bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2170: The SWI/SNF nucleosome-remodeling gene PBRM1 - Another tumor suppressor gene in renal cell carcinomas
Authors: Krause Hans , Ikromov Odiljon , Kamal Eymad All , Miller Kurt , Schostak Martin , Jandrig Burkhard 
Published: August 2012

Abstract
The polybromodomain containing gene PBRM1 was recently discovered to harbor 41% truncating somatic mutations in clear cell renal cell carinomas (ccRCC). Next to the VHL tumor suppressor gene this gene is thought to be the second major cancer gene in ccRCCs. PBRM1 (also called BAF180) belongs to the SWI/SNF-B or PBAF complex and provides functional specificity to this class of chromatin remodelers by binding to acetylated histones via its six bromodomains, two BAH domains, and one HMG domain (the latter binding to nucleosomal DNA). PBRM1 is located on chromosome 3p21 in close vicinity to VHL and SETD2 genes arguing for a putative gatekeeper function in cases where VHL loss alone is insufficient for ccRCCs tumorigenesis. PBRM1 codes for at least three major transcripts of about 7500nt in length whose expression was measured by Q-PCR in 49 cases of paired normal and tumor tissue samples of RCC patients who underwent radical tumor nephrectomy at our clinic between 06/2009 and 10/2010. 20/49 cases showed a marked upregulation of PBRM1 expression whereas in 29/49 cases PBRM1 was clearly downregulated. To assess the contribution of somatic mutations for PBRM1 downregulation we resequenced 29 PBRM1 exons of 48 tumor tissues. Specific truncating mutations were detected in 6 (15.4%) of 39 ccRCCs. These mutations include 5 deletions in exons 1, 10, 16, 23, and 24, as well as one insertion in exon 16. All these heterozygous mutations lead to a decrease of PBRM1 mRNA expression, that was verified by Q-PCR measurements. In addition, 6 coding SNPs (cSNPs) were revealed as well as 5 SNPs in intronic regions, one of the latter is in close vicinity to the splice acceptor site of exon 9. Concurrent expression of three major transcripts (var. 1,2, and 4) is seen in all 46 matched normal and tumor samples analyzed so far. In 22 (47.8%) samples we detected a dominance of var.1 (NM_018165) in normal tissue when compared to the corresponding tumor sample, that preferentially expresses var.4 (NM_181042). So far our data set of 15.4% truncating mutations in 39 cases of ccRCC could not match the exceptional high number of 41% reported in the initial report by the Sanger Institute. Truncating mutations of PBRM1 have been described in breast cancers but were absent in lung carcinomas, despite the fact that LOH at 3p21 is frequently seen in these cancers. Understanding the contribution of PBRM1 expression changes, be it on the genomic level (mutation) and/or mRNA (differential splicing), to clinical disease progression and outcome in kidney cancer needs further investigation.
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 2170. doi:1538-7445.AM2012-2170
Abstract 2171: Human FLCN delays cell cycle progression through late S and G2/M-phases: Effect of phosphorylation and tumor-associated mutations
Authors: Laviolette Laura A. , Wilson Jonas , Koller Julia , Zimmer Michael , Iliopoulos Othon 
Published: August 2012

Abstract
The Birt-Hogg-Dube (BHD) autosomal dominantly inherited syndrome has clinical features that include the development of skin fibrofolliculomas, lung cysts, and renal neoplasia. Renal tumors occur in approximately one third of individuals with BHD. The gene responsible for BHD syndrome is Folliculin (FLCN), which encodes a 68kD phosphoprotein (FLCN). One allele of the FLCN gene is mutated in the germline of &gt;90% of BHD patients and somatic mutations or loss of the wild type FLCN allele are observed in the renal tumors of patients with BHD, suggesting that FLCN acts as a tumor suppressor protein. The human renal cell carcinoma cell line UOK257, derived from a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into the FLCN-deficient UOK257 cells decreased their proliferation rate. Here we tested whether this difference in cell proliferation rate may be partly attributed to the effect of FLCN on cell cycle progression. We synchronized FLCN-deficient UOK257 cells and their isogenic, wild type or mutant FLCN counterparts, by double thymidine block and followed cell cycle progression after release. UOK257 cells expressing wild type FLCN exhibited a slower progression through the late S and G2/M-phases of the cell cycle compared to the vector only controls (FLCN-deficient). The reintroduction of tumor-associated FLCN mutants failed to delay cell cycle progression in UOK257 cells, indicating that the effect of wild type FLCN on cell cycle progression may contribute to its tumor suppressor function. FLCN phosphorylation on serines S62 and S73 fluctuates throughout the cell cycle and peaks in cells arrested at the G2/M boundary following treatment with nocodazole. In keeping with this observation, the reintroduction of a FLCN S62/73 phosphomimetic mutant into the UOK257 cell line resulted in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that orderly changes in FLCN phosphorylation during the cell cycle are linked to and may be required for its effect on cell cycle progression and possibly its activity as a tumor suppressor protein. We expect that these studies will provide insight into the role of FLCN in kidney tumorigenesis and will identify putative new targets for therapeutic intervention.
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 2171. doi:1538-7445.AM2012-2171
Abstract 2173: Heterozygosity for Mtap accelerates lymphomagenesis in Emu-Myc and Pten +/− mice
Authors: Kruger Warren D. , Kadariya Yuwaraj , Tang Baiqing , Al-Saleem Tahseen , Haykawa Kyoko 
Published: August 2012

Abstract
The gene encoding the methionine salvage pathway methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene that is frequently inactivated in a wide variety of human cancers. Loss of MTAP is associated with elevated expression of ornithine decarboxylase (ODC), a key enzyme in the synthesis of polyamines and a known oncogene. Here, we have examined if heterozygosity for a null mutation in Mtap could accelerate tumor development in two different mouse cancer models, Eα-myc transgenic and Pten+/−. We found that the median age of tumor formation in both models was significantly accelerated in Mtap+/− compared to Mtap+/+ mice. In Eα-myc mice, Mtap mutations accelerated the formation of lymphomas from cells in the early pre-B stage and these tumors tended to be of higher grade and have higher expression levels of ODC protein compared to those observed in control Emu-myc Mtap+/+ mice. Supprisingly, examination of Mtap mRNA and protein in highly lymphoma infiltrated tissue in heterozygous animals indicates that &gt;80% of the tumors maintain expression of the Mtap allele. Our findings show that germline inactivation of a single Mtap allele enhances lymphomagenesis in both Emu-myc and Pten+/− mice and is associated with elevated levels of ODC.
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 2173. doi:1538-7445.AM2012-2173
Abstract 2174: MLL3 act as a tumor suppressor gene in pancreatic cancer
Authors: Gupta Sonal , Mukherjee Radha , dal Molin Marco , Goggins Michael , Hebbar Sachin , Maitra Anirban 
Published: August 2012

Abstract
Myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) is a histone 3-lysine 4 methyltransferase, found frequently mutated in a variety of solid tumors, including pancreatic ductal adenocarcinoma where it is the fourth most common somatically mutated gene (excluding homozygous deletions). Despite various somatic mutations, the functional role of MLL3 has not been studied in pancreatic cancer. Upon careful compilation of all the known MLL3 somatic mutations in various solid tumors, no hotspots were identified. However, regardless of the mutation status, we found significantly diminished MLL3 expression in a panel of patient-derived pancreatic tumor cell lines, tumor xenografts and archived patient tumors. Examination of the MLL3 promoter region revealed a CpG island. Methylation of the promoter region was confirmed by methylation-specific PCR in majority of the tumor cell lines and xenografts. Treatment with DNA methyltransferase inhibitor relieved the promoter methylation causing increase in MLL3 transcript expression. Further, knockdown of MLL3 by siRNA in cell lines increased anchorage-independent growth, and enhanced the migration/invasion phenotype of cancer cells. Agilent microarray analysis of two pancreatic cancer cell lines subsequent to knockdown of residual MLL3 function by siRNA, revealed a battery of potential gene targets and pathways regulated by MLL3. The most common Gene Ontology (GO) categories for differentially expressed genes include those involved in cell cycle, cell migration, and DNA repair, underscoring the phenotypes observed with MLL3 siRNA. We indeed observed an increase in MLL3 expression upon DNA damage which was independent of p53 status. Using transgenic mouse model of pancreatic cancer, we are investigating whether loss of MLL3 function in exocrine pancreas cooperates with mutant Kras to accelerate the progression of pancreatic intraepithelial neoplasia (PanIN) to invasive neoplasia.
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 2174. doi:1538-7445.AM2012-2174
Abstract 2180: Identification of nuclear transcription factor Y (NF-Y) as a novel key transcriptional regulator of the tumor-suppressor gene DAPK1
Authors: Schmidt Christopher R. , Oakes Christopher C. , Boutros Michael , Plass Christoph 
Published: August 2012

Abstract
The death-associated protein kinase 1 (DAPK1) belongs to a family of multifunctional Ser/Thr-kinases that plays a crucial role in the mediation of cell death, autophagy and tumor suppression. Loss or reduced expression of DAPK1 occurs in the majority of patients with chronic lymphocytic leukemia (CLL) and many other non-hematological tumors commonly involving epigenetic silencing. To identify novel key DAPK1 transcriptional regulators, we conducted an siRNA screen in HEK293 cells using a custom library targeting over 60 individual genes with known or predicted DNA-binding function and general potential to modulate transcription. Candidate gene selection for siRNA-mediated knock-down was based on previous genome-wide siRNA screening experiments and in silico prediction of binding sites at the DAPK1 promoter region. As endogenous readout, DAPK1 mRNA expression was monitored by qRT-PCR.Using this strategy, we identified nuclear transcription factor Y (NF-Y) as the top positive regulator of DAPK1 that reduces its expression down to 55% of the level determined in untargeted control siRNA-treated cells. NF-Y is a well known transcriptional regulator of genes involved in cell cycle control, apoptosis and stress response. NF-Y consists of 3 subunits, NF-YA, -YB and -YC, forming a trimeric complex which is essential for specific binding of CCAAT boxes located proximal to the transcriptional start sites of genes. In addition to HEK293 cells, we were able to diminish DAPK1 mRNA expression upon siRNA-mediated NF-Y knockdown in a panel of 6 different cancer cell lines. Conversely, co-overexpression of NF-YA,-YB and -YC in HEK293 cells leads to increased expression levels of DAPK1. To investigate whether NF-Y contributes directly or indirectly to DAPK1 transcriptional regulation, DAPK1 luciferase reporter constructs harboring the predicted NF-Y binding site were generated. Point mutation of the reverse CCAAT-box in the DAPK1 promoter constructs significantly reduces the promoter activity down to 60% of the wild-type promoter. Furthermore, NF-Y knockdown significantly reduces the activity of the wild-type DAPK1 luciferase construct down to 55% in reporter assays. Strikingly, the CCAAT-box mutated constructs do not show altered activity after NF-Y depletion, suggesting a direct regulation of DAPK1 by NF-Y. Taken together, these results strongly indicate a direct role for NF-Y in the regulation of basal DAPK1 transcription levels, and also propose a novel mechanism for aberrant transcriptional silencing of DAPK1 in 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 2180. doi:1538-7445.AM2012-2180
Abstract 2181: Characterization of PHF11, a candidate tumor suppressor gene, in esophageal squamous cell carcinoma
Authors: Cheung Wai Ying , Ko Josephine Mun Yee , Yu Zhuoyou , Lung Maria Li 
Published: August 2012

Abstract
Background and aims: Esophageal squamous cell carcinoma (ESCC) has a high incidence in China, with five-year survival rates in Hong Kong of only 10.7%. Loss of chromosome 13q regions is a frequent event in ESCC. A candidate tumor suppressor gene (TSG), PHF11, located at 13q14.2 was identified from our previous chromosome transfer study and shows 100% down-regulation in 18 cancer cell lines, including 16 ESCC cell lines, compared to expression in an immortalized normal esophageal epithelial cell line. This study aims to investigate the functional role of PHF11 in ESCC and to investigate the possible role of PHF11 in transcriptional regulation or histone modification as the proteins in the plant homeodomain finger (PHF) protein family are reported to contribute to the two implicated functions. Methods: Real-time PCR was carried out to validate the expression of PHF11 in tumor tissues of ESCC patients compared to their respective normal counterparts. The two isoforms of PHF11, PHF11a and PHF11b, were cloned into expression vectors and transfected into ESCC cell lines, KYSE150 and KYSE180, respectively. Clones expressing PHF11 were established for colony formation assay and MTT assay. To identify the subcellular localization of PHF11, subcellular fractionation was performed using immortalized normal esophageal epithelial cell lines followed by SDS-PAGE and Western blotting. Results: Real-time PCR verified that 42% of the 41 patient samples showed at least 2-fold down-regulation in PHF11 expression. The colony formation assay showed that the two isoforms of PHF11, PHF11a and PHF11b, have the ability to suppress cell growth using two ESCC cell lines, KYSE150 and KYSE180. The MTT assay also showed that both isoforms of PHF11 have the ability to suppress cell proliferation. Our data showed that PHF11 is localized in the nucleus of the immortalized normal esophageal epithelial cell lines. Conclusions: It was observed that almost half of the patient samples screened showed a significant down-regulation of PHF11, suggesting its possible role as a candidate TSG. Suppression of colony growth and cell proliferation in the PHF11 expressing clones indicate that the protein may suppress tumorigenicity of ESCC cells. The nuclear localization of PHF11 observed in the immortalized normal esophageal epithelial cell line is consistent with a possible role in transcriptional regulation or histone modification, though further studies are required to further investigate this.
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 2181. doi:1538-7445.AM2012-2181
Abstract 2187: Plk2 loss and mTOR signaling in advanced colorectal cancer
Authors: Matthew Elizabeth M. , Yang Zhaohai , El-Deiry Wafik S. 
Published: August 2012

Abstract
Background: Dysregulated cell growth and proliferation can promote tumorigenesis. Mammalian target of rapamycin (mTOR), a central promotor of cell growth and proliferation, is inhibited by Tuberous Sclerosis Complex 1 (TSC1) protein. Polo-like kinases (Plk) 1 & 2 are downstream molecules in the p53 pathway. TSC1 is known to interact with Plk1 in a cell cycle-regulated, phosphorylation-dependent manner. Recently we found that Plk2 impacts mTOR signaling in the same manner as TSC1, and human lung tumor cells deficient in Plk2 grew significantly larger than control tumor cells. We hypothesized that Plk2 functions as a tumor suppressor protein and seek to investigate Plk2 function as it relates to mTOR signaling and tumor suppression. Design: This is a pilot study. Archived pathology specimens from 6 advanced colorectal adenocarcinomas (stages III & IV) were retrieved, and immunohistochemical staining for phosphorylated mTOR (serine 2448), phosphorylated ribosomal S6 (Serine 235/236), Plk2, p53, Ki67, and glucose transporter 1 (Glut1) were performed. The staining pattern was analyzed. Results: Plk2 is expressed in normal colon epithelium, with a punctate staining pattern in the supranuclear region. In colorectal adenocarcinoma, Plk2 demonstrates partial loss of expression, complete loss of expression, or disrupted expression manifested as irregular or abnormal localization. Loss of Plk2 expression is more pronounced in the invasive front in some cases. mTOR shows strong expression in the invasive front, which is presumed to be less hypoxic. Phosphorylated S6 and Glut1 expression partially correlate with phosphorylated mTOR expression but appears more diffuse in some cases. p53 and Ki67 expression is diffuse, rather than specific to the tumor invasive front in the subset of cases examined. Conclusion: Our results support the hypothesis that Plk2 functions as a tumor suppressor molecule. Loss of Plk2 expression along with accentuated expression of phosphorylated mTOR, phosphorylated S6, and Glut1 at the invasive front at least in some advanced colorectal carcinomas suggest that interaction between Plk2 and TSC1 / mTOR signaling molecules plays a role in tumor progression during hypoxic condition. Further study with a larger number of tumor samples and tumor cell lines is needed to confirm the above findings.
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 2187. doi:1538-7445.AM2012-2187
Abstract 219: Glycosylation-dependent effect of CD109 on TGF-beta1 and EGF signaling in human glioblastoma cells
Authors: Murakumo Yoshiki , Takahashi Masahide 
Published: August 2012

Abstract
CD109, a glycosylphosphatidylinositol-anchored cell surface glycoprotein, is a negative regulator of TGF-beta1 signaling, whose expression is predominantly detected in squamous cell carcinomas of esophagus, lung, uterus and oral cavity. In the Northern blot analysis using various human tumor cell lines, we found CD109 expression in cell lines derived from human glioblastomas, however, the significance of CD109 in glioblastoma cells has not yet been elucidated. Here, we present the glycosylation-dependent effect of CD109 on TGF-beta1 and EGF signaling in glioblastoma cells. SK-MG-1 cells overexpressing CD109 exhibited downregulation of Smad2 phosphorylation after TGF-beta1 stimulation and upregulation of EGFR and ERK1/2 phosphorylation after EGF stimulation, indicating that CD109 is involved in not only negative regulation of TGF-beta1 signaling but also positive regulation of EGF signaling. However, in other glioblastoma cell lines, U251MG and MG178, CD109 overexpression showed no significant effect on TGF-beta1 and EGF signaling. CD109 overexpression also enhanced cell proliferation and migration in SK-MG-1 cells, but not in the other two cells. Western blot analysis showed that molecular mass of CD109 of SK-MG-1 cells was a bit high compared with those of the other two cell lines, and deglycosylation analysis revealed enhanced glycosylation of CD109 in SK-MG-1 cells. TGF-beta1 signal in U251MG and MG178 was suppressed when the medium with hyperglycosylated soluble form of CD109 was used for TGF-beta1 stimulation. Our results suggest the glycosylation-dependent effect of CD109 on cell biology of glioblastoma 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 219. doi:1538-7445.AM2012-219
Abstract 2191: Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers
Authors: Yoo Nam Jin , Kim Min Sung , Lee Sug Hyung 
Published: August 2012

Abstract
DNMT3A, a DNA methyltransferase that functions for de novo methylation, is important in development and many cellular processes related to tumorigenesis. Somatic mutations of DNMT3A gene, including recurrent mutations in its Arg-882, were recently reported in acute myelogenous leukemia (AML), strongly suggesting its role in development of AML. To see whether DNMT3A mutation occurs in other malignancies as well, we analyzed DNMT3A in 916 cancer tissues from 401 hematlogoic malignancies (AML, acute lymphoblastic leukemias (ALL), multiple myelomas and lymphomas) and 515 carcinomas (lung, breast, prostate, colorectal and gastric carcinomas) by a single-strand conformation polymorphism (SSCP) assay. We identified DNMT3A mutations, especially the Arg-882 mutations, in adulthood AML (9.4%). In addition, we found DNMT3A mutations in a pre-B-ALL and three lung cancers at lower frequencies. Allelic loss of DNMT3A was frequently observed in most cancer types analyzed, including lymphomas (48.1%), gastric cancers (23.5%) and lung cancers (18.3%) irrespective of DNMT3A mutation. Also, loss of DNMT3A expression was common in lung cancers (46.4%) and was associated with the allelic loss. Our data indicate that DNMT3A gene is mutated mainly in AML but it occurs in other cancers such as ALL and lung cancer despite the lower incidences. Also, the data suggest that DNMT3A is altered in many cancers types by various ways, including somatic mutations, allelic loss and loss of expression that might play roles in tumorigenesis.
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 2191. doi:1538-7445.AM2012-2191