bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2104: Molecular alterations in JAK1 and JAK2 genes in head and neck squamous cell carcinoma
Authors: Carvalho Thaís G. , Carvalho André Lopes , Vettore André Luiz 
Published: August 2012

Abstract
Among the ten most common cancers are the head and neck tumors, with more than 600,000 new cases diagnosed annually worldwide, the majority (90%) represented by the head and neck squamous cell carcinomas (HNSCC). Somatic mutations occur in the genomes of all dividing cells, both normal and neoplastic. The JAK-STAT signaling pathway controls important cell events such as survival, proliferation and differentiation. The presence of mutations in the phosphorylation dominion of protein kinases as JAK family have been linked to development of different kinds of tumors such as hematological, breast, lung and gastric cancers. Furthermore, inhibitors of protein kinases (Gefitinib and Erlotinib) have demonstrated a remarkable efficacy in treatment of some cancers. To date, we do not succeeded in finding reports linking mutations in members of the JAK-STAT pathway and HNSCC. Therefore it is necessary to plunge into molecular research that could identify failures in the cellular machinery with consequent discovery of potential molecular targets and drug direct delivered to them. The present work aims to evaluate the presence of mutations in the JAK-STAT signaling pathway members (JAK1 and JAK2) and verify the expression level of these genes in HNSCC samples. For the mutation detection, primers were designed to cDNA molecules and allowed the amplification of contiguous 700-bp fragments that cover the entire coding region of each gene. The JAK1 and JAK2 genes were investigated in 20 HNSCC samples and no mutation was detected. Polymorphisms were found in JAK1 at codons 193 (20%), 659 (5%), 683 (25%), 699 (10%), 733 (25%) and 1032 (20%) and in JAK2 codons 163 (60%), 830 (85%) and 1063 (5%). In addition we evaluated the expression level of these genes in 87 HNSCC samples and both were found downreguted in the majority of HNSCC samples (JAK1 in 82% and JAK2 in 81%).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2104. doi:1538-7445.AM2012-2104
Abstract 2109: PIK3CA mutations in hepatocellular carcinoma in Korea
Authors: Kim Heesue 
Published: August 2012

Abstract
PI3K/AKT pathway plays a pivotal role in HCC. Mutant PIK3CA, encoding the p110a catalytic subunit, stimulate the AKT pathway and promotes cell growth in various cancers. PIK3CA mutations have been researched in many cancer types and reported low frequency of PIK3CA mutation in HCC except Korea’ case. To investigated the frequency of PIK3CA mutations in Korean patients with HCC. We sequenced the exon2, 4, 5, 7, 8, 9, 10, 20 and 21 of PIK3CA in 268 HCC samples. In these experiments, the mutation were not detected in exon4, 7, 9, 20 and detected 1 of 268 at unknown SNP (G278A) in exon2 and at unknown SNP (C848G) in exon5, 1 of 265 at unknown SNP (C1306A) and 2 of 265 at unknown SNP (C1373A) in exon8, each of 262 at unknown SNP (T2970A) and SNP (G3026A) in exon21. However, exon10 were detected 1 of 266 at unknown SNP (C1629T), 1 of 268 at G1635T (E545D) and 266 of 266 at A1634C (E545A) in 268 HCC samples. Additional experiments through normal tissue and cloning experiments realized double peak at A1634C of exon10 is not mutation and maybe arose as a result gene duplication on 22q11 partial region because exon10 primer have higher efficiency. Our study suggests no clinical characteristic relationship between HCC and mutated of PIK3CA. In conclusion, our results with using large sample size suggest the mutations in PIK3CA gene of Korean patients’ frequency is low as like other countries have been previously reported.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2109. doi:1538-7445.AM2012-2109
Abstract 2112: CA-microsatellite instability as a factor of branch migration impeding in Holliday junctions
Authors: Karpechenko Natalia Y. , Dolinnaya Nina G. , Popenko Vladimir I. , Yakubovskaya Marianna G. , Gasanova Victoria K. 
Published: August 2012

Abstract
The efficient and accurate repair of DNA double-strand breaks is critical for cell survival. HR provides an “error-free” way for the break repair. There is no loss of genetic information when homolog or sister chromatid are used for repair. They are mainly involved in HR and the frequency of non-sister chromatid interaction is greatly lower. However, when recombination occurs between non-sister chromatids, in the half of these cases it leads to loss of heterozygosity (LOH). This genetic alteration represents an important step in multistage carcinogenesis. Recently, the impact of LOH caused by HR in carcinogenesis of inherited cancer has been demonstrated to exceed impacts of point mutagenesis and non-homologous end joining. HR can be modulated by a variety of factors, and deep knowledge of the molecular background of this process is essential to predict and control corresponding genetic rearrangements. Some microsatellites represent “hot-spots” of recombination. In particular, one of the most abundant microsatellites, CA-repeats, enhances recombination between DNA molecules as observed in bacteria and eukaryotes. Previously we described spontaneous DNA-DNA interaction of homologous duplexes via HJ formation, and based on this investigation we elaborated the model system for HJs. We formed several types of HJs using: (1) random fragments restricted from pUC19; (2) fragments of the same sequence but amplified via PCR; (3) restricted fragments of the pE10 plasmid, harboring (CA/TG)31-repeat; (4) corresponding PCR products of the pE10 plasmid. Using different DNA polymerases we demonstrated that PCR amplification caused repetitive unit deletions/insertions in the (CA/TG)31-tract. It leaded to formation in PCR product of the fragment with (CA/TG)31-repeat of heteroduplexes and homoduplexes, differing mainly by one repetitive unit that is in accordance with previously published data. Corresponding restricted fragments with (CA/TG)31-repeats were significantly more stable. Using electron microscopy we showed that the majority of HJs formed by the PCR fragments with (CA/GT)31-repeats had their cross-points at the repetitive region, while the cross points of HJs formed by restricted fragments with (CA/TG)31-repeats and by entirely random sequences were mainly localized at the ends of the fragments. Demonstrated influence of (CA/TG)n-repeat instability on the branch migration is discussed in respect of the role of CA-microsatellites in homologous recombination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2112. doi:1538-7445.AM2012-2112
Abstract 2119: DDB2 and XPC influence ATR and ATM recruitment and regulate DNA damage response upon UV irradiation
Authors: Ray Alo , Milum Keisha , Battu Aruna , Wani Altaf 
Published: August 2012

Abstract
DNA damage response (DDR) pathways control the activation of DNA repair mechanisms, the activation and eventual release of cell cycle checkpoints to prevent replication of damaged DNA, and apoptosis as a last resort. These processes suggest the coordination of numerous proteins required to preserve genomic integrity. ATR and ATM kinases are central to checkpoint activation in response to DNA damage and replication stress. Activated ATR and ATM phosphorylate several proteins involved in DNA repair and cell cycle arrest. The nature of the signal, which activates ATR and ATM in response to UV damage, is not clear. Here, we showed that DDB2 and XPC, two early damage recognition factors, promote ATR and ATM recruitment and phosphorylation. ATR and ATM localize to the damage site and physically interact with XPC and DDB2. ATR and ATM recruitment and their phosphorylation are affected in cells defective in DDB2 and XPC function. In contrast, ATR- and ATM-deficiency do not regulate DDB2 and XPC recruitment to the damage site. Consequently, phosphorylation of ATR and ATM substrates Chk1, Chk2, H2AX, and BRCA1 was significantly reduced or abrogated in mutated cells, indicating that defective DDB2 and XPC function impair checkpoint signal transduction cascade in response to UV damage. Furthermore, DDB2 and XPC also regulate BRCA1 and Rad51 recruitment to the damage site, implicating their role in homologous recombination-mediated DNA repair pathway. Collectively, these data showed that ATR and ATM are present in the preincision complex with XPC, and influence DNA repair and checkpoint signaling pathways. In support of this, we revealed that depletion of ATR and ATM influence NER efficiency. These results are consistent with a model in which DDB2 and XPC cross-talk with ATR and ATM during maintenance of genomic integrity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2119. doi:1538-7445.AM2012-2119
Abstract 2124: Non-homologues end joining mediates fatty acid synthase(FASN)-associated resistance to DNA-damaging chemotherapeutics
Authors: Wu Xi , Serrano Moises , Zou Yue , Zhang Jian-Ting 
Published: August 2012

Abstract
Fatty acid synthase (FASN) is the sole mammalian enzyme capable of de novo lipid synthesis. Except in lipogenic tissues, FASN expression and activity is largely repressed by dietary fat. In contrast, abnormally elevated FASN expression and activity have been found in many types of human cancers. In vivo and in vitro studies showed that inhibition of FASN led to selective cytostatic and cytotoxic effect in cancer tissues and cells, with minimal adverse effect towards normal tissues. Clearly, FASN is no longer just an anabolic protein, but also provides growth and survival advantages to tumor cells. It has also been found that ectopic overexpression of FASN causes resistance to DNA-damaging drugs including doxorubicin, mitoxantrone, and etoposide as well as to ionizing radiation (IR), but not to non-genotoxic drugs such as vinblastine and paclitaxel. This finding suggests that FASN overexpression may regulate the DNA damage/repair pathway to help breast cancer cells survive DNA-damaging treatments. In this study, we tested this hypothesis. We found that FASN expression had profound effect on the rate of γ-H2AX clearance after exposure to IR or doxorubucin. While knocking down FASN delayed γ-H2AX clearance, FASN overexpression increased γ-H2AX clearance. Using neutral comet assay, we also found that double strand DNA break (DSB) induced by doxorubicin was increased by knocking down FASN expression but attenuated by increasing FASN expression. Furthermore, using a host-cell reactivation based assay, we showed that FASN overexpression significantly increased Non-homologous End Joining DNA repair activity. Together, we conclude that FASN likely plays an important role in regulating DSB repair in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2124. doi:1538-7445.AM2012-2124
Abstract 2138: Tumorigenic and migratory potential of Ral GTPases in non-small cell lung cancers
Authors: Guin Sunny , Ru Yuanbin , Mishra Rangnath , Vasu Vihas T. , Owens Charles , Finigan James H. , Kern Jeffrey A. , Theodorescu Dan 
Published: August 2012

Abstract
The Ral GTPase family, consisting of the Ral A and B isoforms contributes to tumor formation, invasion and metastasis, however their role in non-small cell lung cancer (NSCLC) is yet to be validated. Recently, we investigated the role of Ral GTPases in NSCLC by in vitro expression, colony formation and migration assay, in vivo tumor formation experiments, and analysis of microarray data from NSCLC patients. In vitro, Ral A and Ral B was expressed in all NSCLC cell lines studied (14) to varying levels. Increased expression of Ral A or Ral B was more frequent in Ras mutant cell lines (Ral A elevated in 2/8 cell lines with mutant KRas vs. 0/6 cell lines with WT KRas, Ral B elevated in 5/8 cell lines with mutant KRas vs. 2/6 WT KRas). Soft agar experiments with transient knockdown of Ral A, Ral B and Ral A+B in these cell lines demonstrated significant decrease (p&lt;0.05) in colony formation. Dual knockdown of Ral A and B had a 2 to 3 fold decrease (p&lt;0.05) in NSCLC cell motility in wound healing assays. In vivo, knockdown of Ral GTPases resulted in reduced subcutaneous tumor growth (p&lt;0.05) in mice injected with the knockdown cells. Microarray data from NSCLC patients was analyzed to study the correlation between Ral A and B expression with overall patient survival. High Ral A expression was associated with poor patient survival in these microarray datasets (p&lt;0.05). The above observations demonstrate that Ral GTPases play a role in lung cancer tumorigenesis and migration. In the Ras signaling cascade, Ral GTPases are downstream of Ras along with PI3K and MAPK signaling pathways. KRas mutations in NSCLC carry a poor patient prognosis. Based on our observations, we posit that Ral GTPases can be a valid target for drug development against KRas mutated lung cancers along with PI3K and MEK inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2138. doi:1538-7445.AM2012-2138
Abstract 2144: RasGRP1 induces autophagy in primary human epidermal keratinocytes resembling fail-safe mechanisms triggered by oncogenic Ras
Authors: Fonseca Lauren L. , Lorenzo Patricia S. 
Published: August 2012

Abstract
RasGRP1 is a guanyl nucleotide exchange factor for Ras that is abundantly expressed in lymphocytes, regulating their maturation and activation. Its aberrant expression has been associated to transformation in various cell types, although the role in human cancer remains largely unexplored. Our lab has previously demonstrated expression of RasGRP1 in epidermal keratinocytes, followed by studies that showed a critical role in skin carcinogenesis in mouse models of cutaneous squamous cell carcinoma through its ability to increase the dosage of active Ras. To explore whether RasGRP1 could contribute to transformation of human keratinocytes, we utilized primary epidermal keratinocytes (HEK) isolated from neonatal foreskin. In a model of tissue reconstruct, or 3-D culture, HEK manipulated to overexpress RasGRP1 (RasGRP1+) failed at generating a stratified epithelium. In fact, the RasGRP1 + cells underwent changes resembling autophagy and cell death in culture, with vacuolated cytoplasm as well as rounded bodies. Autophagy was confirmed at the molecular level by measuring increases in the LC3-II species by Western blot and the formation of a LC3 punctate pattern by immunofluorescence. Surprisingly, there was no caspase-3 activation in the RasGRP1+ HEK despite the morphological signs of apoptosis, although we noticed an increase in the expression of the BH3-only protein NOXA as early as 48 hours post RasGRP1 overexpression. Since oncogenic signals are known to induce fail-safe mechanisms that restrict cell expansion, we presumed that the changes observed in the HEK cell overexpressing RasGRP1 were due to Ras hyperactivation (oncogenic)-induced cell death. As predicted, levels of active Ras-GTP were 3 times higher in the RasGRP1+ cells compared to the wild type HEK, with a preponderance of the H-Ras isoform being activated. In line with these observations, enforced expression of an oncogenic version of the H-Ras isoform (H-RasQ61L) also resulted in cytoplasmatic vacuolization of HEK and increases in LC3-II levels. In contrast to the RasGRP1+ cells, H-RasQ61L caused activation of caspase-3 while increases in NOXA were delayed compared to those caused by RasGRP1. While RasGRP1 and oncogenic H-RasQ61L differ in some aspect of their downstream molecular pathways, probably as a result of the magnitude of Ras activation, the present findings reveal a novel RasGRP1-Ras axis that can lead to oncogenic signals in human keratinocytes. This warrants further investigation into the potential participation of RasGRP1 in keratinocyte transformation, particularly contributing to cutaneous squamous cell carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2144. doi:1538-7445.AM2012-2144
Abstract 2147: The RRas2/TC21 GTPase is essential for breast tumorigenesis and lung metastasis
Authors: Larive Romain M. , Cañamero Marta , Bustelo Xosé R. 
Published: August 2012

Abstract
Rras2/TC21 is a Ras superfamily GTPase with still unknown functions in vivo. Several observations suggest that this protein may be involved in tumorigenic processes. Thus, it has been shown that the expression of constitutively active RRas2 mutants leads to high levels of cell transformation in vitro. Moreover, this GTPase has been found overexpressed in a number of tumors, including lymphomas, oral and esophageal carcinoma, and breast cancer. To address the role of this protein in epithelial tumors, we have carried out an extensive characterization of this GTPase using RRas2 knockout mice and shRNA knockdown tumor cells. These studies revealed that RRas2 is not important for the development and/or malignant progression of skin and oral squamous cell carcinoma. Instead, we have observed that the RRas2 deficiency severily impairs breast cancer tumorigenesis and the tropism of metastatic cancer cells to the lung. The characterization of the role of RRas2 in primary tumorigenesis indicates that this GTPase is important for the proliferation and angiogenesis of tumors. In the case of metastasis, RRas2 is important for the survival and proliferation of cancer cells in the lung parenchyma. By contrast, this GTPase is not required for the lymph node infiltration, intravasation, or extravasation of cancer cells. Interestingly, the requirement of RRas2 is still maintained in breast cancer cells that express active mutants of K-Ras, indicating that RRas2 plays essential roles downstream of both Her2 and K-Ras. Signaling experiments indicate that RRas2 contributes to those processes by modulating the activation of phosphatidylinositol 3-kinase ≤ and downstream targets such as Akt, FoxO1/FoxO3 and S6 ribosomal protein.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2147. doi:1538-7445.AM2012-2147
Abstract 215: Mechanisms of p53 activation by NIAM, nuclear interactor of ARF and MDM2
Authors: Reed Sara , Tompkins Van , Hagen Jussara , Thies Katie , Cryderman Diane , Wallrath Lori , Quelle Dawn 
Published: August 2012

Abstract
Nuclear interactor of ARF and Mdm2, NIAM, is a novel regulator of the ARF-Mdm2-p53 tumor suppressor pathway. It collaborates with ARF, promotes p53 transcriptional activity, and is negatively regulated by Mdm2-mediated ubiquitination and proteasome degradation. How NIAM activates p53 is not known, however its ability to do so in ARF-null cells reveals it is an ARF-independent process. Our preliminary data suggest that NIAM could activate p53 by either competing Mdm2 away from p53-Mdm2 complexes and/or by inducing lysine 120 acetylation of p53 via the Tip60 acetyltransferase. p53 acetylation at K120 is known to be regulated by two different histone acetyltransferases, Tip60 and MOF, and to promote the specific upregulation of apoptotic genes by p53. Our preliminary data show that NIAM interacts with Tip60 and strongly promotes p53 acetylation of K120, suggesting a functional NIAM-Tip60 interaction in vivo. Tip60 is an established chromatin modifying protein that influences chromatin structure and cancer gene expression. Consistent with these characteristics of Tip60, we discovered that NIAM is a chromatin-associated protein that binds to transcriptionally active regions of the genome. Other findings connect Tip60 and NIAM. Tip60 acts through p53, ARF and Myc to control transcription and promote the DNA damage checkpoint response. We found that NIAM, like Tip60, localizes to sites of DNA repair in response to DNA damage and it is already established that the absence of either protein leads to chromosomal instability. These compelling observations link NIAM with chromatin regulation and DNA damage repair, potentially via Tip60 signaling, all of which are important for the maintenance of chromosomal stability and prevention of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 215. doi:1538-7445.AM2012-215
Abstract 2152: p38α MAPK regulates signal transduction between estrogen receptor (ER) and its antagonist by switching ER signaling from the classical to the non-classical pathway
Authors: Chen Guan , Zhi Huiying , Hou Songwang , Wang Phillip , Huang Jian , Basir Zainab , Chitambar Christopher R. , Qi Xiaomei 
Published: August 2012

Abstract
Estrogen receptor ≤ (ER) plays a decisive role in breast cancer growth through regulating gene expression via the classical {ERE (estrogen-response element) binding} and the non-classical (AP-1 recruitment by interacting with c-Jun) pathways and serves as the only target for hormone therapy. However, anti-estrogen acts on several cascades beside ER and the implications of these “off-target” effects on hormone sensitivity remain unexplored. Here we report that p38α MAPK is selectively activated by treatment of breast cancer cells with the antiestrogen tamoxifen (TAM) and activated p38α in turn switches ER signaling from the classical to the non-classical pathway leading to increased hormone sensitivity. This occurs primarily through p38α phosphorylating ER/S118 leading to its S118-dependent proteasome-degradation through the E3 ligase E6AP resulting in decreased ERE activity. Unexpectedly, Ser-118 is also required for ER to form a complex with p38α, for p38α to stimulate AP-1, to inhibit ERE, and to sensitize breast cancer cells to TAM-induced growth inhibition and ER/S118 phosphorylation alone is both necessary and sufficient for ER binding to the AP-1 DNA. These results indicate that Ser-118 phosphorylation serves as a central switch for p38α to regulate the ER signaling distribution, which may be targeted to increase breast cancer hormone sensitivity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2152. doi:1538-7445.AM2012-2152