bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1560: Loss-of-function JAK1 mutations reveal a new role of protein tyrosine kinase mutations in human cancer
Authors: Ren Yuan , Zhang Yonghong , Liu Richard Z. , Fenstermacher David A. , Wright Kenneth L. , Teer Jamie K. , Wu Jie 
Published: May 2015

Abstract
Protein tyrosine kinases (PTKs) have been perceived mostly as proto-oncogenes. PTK mutations that have been studied in human cancer usually have increased kinase activities to drive malignant phenotypes. Thus, these PTK mutations are gain-of-function (GOF) mutations. By analyzing the targeted exome sequencing data of 3,274 human tumors from 48 different tissues in the Total Cancer Care (TCC) tumor bank, we have found JAK1 truncating mutations in 36 of 635 gynecologic tumors. The highest JAK1 truncating mutation rate (9.5%) was found in endometrial cancer. These truncating mutations result in the loss of the JAK1 PTK domain. Thus, they are loss-of-function (LOF) mutations. JAK1 truncating mutations in the Cancer Cell Line Encyclopedia (CCLE) databank also occur most often in endometrial cancer cell lines. Analysis of mutation sites identified three mutation hot spots. Re-sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed JAK1 mutations and revealed that these JAK1 mutations are somatic. JAK1 and JAK2 mediate interferon (IFN)-γ-regulated tumor immune surveillance. Recurrent JAK2 LOF mutations were also found in TCC tumors but at lower rates. Similar to JAK1, the highest rate of LOF JAK2 mutations was found in endometrial/uterine cancer. No JAK1 or JAK2 truncating mutation was identified in 130 samples from hematological malignancies. Functional assays show that JAK1-deficient cancer cells are defective in IFN-γ-induced expression of tumor antigen processing machinery proteins LMP2 and TAP1 and cell surface expression of HLA molecules. These data identify recurrent JAK1 deficiency in endometrial cancer that could impair tumor antigen presentation by the MHC class I complex to cytotoxic T lymphocytes. Our findings suggest that JAK1 is a PTK tumor suppressor and reveal a novel mechanism of tumor immune evasion via LOF mutations in a PTK.
Citation Format: Yuan Ren, Yonghong Zhang, Richard Z. Liu, David A. Fenstermacher, Kenneth L. Wright, Jamie K. Teer, Jie Wu. Loss-of-function JAK1 mutations reveal a new role of protein tyrosine kinase mutations in human 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 1560. doi:10.1158/1538-7445.AM2014-1560
Abstract 1564: Spanxa1 is a novel mediator of epithelial-mesenchymal transition in lung cancer
Authors: Hsu Shih-Chun , Hsiao Yi-Jing , Yu Sing-Liang , Lee Ming-Shyue 
Published: May 2015

Abstract
SPANX (Sperm protein associated with the nucleus, X-linked) gene family express throughout spermatogenesis in agreement with a potential role in sperm development. It has been reported as a CTA (Cancer/Testis Antigen), which was highly expressed in testis and several cancers, such as gliobastoma, melanoma, testicular germ tumor and hematologic malignancies. Nevertheless, the function and molecular mechanism of SPANX involved in the cancer progression are greatly unknown. We found that the SPANX gene family member A1 (SPANXA1) was high-expressed in CL1-0, a less metastatic lung cancer cell line, and low-expressed in CL1-5, a more metastatic cell line. In vitro assays showed that the enforced expression of SPANXA1 suppressed the abilities of migration and invasion, and induced a dramatically mesenchymal - epithelial transition (EMT). In contrast, knock-down SPANXA1 could increase the cell mobility and invasiveness. To identify the underlying mechanism of SPANXA1, RNAs derived from SPANXA1-expressed cells and mock controls wrer assayed by gene expression microarrays and pathway analysis. The results showed that 1024 genes were differentially expressed in presence of SPANXA1 and six of top ten pathways belonged to EMT-related pathways analyzed by MetaCore software. The fact implied that SPANXA1 largely induces the EMT-related signalings. Quantitative RT-PCR assays were used to validate the altered expression of certain important genes induced by SPANXA1 in the identified pathways. The EMT regulating transcription factor, Slug, was decreased in SPAXA1-overexpressed cells and it also acts as a repressor for E-cadherin expression. We found that SPANXA1 mainly localized at nucleus and inhibited the formation of filopodia assayed by immunofluoresence staining. To explore the function of SPANXA1 in the nucleus, we performed Chromatin IP sequencing and the results elucidated that SPANXA1 might bind onto chromosome and regulate gene expressions. Furthermore, mouse model demonstrated that the distal metastasis was dramatically decreased in SPANXA1-overexpressed cells compared with the mock controls. These data suggest that SPANXA1 is a novel EMT modulator involved in lung cancer progression and implies the potential therapeutic role of SPANXA1 in the future.
Citation Format: Shih-Chun Hsu, Yi-Jing Hsiao, Sing-Liang Yu, Ming-Shyue Lee. Spanxa1 is a novel mediator of epithelial-mesenchymal transition in lung 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 1564. doi:10.1158/1538-7445.AM2014-1564
Abstract 1585: Chronic induction of breast cell carcinogenesis by multiple environmental and dietary carcinogens
Authors: Pluchino Lenora A. , Wang Hwa-Chain R. 
Published: May 2015

Abstract
Breast cancer, the most common type of cancer among North American
and European women, is mostly sporadic and attributable to long-term exposure
to small quantities of multiple carcinogens.
To understand how multiple carcinogens act together to induce breast
cell carcinogenesis, we investigated the activity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK), the environmental carcinogen benzo[a]pyrene (B[a]P), and the dietary
carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Non-cancerous human breast epithelial MCF10A
cells were exposed to NNK, B[a]P, and PhIP sequentially or in combination and
then analyzed for the acquisition of cancerous properties/endpoints. Transient endpoints included DNA damage, Ras-Erk-Nox pathway
activation, reactive oxygen species (ROS) elevation,
and increased cell proliferation. Constitutive endpoints
included reduced dependence on growth factors,
anchorage-independent growth, Ras-Erk-Nox pathway activation, and increased ROS
and cell proliferation. To detect agents that
can intervene with cellular carcinogenesis induced by NNK, B[a]P, and PhIP, we
investigated the activity of green tea catechins effective in blocking these
cancerous endpoints. Our study revealed, for the
first time, that combined NNK and B[a]P enhanced
breast cell carcinogenesis chronically induced by PhIP. Co-exposure was more potent than sequential exposure to
induce initiation of cellular carcinogenesis measured by induction of transient
endpoints in a single exposure and progression of carcinogenesis measured by
cellular acquisition of constitutive endpoints in cumulative exposures. Our study also revealed that combined ECG and EGCG, at non-cytotoxic levels, was more effective
than individual agents in intervention of cellular carcinogenesis induced by
combined NNK, B[a]P, and PhIP. Thus, co-exposure
to NNK, B[a]P, and PhIP should be critically examined in epidemiological
studies to reveal the impact of these carcinogens in the development of
sporadic breast cancer. Use of combined
ECG and EGCG should be seriously considered for chemoprevention of breast cell
carcinogenesis associated with long-term exposure to environmental and dietary
carcinogens.
Citation Format: Lenora A. Pluchino, Hwa-Chain R. Wang. Chronic induction of breast cell carcinogenesis by multiple environmental and dietary carcinogens. [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 1585. doi:10.1158/1538-7445.AM2014-1585
Abstract 1587: Mechanistic role of cytochrome P4501B1 in DNA adduct formation by 3-methylcholanthrene in mice: Implications for lung cancer in humans
Authors: Moorthy Bhagavatula , Zhou Guodong , Wang Lihua , Kondraganti Sudha R. , Jiang Weiwu 
Published: May 2015

Abstract
Humans are frequently exposed to polycyclic aromatic hydrocarbons (PAHs). Cytochrome P450 (CYP)1A and 1B1 enzymes are known to play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to DNA-binding metabolites, which in turn mediate carcinogenesis in target organs such as lung, breast, and skin. In this investigation, we tested the hypothesis that mice lacking the gene for Cyp1b1 will show attenuation of MC-DNA adduct formation, compared to WT mice. Eight week-old female wild type (WT) (C57BL/6J) mice or mice lacking the gene for Cyp1b1 were treated with MC (100 µmol/kg), once daily for 2 days, and animals sacrificed 1 day after the last treatment. DNA adducts from liver and lung genomic DNA were analyzed by the 32P-postabeling assay. Control animals received only the vehicle corn oil (CO). In WT mice, CO-treated group did not show any adducts, whereas MC-treated animals showed 11 adduct spots in the lung. In Cyp1b1-null mice, although there were no qualitative differences in the pulmonary adduct pattern, the levels of each adduct was markedly suppressed (25-90%), with total levels of adducts being about 15% of those formed in WT mice. In liver of WT as well as Cyp1b1-null mice, MC induced formation of 11 adducts, and the adduct pattern was similar to that of lung, but the total levels of adducts in WT mice were about a third of those seen in the lungs of the corresponding animals. In Cyp1b1-null mice, MC adducts were significantly decreased compared to WT mice, but the extent of attenuation in liver was lesser than that in lung. These results suggest that CYP1B1 plays a major role in formation of DNA adducts from MC. Because DNA adducts are pre-mutagenic lesions, our results are highly relevant to PAH-mediated pulmonary carcinogenesis. Our data suggest that CYP1B1 could be a molecular target for developing preventive and therapeutic strategies against lung cancer in humans.
Citation Format: Bhagavatula Moorthy, Guodong Zhou, Lihua Wang, Sudha R. Kondraganti, Weiwu Jiang. Mechanistic role of cytochrome P4501B1 in DNA adduct formation by 3-methylcholanthrene in mice: Implications for lung cancer in humans. [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 1587. doi:10.1158/1538-7445.AM2014-1587
Abstract 1588: Detection in vivo of a novel endogenous etheno DNA adduct derived from arachidonic acid and the effects of antioxidants on its formation
Authors: Fu Ying , Dyba Marcin , Pan Jishen , Schultz Casey , Yang Peiying , Desai Dhimant , Amin Shantu , Chung Fung-Lung 
Published: May 2015

Abstract
Previous studies showed that the 7-(1′,2′-dihydroxyheptyl) substituted etheno DNA adducts are products from reactions with epoxide of (E)-4-hydroxy-2-nonenal (HNE), an oxidation product of n-6 polyunsaturated fatty acids (PUFAs). In this work, we report the detection of 7-(1′,2′-dihydroxyheptyl)-1,N6-ethenodeoxyadenosine (DHHedA) in rodent and human tissues by two independent methods: a 32P-postlabeling/HPLC method and an isotope dilution liquid chromatography electrospray ionization tandem mass spectrometry method (ID-LC-ESI-MS/MS). This study demonstrated for the first time that DHHedA is a background DNA lesion in vivo. We showed that DHHedA can be formed upon incubation of arachidonic acid (AA) with deoxyadenosine (dA), supporting the notion that n-6 PUFAs are the endogenous source of DHHedA formation. Because the cyclic adducts are derived from the oxidation of PUFAs, we subsequently examined the effects of antioxidants, α-lipoic acid, polyphenon E and vitamin E on the formation of DHHedA and γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG), a widely studied acrolein-derived cyclic adduct arisen from oxidized n-3 and n-6 PUFAs, in the livers of Long Evans Cinnamon (LEC) rats. LEC rats are inflicted with elevated lipid peroxidation and prone to the development of hepatocellular carcinomas. The results showed that while the survival of LEC rats was increased significantly by dietary α-lipoic acid, none of the antioxidants inhibited the formation of DHHedA and only polyphenon E treatment decreased the formation of γ-OHPdG. In contrast, vitamin E caused an increase in the formation of both γ-OHPdG and DHHedA in the livers of LEC rats. This work was supported by the NCI grant: RO1-CA-134892.
Citation Format: Ying Fu, Marcin Dyba, Jishen Pan, Casey Schultz, Peiying Yang, Dhimant Desai, Shantu Amin, Fung-Lung Chung. Detection in vivo of a novel endogenous etheno DNA adduct derived from arachidonic acid and the effects of antioxidants on its formation. [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 1588. doi:10.1158/1538-7445.AM2014-1588
Abstract 1948: Human papillomavirus enhances oral cancer stem cell phenotype by regulating microRNA-181
Authors: Lee Sung Hee Hee , Rigas Nicole , Lee Chang-Ryul , Han Jiho , Kim Reuben , Kang Mo , Park No-Hee , Shin Ki-Hyuk 
Published: May 2015

Abstract
High-risk human papillomaviruses (e.g., HPV-16 and HPV-18) are closely associated with the development of human head and neck squamous cell carcinomas (HNSCC), including malignant lesions in the oral cavity. However, less is known about the possible role and the underlying mechanisms of HPV in enhancing cancer progression and promoting the virulence of cancer, including oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs) play crucial role in cancer progression, metastasis and recurrence, and are epigenetically regulated by microRNAs (miRNAs). Recent studies demonstrated that miRNA expression is affected by HPV status in HNSCC, suggesting a possible role of HPV in epigenetic regulation of CSCs. In this study, we investigated the role of high-risk HPV on malignant and CSC phenotypes as well as epigenetic regulation in OSCC. Incorporation of HPV-16 whole genome into HPV-negative OSCCs resulted in enhancement of malignant phenotypes (e.g., increased anchorage independent growth, proliferation in organotypic epithelial raft culture, and tumorigenicity in nude mice) and CSC phenotypes (e.g., increased CSC-related markers, self-renewal, and migration/invasion). High-throughput miRNA expression analysis revealed that miRNA-181 family members were significantly underexpressed in the HPV16-harboring OSCCs. HPV-16 downregulated the promoter activity of miR-181a. Furthermore, restoration of miR-181 in the presence of HPV-16 suppressed CSC-like phenotype. Taken together our data indicate that high-risk HPV enhances stemness phenotypes in OSCC by epigenetic regulation of miR-181 expression.
Citation Format: Sung Hee Hee Lee, Nicole Rigas, Chang-Ryul Lee, Jiho Han, Reuben Kim, Mo Kang, No-Hee Park, Ki-Hyuk Shin. Human papillomavirus enhances oral cancer stem cell phenotype by regulating microRNA-181. [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 1948. doi:10.1158/1538-7445.AM2014-1948
Abstract 1950: SMURF1 inhibition reduces cancer stem cell-like population in head and neck squamous cell carcinoma
Authors: Khammanivong Ali , Gopalakrishnan Raj , Dickerson Erin B. 
Published: May 2015

Abstract
Cancer stem cells (CSCs) possess capabilities for long-term survival (quiescence), self-renewal, and tumor initiation thought to be responsible for drug resistance and treatment failures for many malignancies, including head and neck squamous cell carcinoma (HNSCC). Previously, we showed that the activity of bone morphogenetic protein (BMP), a key regulator of cell differentiation, proliferation, migration, and apoptosis, is inhibited in CSC-like populations enriched from HNSCC cell lines. In contrast, the BMP signaling inhibitor SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) and CD44, a marker of CSCs, were upregulated.
Objectives: In this study, we characterized the role of SMURF1 for CSC maintenance and differentiating growth and identified a population of cells regulated by SMURF1.
Methods: We generated a stable knockdown of SMURF1 expression in CSC-like populations using a lentivirus delivered shRNA interference construct. Long-term colony formation and Calcein AM dye efflux assays were performed to assess CSC maintenance and differentiating growth.
Results: Knockdown of SMURF1 expression by shRNA reduced viability and colony formation of CSC-like cells grown in three-dimensional culture. Furthermore, reduced SMURF1 expression diminished the number of cells capable of dye efflux and decreased CD44 expression (CD44-high) in a select cell population.
Conclusion: We interpret our data to suggest that SMURF1 inhibition of BMP signaling potentiates the long-term survival of HNSCC CSCs. Reduced dye efflux and expression of CD44-high cells suggests decreased maintenance of CSC-like populations along with an increased potential for differentiating growth. Targeting SMURF1 may provide a long-term benefit for HNSCC treatment to reduce resistant CSC populations and disease recurrence.
Citation Format: Ali Khammanivong, Raj Gopalakrishnan, Erin B. Dickerson. SMURF1 inhibition reduces cancer stem cell-like population in head and neck 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 1950. doi:10.1158/1538-7445.AM2014-1950
Abstract 1951: Role of embryonic signaling pathways in lung cancer
Authors: Singh Samer , Nguyen Dao M. , Capobianco Anthony J. , Robbins David J. 
Published: May 2015

Abstract
Background: Embryonic signaling pathways that play an important role during embryo development, later on support the maintenance of adult stem cells and are also found activated in various cancers. The activated embryonic signaling, mainly Hedgehog (HH), WNT and NOTCH, have been shown to be activated in a number of cancers and demonstrated to promote growth, provide survival advantage and resistance to various drugs. The role of these embryonic signaling pathways in the development of lung cancer is not well defined. Identification of particular pathways active in cancer and elucidation of their mechanism of action in cancer development could provide a basis of devising a successful therapeutic intervention.
Objective: Define the role of embryonic signaling pathways in cancer cells.
Methodology: The presence and functional interaction of various embryonic signaling pathways in lung cancer was evaluated using human non-small cell lung carcinoma cell lines (e.g. HOP62, A549, H23, H522) as model system. The signaling pathways were inhibited using specific small molecule inhibitors and shRNAs mediated knockdown of the pathway components. The lentiviruses expressing shRNA were made and used to deliver the shRNA in NSCLC cells. The effect on the target gene expression (quantitative real time RT-PCR and western blotting), cell proliferation (ATP quantitation), cell migration (scratch/wound assay) and anchorage independent growth (soft agar assay), was evaluated. Currently, the activation of pathways in cancer cells of primary lung cancer samples is being evaluated by immunohistochemistry (IHC) and RNA in situ hybridization (ISH).
Preliminary Results and Conclusions: Attenuation of individual embryonic signaling pathways using specific small molecule inhibitors and shRNAs, indicated crosstalk and hierarchy of these pathways in controlling various processes in tested cancer cells. Our results suggest the predominance of HH signaling in non-small cell lung carcinoma. We are in the process of expanding our observation to more cell lines and human cancer samples. Our work will establish the role of embryonic signaling pathways in lung cancer and would further help in establishing a framework for future therapeutic intervention.
Citation Format: Samer Singh, Dao M. Nguyen, Anthony J. Capobianco, David J. Robbins. Role of embryonic signaling pathways in lung 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 1951. doi:10.1158/1538-7445.AM2014-1951
Abstract 1954: RNA-binding protein Musashi1 activates STAT3 signaling via PKR phosphorylation and promotes tumorigenicity of glioblastoma cells
Authors: Chen Hsiao-yun , Chiou Shih-Hwa 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is one of the deadly malignant brain tumors for human. GBM is easily recurrent and resistant to the clinical approaches. Those clinical interventions are considered a minor stress, therefore, promotes tumorigenicity of cancer cells. RNA-binding protein, Musashi-1 (Msi-1), is highly expressed in the central nervous system and it is known to act a vital role in regulation of neuron cell development. Moreover, Msi-1 is elevated in several cancer tissues and confirmed as a positive regulator in cancer progression. In this present article, we hypothesized that Msi-1 promotes cell tumorigenicity and enhances drug resistance under expose to stress condition in human GBM cells. We validated over expression of Msi-1 lead a protective effect in mitigating drug-induced cells death. Under stress stimulation, overexpression of Msi-1 triggers Msi-1-granules generation, stress granules (SGs) markers such as p-PKR, p-PERK and p-eIF2-α phosphorylation. The activated-PKR contributes down-stream leading to enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3, thereby enhancing tumorigenicity in GBM cells. Knocking down of Msi-1 and PKR obviously antagonist those finding, inhibitors of PKR and STAT3 reduced cells viability under expose to stress condition. Our findings concluded that Msi-1 contributes a positive role in regulation of tumorigenicity and drug resistance to GBM cells under stress condition by modulating PKR/STAT3 mechanism.
Citation Format: Hsiao-yun Chen, Shih-Hwa Chiou. RNA-binding protein Musashi1 activates STAT3 signaling via PKR phosphorylation and promotes tumorigenicity of glioblastoma 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 1954. doi:10.1158/1538-7445.AM2014-1954