bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 194: Deregulation of miR-222-ABCG2 regulatory module in tongue squamous cell carcinoma contributes to chemoresistance and enhanced metastatic potential
Authors: Wang Anxun , Zhao Luodan , He Qianting , Zhao Tingting , Wang Wei , Zhou Xiaofeng 
Published: August 2015

Abstract
Chemoresistance often associated with other clinical characteristics, such as enhanced metastatic potential. However, the underlying molecular mechanism remains unclear. Our previous studies had revealed that microRNA-222 (miR-222) regulates the cell invasion [Cancer Genomics Proteomics 2009 6:131-138], and plays a role in cell proliferation in tongue squamous cell carcinoma (TSCC) [FEBS Lett. 2010 584(18):4115-20]. The aim of this study is to elucidate the role of miR-222-ABCG2 pathway in the association of cisplatin (cDDP) resistance with enhanced cell migration and invasion ability in TSCC. First, we confirmed the association between cDDP resistance (measured by IC50) and metastatic potential (assessed by migration and invasion assays) using TSCC cell lines and primary cultures from TSCC cases. The siRNA-mediated ABCG2 knockdown led to enhanced cDDP responsiveness, and reduced metastatic potential in TSCC cells. On the contrary, ABCG2 overexpression induced cDDP resistance, and enhanced cell migration and invasion in TSCC cells. Bioinformatics analysis revealed that ABCG2 is a target gene of miR-222, and the direct interaction of miR-222 with ABCG2 mRNA was confirmed by luciferase reporter gene assay. Functional analyses indicated that miR-222 downregulated the expression of ABCG2 gene and enhanced cDDP responsiveness, as well as reduced cell migration and invasion in TSCC cells. Thus, our results confirmed the association between cDDP resistance and enhanced metastatic potential in TSCC. ABCG2 is a direct target gene of miR-222, and deregulation of miR-222-ABCG2 regulatory module in TSCC contributes to both cDDP resistance and enhanced metastatic potential.
Citation Format: Anxun Wang, Luodan Zhao, Qianting He, Tingting Zhao, Wei Wang, Xiaofeng Zhou. Deregulation of miR-222-ABCG2 regulatory module in tongue squamous cell carcinoma contributes to chemoresistance and enhanced metastatic potential. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 194. doi:10.1158/1538-7445.AM2015-194
Abstract 1945: Self-phosphorylation primes JNK2 for activation by MKK4 in glioblastoma and non-small cell lung carcinoma
Authors: Kaoud Tamer S. , Dalby Kevin N. 
Published: August 2015

Abstract
JNKs (c-Jun N-terminal kinases) are members of the mitogen-activated protein kinase (MAPK) family, known primarily for their response to cell stress. JNK activation is mediated cooperatively by both MKK4 and MKK7. Uniquely, c-Jun N-terminal kinase 2 (JNK2) isoform has been reported to be constitutively activated (without MKK4/7). Recent studies in glioblastoma and lung carcinoma have identified important roles for JNK2 constitutive activation (but not JNK1). Using phospho-specific antibodies, recombinant activated (MKK4 & MKK7), inactivated (JNK1 & JNK2) and phos-tag PAGE, we have identified that JNK2 self-phosphorylation results in the production of active JNK2 (phosphorylated on both Thr-183 and Tyr-185) and a form of mono-phosphorylated JNK2 (phosphorylated only on Thr-183) whose activation is MKK4-dependent (phosphorylates Tyr-185), but MKK7-independent. The effect of MKK4 on JNK2 constitutive activation has been further investigated in mouse embryonic stem cells that have MKK4 and/or MKK7 knocked out. MKK4 but not MKK7 existence in these cell lines enhanced JNK2 autoactivation. Interestingly, knockdown of MKK4 or JNK2 in U78MG glioblastoma cell line, A549 non-small cell lung carcinoma cell line and HEK293 cells dramatically decreased JNK2 constitutive activation and inhibited A549 cellular growth and anchorage-independent growth that have been reported to be regulated by JNK2 constitutive activity. As a conclusion, our data demonstrates for the first time that JNK2 autophosphorylation primes its activation by MKK4. This phenomenon can allow JNK2 activity to be further regulated by discrete cellular signals.
Citation Format: Tamer S. Kaoud, Kevin N. Dalby. Self-phosphorylation primes JNK2 for activation by MKK4 in glioblastoma and non-small cell lung carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1945. doi:10.1158/1538-7445.AM2015-1945
Abstract 1949: Oncogenic signaling in amphiregulin- and EGFR-expressing PTEN-null human breast cancer
Authors: Kappler Christiana S. , Guest Stephen T. , Smith Ericka L. , Irish Jonathan C. , Garrett-Mayer Elizabeth , Kratche Zachary , Ethier Stephen 
Published: August 2015

Abstract
A subset of triple negative breast cancer (TNBC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) and loss of PTEN, and patients with these factors have a poor prognosis. In addition, approximately half of all basal breast cancers show autocrine activation of EGFR by amphiregulin (AREG), resulting in altered receptor trafficking and downstream signaling. However, despite the strong rationale for targeting EGFR in the treatment of TNBC, EGFR inhibitors have performed poorly in clinical trials. To further analyze the signaling processes active in this subset of TNBC, we performed reverse-phase protein array (RPPA) analysis on SUM149 cells, a highly tumorigenic and metastatic PTEN-null cell line that expresses high levels of AREG and EGFR, and MCF10A cells, a non-transformed mammary epithelial cell line cultured in the presence of either EGF or AREG. This analysis identified a number of signaling components mediated specifically by amphiregulin, including marked changes in integrin expression and increased levels of fibronectin, which is known to be a mediator of invasive capacity via interaction with integrin β1. RPPA analysis also revealed elevated AKT activity in SUM-149 cells, which was not surprising given the lack of PTEN expression. Interestingly, this AKT activity is not abrogated by treatment with the EGFR inhibitor gefitinib, nor by treatment with PI3K inhibitors. These findings and the results of preliminary experiments in SUM149 cells re-expressing PTEN suggest that AKT activity in these cells is, at least partly, independent of EGFR and PI3K activity. In addition, expression profiling demonstrated that AREG-activated EGFR regulates gene expression differently than EGF-activated EGFR, and functional analysis via genome-scale shRNA screening identified a set of genes, including PLK1 and BIRC5, that are regulated by EGFR in MCF10A cells but uncoupled from EGFR signaling in SUM149 cells, although they are essential for the survival of SUM-149 cells. Thus, our results demonstrate that in cells with constitutive EGFR activation and PTEN loss, critical survival genes are uncoupled from regulation by EGFR, a mechanism that is likely to mediate resistance to EGFR inhibitors.
Citation Format: Christiana S. Kappler, Stephen T. Guest, Ericka L. Smith, Jonathan C. Irish, Elizabeth Garrett-Mayer, Zachary Kratche, Stephen Ethier. Oncogenic signaling in amphiregulin- and EGFR-expressing PTEN-null human breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1949. doi:10.1158/1538-7445.AM2015-1949
Abstract 1955: IKKϵ maintains MEK activation and suppresses non-canonical NF-κB signaling in triple-negative breast cancer
Authors: House Carrie , Grajales Valentina , Wubneh Helmae , Kimble Danielle , Kim Marianne , Annunziata Christina 
Published: August 2015

Abstract
Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multifaceted pathway interactions and compensatory signaling. We hypothesized that a subset of TNBCs expresses IKKϵ to promote a specific NF-κB signaling program that can enhance metastatic potential. Our data suggest that IKKϵ supports MEK activation and suppresses non-canonical signaling by the p52 NF-κB transcription factor. We found that NF-κB p52 expression is inversely proportional to activated MEK. We further demonstrate that IKKϵ and MEK cooperate to support viability and invasion potential under adherent conditions, whereas the p52 transcription factor supports viability under non-adherent conditions, underscoring the contrasting roles of these proteins. This study illustrates the diverse roles of NF-κB signaling components in TNBC, and highlights the adaptability of NF-κB in maintaining cancer cell survival under different microenvironments. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.
Citation Format: Carrie House, Valentina Grajales, Helmae Wubneh, Danielle Kimble, Marianne Kim, Christina Annunziata. IKKϵ maintains MEK activation and suppresses non-canonical NF-κB signaling in triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1955. doi:10.1158/1538-7445.AM2015-1955
Abstract 1957: Negative regulation of Sox9 by glycogen synthase kinase 3 beta phosphorylation and SCFFbw7-dependent ubiquitination in cancer
Authors: Hong Xuehui , Liu Wenyu , Inuzuka Hiroyuki , Liu Lianxin , Pine Sharon R. 
Published: August 2015

Abstract
Sox9 is a member of the SOX [Sry-related high-mobility group (HMG) box] family of transcription factors, with known functions in proliferation, epithelial-mesenchymal transition (EMT), stem cell maintenance and senescence. Sox9 protein levels are elevated in several different cancer types, including lung cancer and osteosarcoma. Furthermore, Sox9 overexpression is associated with poor survival in both cancer types. We recently reported that Sox9 is a direct transcriptional target of the Notch signaling pathway and mediates Notch1-induced EMT in lung cancer (Capaccione et al., Oncotarget, 2014). Fbxw7 (F-box and WD repeat domain-containing 7) is a member of the SCFFbw7E3 ubiquitin ligase complexthat targets several oncogenic proteins for degradation, including Notch1. We hypothesized that Sox9 is targeted for degradation by SCFFbw7. Knocking down or overexpressingFbxw7 significantly increasedor decreased, respectively, endogenous Sox9 protein levels in lung cancer and osteosarcoma cell lines. In addition, overexpression of Fbxw7 resulted in active degradation of ectopic Sox9 protein levels, when assessed in combination with cycloheximide, and did so in a dose dependent-manner.Furthermore, both Sox9 and FBXW7 were detected in immunoblots after the reciprocal protein was immunoprecipitated. Because substrate degradation by SCFFbw7 is typically phosphorylation-dependent, frequently by glycogen synthase kinase (GSK)3-beta, we examined whether modulation of GSK3-beta could affect FBXW7-induced Sox9 degradation. Treatment of cells with the GSK3-beta inhibitor, CHIR99021, completely abolished Sox9 degradation by ectopically overexpressed FBXW7, in a dose-dependent manner. We next identified four putative phosphorylation sites within potential FBXW7 degron motifs in Sox9.Mass spectrophotometric analysis confirmed these sites within Sox9 are indeed phosphorylated.In summary, we found that the E3 ubiquitin ligase complex (SCFFbw7) targets Sox9 for ubiquitin-mediated degradation in a GSK3-beta-mediated Sox9 phosphorylation-dependent manner. As a result, this negative regulation of Sox9 by GSK3-beta/FBXW7 could lead to inhibition of Sox9-mediated proliferation, EMT and stemness. This new regulatory mechanism of Sox9 could have diagnostic and therapeutic implications for lung cancer, osteosarcoma, as well as other cancers.
Citation Format: Xuehui Hong, Wenyu Liu, Hiroyuki Inuzuka, Lianxin Liu, Sharon R. Pine. Negative regulation of Sox9 by glycogen synthase kinase 3 beta phosphorylation and SCFFbw7-dependent ubiquitination in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1957. doi:10.1158/1538-7445.AM2015-1957
Abstract 1969: Regulation of cell cycle progression in BRAFV600E inhibitor-resistant human melanoma by histone deacetylase inhibitor
Authors: Toresss-Collado Antoni X. , Nazarian Ramin , Jazirehi Ali R. 
Published: August 2015

Abstract
The BRAFV600E specific inhibitor vemurafenib blocks MAPK pathway and induces cell cycle arrest at the G0/G1 phase leading to apoptosis of melanomas. To gain an understanding of the dynamics of cell cycle regulation during vemurafenib therapy, we established several vemurafenib-resistant (VemR) human melanoma sublines from BRAFV600E vemurafenib-sensitive parental lines. Vemurafenib provoked G0/G1 phase arrest in parental but not in VemR sublines. We hypothesized that the refractoriness of VemR sublines to vemurafenib-mediated cell cycle inhibition can be partially rescued by the chromatin modifier SAHA. SAHA promoted G2/M arrest at expense of the S phase irrespective of vemurafenib sensitivity. In parental lines, combination of SAHA and vemurafenib induced both G0/G1 arrest and apoptosis, whereas in VemR sublines combination induced G0/G1 as well as G2/M arrest resulting in dramatic cytostasis. VemR sublines preferentially exhibited ERK1/2 and AKT hyperphosphorylation. Gene expression profiling revealed MAPK hyperactivation and deregulations of cyclins and cyclin-dependent kinases (CDK) in VemR sublines, all of which were reversed by SAHA; changes that may explain the cytostatic effects of SAHA. These results suggest that unresponsiveness of VemR sublines to the biological effects of vemurafenib may be amenable by SAHA. These in vitro results, while require further investigation may provide rational biological basis for combination therapy in the management of VemR melanoma.
Citation Format: Antoni X. Toresss-Collado, Ramin Nazarian, Ali R. Jazirehi. Regulation of cell cycle progression in BRAFV600E inhibitor-resistant human melanoma by histone deacetylase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1969. doi:10.1158/1538-7445.AM2015-1969
Abstract 1978: Relationship between transcription factor TWIST1 and microRNA34a in metastatic cancer cells
Authors: Khan Md. Asaduzzaman , Tania Mousumi , Wei Chunli , Fu Junjiang 
Published: August 2015

Abstract
Background: Micro RNAs (miRNAs) are the important tools in RNA-interference (RNAi) technology, which is comparatively recent but one of the most promising bio-molecular tools for gene regulation. MiRNAs can interfere with certain genes in target specific manner, and they are being extensively investigated for cancer therapeutics. This study investigated the role of miR-34a on the expression of transcription factor TWIST1, which is involved in metastatic carcinomas.
Methods: The expression of miR34a and TWIST1 was measured by quantitative polymerase chain reaction (qPCR) analysis in different cancer cell lines and breast cancer tissues. Then we have transfected the precursor and inhibitor of miR-34a into another TWIST1 rich 4T1 cancer cell, and isolated the total RNA and miRNAs for the analysis of TWIST1 expression, as well as miR-34a.
Results: Initially, we have observed that miR34a is highly expressed in lower invasive MCF7 and T47D cancer cells, whereas its expression in higher invasive MDA-MB-231, MDA-MB-435 and BT-549 cancer cells is low. Oppositely, TWIST1 expression is relatively lower in MCF7 and T47D cells, but higher in MDA-MB-231, MDA-MB-435 and BT-549 cells. This inverse relationship indicated that TWIST1 might be a target of miR-34a. Interestingly transfection of miR34a precursor inhibited TWIST1 expression in 4T1 cancer cells.
Conclusions: This study reports that miR-34a has reverse correlation with the high TWIST1 expression in metastatic breast cancer. Regulation of TWIST1 by miR-34a might be a potential tool in cancer diagnostics and therapeutics, especially for the treatment of metastatic cancers.
Funding support: This work was supported in part by the NSFC (81172049), the Science and Technology Innovation Team of Colleges and Universities of Sichuan Province (13TD0032), the Applied Basic Research Program of Science and Technology Department of Sichuan Province (14JC0797,)and Luzhou City Special Foundation (2013LZLY-J10).Corresponding author email:fujunjiang@hotmail.com
Citation Format: Md. Asaduzzaman Khan, Mousumi Tania, Chunli Wei, Junjiang Fu. Relationship between transcription factor TWIST1 and microRNA34a in metastatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1978. doi:10.1158/1538-7445.AM2015-1978
Abstract 1981: Regulation of NF-kB signaling pathway by glucocorticoid in breast cancer cells
Authors: Lopez-Dee Zenaida , Ling Jun 
Published: August 2015

Abstract
Steroid hormone signaling through nuclear receptors plays critical roles in every stage of breast cancer development. Although estrogen receptor (ER) and progesterone receptor (PR) are well studied, due to the high heterogeneity of breast cancer, therapies targeting these nuclear receptors are still not effective enough or generate inconsistent and even controversial results. In this study, we focused on the glucocorticoid (GC)/ glucocorticoid receptor (GR) signaling to investigate how it regulates NFkB activity that leads to differential outcomes in different subtypes of breast cancer. A qRT-PCR array containing a curated NF-kB responsive gene set (84 genes) was utilized in this study to analyze the effect of GC/GR on basal and luminal subtypes of breast cancer cells. It was identified that MDA-MB-231 cells (basal subtype) were more responsive than MCF7 cells (luminal subtype) to GC treatment as the former showed more down- or up-regulated NF-kB target genes. Negative regulation of the NF-kB target genes was more prevalent in both cells, which is consistent with the general rule of trans-repression of NF-kB by GR. However, there were also a number of NF-kB target genes up-regulated by GC in both subtypes of breast cancer cells, suggesting that the trans-activation of NF-kB by GR may also play an important role in breast cancer cell growth and pathological behaviors. Among the differentially expressed genes in both cell types, genes with functions in cell migration and adhesion are highly regulated, such as CXCL1, CCL2, ICAM1, VCAM1, BIRC3 and SNAP25, implying that GC may mainly regulate the invasion and metastasis of breast cancer cells via NF-kB signaling. Biochemical studies identified that GR was activated by GC differently in MDA-MB-231 and MCF7 cells; the interaction between GR and various NF-kB subunits were also different in these cells, thus elucidating part of mechanisms underlying the differential regulation of NF-kB by GC in different subtypes of breast cancer cells.
Citation Format: Zenaida Lopez-Dee, Jun Ling. Regulation of NF-kB signaling pathway by glucocorticoid in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1981. doi:10.1158/1538-7445.AM2015-1981
Abstract 2039: Trim21: A novel regulator of Par-4 and oncogenic signaling
Authors: Nguyen Jeffrey , Irby Rosalyn 
Published: August 2015

Abstract
Prostate apoptosis response protein 4 (Par-4) is a tumor suppressor that induces apoptosis selectively in cancer cells. Although Par-4 levels have been shown to be regulated by ubiqutin-mediated proteolysis, it is not known whether Par-4 function is regulated by ubiquination. To identify novel protein interaction partners of Par-4, we used co-immunoprecipitation of Par-4, followed by in-solution trypsin digestion and mass spectrometry. We demonstrate that Trim21, an E3 ligase that acts as a negative regulator of inflammatory signaling partially through ubiquitination of various downstream transcription factors, is a novel Par-4 interacting protein, and may regulate the activity of Par-4. Furthermore, similar to Par-4, we found that Trim21 inhibits Akt activation. Our studies reveal that Trim21 is a novel E3 ligase of Par-4, and extends its role from regulation of immune signaling to regulation of apoptosis and oncogenic signaling in colon cancer cells.
Citation Format: Jeffrey Nguyen, Rosalyn Irby. Trim21: A novel regulator of Par-4 and oncogenic signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2039. doi:10.1158/1538-7445.AM2015-2039
Abstract 2051: Regulation of RNA processing by PADI4 pathway
Authors: Tanikawa Chizu , Ueda Koji , Nakamura Yusuke , Matsuda Koichi 
Published: August 2015

Abstract
We recently reported that p53 regulated protein citrullination through the transcriptional regulation of PADI4 that converts an arginine residue in proteins to a citrulline residue. In response to DNA damage, p53-PADI4 pathway induced citrullination of NPM1, Histone H4, and Lamin C, and subsequently promoted apoptotic pathway. To elucidate entire roles of p53-PADI4 pathway, we screened novel targets by LC-MS analysis and found that majority of hnRNP family members are citrullinated by ectopic expression of PADI4. LC-MS analysis and specific antibody revealed citrullination of hnRNP G at arginine 223 residue. In addition, citrullination of hnRNP G inhibited interaction with RNA helicases or other hnRNP family members. Citrullination motif analysis revealed the enrichment of D, G, S, E, and A at -1 (56.0%), +1 (55.8%) and +2 (45.8%) position. Since hnRNP family is involved in RNA processing, we conducted RNA sequence analysis by using bone marrow from Padi4+/+ or Padi4-/- mice. As a result, Padi4 was shown to alter the splicing pattern of several genes. Moreover, Padi4-/-p53+/- mice exhibited significantly shorter survival time compared with Padi4+/+p53+/- mice. Our finding revealed a novel role of p53-PADI4 pathway in RNA splicing and human carcinogenesis.
Citation Format: Chizu Tanikawa, Koji Ueda, Yusuke Nakamura, Koichi Matsuda. Regulation of RNA processing by PADI4 pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2051. doi:10.1158/1538-7445.AM2015-2051