RASA1 promoted soft-agar colony formation and invasion of melanocytes and melanoma cells with BRAF mutation as a consequence of the elevated Ras activity.
Here, we established the functional significance of novel somatic missense mutations in RASA1 identified in our WGS study. Collectively, these data implicated that RASA1 inactivation by loss of expression and/or mutation may promote melanoma tumorigenesis.
Citation Format: Hyeran Sung, Li Ding, Krishna L. Kanchi, Jane L. Messina, Vernon K. Sondak, Mulé J. James, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim. RASA1 alteration promotes melanoma tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 442. doi:10.1158/1538-7445.AM2014-442