bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2798: Tyrosine phosphorylation of LDH-A is important for cancer cell redox homeostasis and tumor growth
Authors: Fan Jun , Hitosugi Taro , Chung Tae-Wook , Wang Xu , Gu Ting-Lei , Roesel Johannes L. , Chen Zhuo (Georgia) , Boggon Titus , Khuri Fadlo R. , Kang Sumin , Chen Jing 
Published: June 2012

Abstract
Cancer cells take up more glucose than normal tissue and favor aerobic glycolysis, generating lactate through a NADH-dependent enzyme, lactate dehydrogenase A (LDH-A). This is the last step of glycolysis that permits the regeneration of NAD+, which is needed as an electron acceptor to maintain cytosolic glucose catabolism. Therefore, most tumor cells are reliant on lactate production for their survival. LDH-A gene expression is believed to be upregulated by both HIF and Myc in cancer cells to achieve increased lactate production, and expression of LDH-A was previously implicated to be involved in tumour initiation and growth. However, how oncogenic signals activate LDH-A to regulate cancer cell metabolism remains unclear. Our phospho-proteomics studies revealed that oncogenic fibroblast growth factor (FGF) receptor type 1 (FGFR1) tyrosine kinase directly phosphorylates LDH-A. Structural and biochemical studies revealed that phosphorylation at Y10 and Y83 activates LDH-A by promoting the formation of active, tetrameric LDH-A and binding of LDH-A substrate NADH, respectively. Moreover, we found that LDH-A is commonly phosphorylated at Y10 in diverse human cancer cells by multiple oncogenic tyrosine kinases including BCR-ABL, FLT3 and JAK2, which represents an acute molecular mechanism underlying increased lactate production in cancer cells. Furthermore, cancer cells with stable knockdown of endogenous LDH-A and rescue expression of a catalytic hypomorph LDH-A mutant, Y10F, show decreased cell proliferation and ATP levels under hypoxia, increased mitochondrial respiration to sustain glycolysis by providing NAD+, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation activates LDH-A to promote the Warburg effect and tumor growth by regulating NADH/NAD+ redox homeostasis in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2798. doi:10.1158/1538-7445.AM2011-2798
Abstract 2806: Inactivation of PBRM1, a gene frequently mutated in clear cell renal carcinoma, suppresses tumor growth
Authors: Dachuan Huang , Kiat Ong Choon , Tean Teh Bin , Huimin Bernice Wong , Chan-on Waraporn , Subimerb Chutima , Furge Kyle , Futreal Andrew 
Published: June 2012

Abstract
The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell renal carcinoma (ccRCC), the commonest histological subtype. However, our previous work has demonstrated that VHL loss alone is insufficient for ccRCC tumourigenesis arguing the need for additional genetic events. Recently, we have sequenced of the protein coding exome in 257 cases of primary renal carcinoma (RCC) and reported the identification of the SWI/SNF chromatin remodeling complex gene Polybromo 1 (PBRM1) as a second major RCC cancer gene with truncating mutations in 41% (85/257) of cases. In particular, all 9 cases with a SETD2 mutation have a mutation in either PBRM1 or VHL, with 7 of 9 cases having mutations in all three genes. The concomitant VHL, PBRM1 and SETD2 mutations, with all three genes mapping to chromosome 3p, suggest that the mutations are non-redundant functionally.
To obtain further evidence that PBRM1 can act as a cancer gene, transcriptional profiling before and after PBRM1 knockdown was performed using gene expression microarrays. The results showed that PBRM1 activity regulates pathways associated with chromosomal instability and cellular proliferation. Consistently, knockdown of PBRM1 RNA resulted in a significant increase in proliferation 4/5 RCC lines. No effect was seen, however, in A704 cell, which carries a homozygous truncating PBRM1 mutation, confirming the specificity of the assay. Further, knockdown of PBRM1 resulted in significantly increased colony formation in soft-agar and increased cell migration indicative of an increase in transformed phenotype. Taken together, these data support PBRM1 having a tumor suppressor role in ccRCC.
Therefore, understanding the contribution of PBRM1 mutation to clinical disease progression and outcome as well the potential for exploiting SWI/SNF complex abrogation therapeutically are important future areas of renal cancer research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2011-2806
Abstract 2808: Characterization of KRAS rearrangements in metastatic prostate cancer
Authors: Wang Xiao-Song , Shankar Sunita , Dhanasekaran Saravana M. , Ateeq Bushra , Sasaki Atsuo T. , Jing Xiaojun , Robinson Daniel , Cao Qi , Gopalan Anuradha , Reuter Victor E. , Cantley Lewis C. , Rubin Mark A. , Palanisamy Nallasivam , Varambally Sooryanarayana , Chinnaiyan Arul M. 
Published: June 2012

Abstract
In this study, we employed a novel integrative genomic-based approach to explore driving gene fusions contributing to the progression of advanced prostate cancer. This method, called amplification breakpoint ranking and assembly (ABRA), leverages the in vivo amplification and breakpoint analysis in cancer cells to assemble novel gene fusions and predict their tumorigenicity. Using ABRA, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line- which was originally derived from a metastatic prostate cancer to the brain. Interestingly, analysis of tissues revealed that 2 out of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a chimerical protein which is readily ubiquitinated and relative instable, whereas specific knock-down of the fusion attenuates cell invasion and xenograft growth. Further, ectopic expression of the UBE2L3-KRAS fusion protein in NIH 3T3 fibroblasts and RWPE prostate epithelial cells exhibits substantial transforming activity in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates the MEK/ERK pathway, which is commonly engaged by oncogenic mutant KRAS. Instead, it enriches Ras proteins in late endosome, and diverts signaling to the AKT and p38 MAPK pathways. While a number of oncogenic activating point mutations of KRAS have been identified, this is the first description of a mutant chimeric version of KRAS that is oncogenic and thus may represent a new class of cancer-related alteration. This study also suggests that this aberration may drive metastatic progression in a subset of prostate cancers, which may be targeted by anti-KRAS therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2808. doi:10.1158/1538-7445.AM2011-2808
Abstract 2817: An RNA aptamer is a potential biomarker for pancreatic cancer
Authors: Ray Partha , Sullenger Bruce A. , White Rebekah R. 
Published: June 2012

Abstract
Introduction: The symptoms of pancreatic cancer are usually non-specific and late. Existing tumor markers (such as CA19-9 and CEA) are neither sensitive nor specific enough to serve as useful screening tests. Tools for earlier detection could increase the proportion of patients who are cured with surgical resection.
Aptamers are oligonucleotide ligands that are identified from large libraries of RNA or DNA molecules using an iterative selection process known as SELEX (Systematic Evolution of Ligands by Exponential Enrichment). Aptamers bind their specific targets with high affinity and specificity and can be used for the dual purpose of identifying novel biomarkers and detecting them in biological specimens.
Methods: In order to select for aptamers against molecules that are selectively secreted by cancerous cells but not by normal cells, “positive/negative” SELEX was performed using the conditioned media (the “secretome”) of the MiaPaCa2 human pancreatic ductal adenocarcinoma cell line (positive selection) and the immortalized, non-cancerous human pancreatic ductal cell line HPDE (negative selection). Standard radioactive filter-based binding assays were used to measure binding.
Results/Conclusion: We have successfully selected several nuclease resistant (2′-fluoro-modified) RNA aptamers that differentially bind the secretome of pancreatic cancer cells compared to non-cancerous cells. One of the aptamers (M9-5) binds pancreatic cancer patient sera with high affinity compared to control sera collected from healthy donors. So far, the aptamer has demonstrated specific binding in 20 of 22 patients with histologically-proven pancreatic cancer and none of 20 healthy donors. In addition, paired serum samples obtained from two patients pre- and post-chemoradiation therapy and one patient pre- and two months post-resection have demonstrated a decrease in M9-5 binding with decreased tumor burden. Notably, the serum CA19-9 and CEA levels in several of these patients were normal, indicating that our biomarker might be more sensitive than these existing serum biomarkers for pancreatic cancer. M9-5 binding to the MiaPaCa2 “secretome” is sensitive to Proteinase K treatment indicating that the aptamer target is a protein. Currently, we are using a biotinylated version of the aptamer to affinity purify the target and identify it by mass-spectrometric techniques.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2817. doi:10.1158/1538-7445.AM2011-2817
Abstract 2818: Urinary MMP-2 and MMP-9 predict the presence of ovarian cancer in women with normal CA125 levels
Authors: Coticchia Christine M. , Curatolo Adam S. , Zurakowski David , Matulonis Ursula A. , Moses Marsha A. 
Published: June 2012

Abstract
Currently, the only widely used biomarker for monitoring ovarian cancer status and response to therapy is the cancer antigen 125 (CA125). Interestingly, the majority of newly developed ovarian cancer multi-marker assays also rely heavily on serum CA125 levels as one of the biomarkers in their panels. However, 20% of women with advanced ovarian cancer have blood CA125 levels within the normal range of 35 U/mL and below. These women represent a cohort of patients for whom no clinically useful biomarkers are available for monitoring disease status, stage or response to therapy. To address this need, we asked whether a panel of urinary biomarkers that we have previously validated for use in other cancers, could predict the presence of disease in women with ovarian cancer possessing normal CA125 levels. Urine samples were collected from 81 healthy controls and 26 ovarian cancer patients with blood CA125 levels below 35 U/mL. Using monospecific ELISAs, we determined that urinary levels of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and the neutrophil gelatinase lipocalin 2 (NGAL) are detected at significantly higher levels in the urine of ovarian cancer patients than in the urine of healthy controls. Additionally, receiver-operating characteristic (ROC) area under the curve (AUC) analysis of these groups revealed that, individually, MMP-2, MMP-9 and NGAL each could significantly distinguish ovarian cancer patients with CA125 &lt; 35 U/mL from controls. The best combination of biomarkers for predicting the presence of disease was MMP-2 plus MMP-9 with an ROC AUC of 0.7332 (P&lt;0.01). When these biomarkers were multiplexed with age, a know risk factor of ovarian cancer, the diagnostic accuracy of these biomarkers increased to an AUC of 0.820 (P&lt;0.001). This combination of urinary MMP-2, MMP-9 and age demonstrated excellent diagnostic capability in differentiating ovarian cancer patients from healthy controls among the cohort of patients for whom CA125 values were uninformative.
Acknowledgments: The authors gratefully acknowledge the support of Ovations for the Cure of Ovarian Cancer (MAM and UAM) and the Stuart Weitzman Foundation (MAM).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2818. doi:10.1158/1538-7445.AM2011-2818
Abstract 2841: Inducible modulation of NF-kappaB in macrophages reveals that timing of intervention may be critical to therapeutic outcome during mammary tumorigenesis
Authors: Barham Whitney , Connelly Linda , Onishko Halina M. , Chen Lianyi , Sherrill Taylor , Zabuawala Tahera , Ostrowski Michael , Blackwell Timothy , Yull Fiona 
Published: June 2012

Abstract
Elevated levels of NF-kappaB signaling are associated with multiple cancers. Therefore, it is not surprising that inhibitors of NF-kappaB are being investigated as potential therapeutics. While extensive efforts are being made to identify inhibitors there is less focus on investigating the effects of inhibition in specific cell types and during defined stages of tumor progression. We have developed murine transgenic models that enable us to induce expression of an activator or inhibitor of NF-kappaB in macrophages, by adding doxycycline to the drinking water of mice. We have combined these with the Polyoma model of mammary cancer to investigate the effects of modulation of NF-kappaB signaling specifically within macrophages. Given several recent publications we were predicting that activation of NF-kappaB would have pro-tumor effects. However, using a tail vein injection model, our data identifies a stage during progression in which activation of NF-kappaB in macrophages significantly limits metastasis. Activation of NF-kappaB alters immune cell populations and results in rapid killing of tumor cells during the seeding phase. In this model inhibition of NF-kappaB in macrophages during this critical stage of metastasis is pro-tumor. This suggests that while inhibition of NF-kappaB at later stages of tumor progression may have therapeutic benefit, inhibition during the seeding phase my lead to the opposite effect. Our studies highlight the importance of continued investigation into aspects of cell specificity and timing that may change the potential outcome of a clinical trial using NF-kappaB inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2841. doi:10.1158/1538-7445.AM2011-2841
Abstract 2846: Pigment epithelium-derived factor (PEDF) functions as a brain metastasis suppressor of breast cancer
Authors: Fitzgerald Daniel P. , Palmieri Diane , Qian Yongzhen , Deshpande Monika , Subramanian Pretti , Graves Christian , Davis Sean , Meltzer Paul , Camphausen Kevin , Becerra Patricia S. , Steeg Patricia S. 
Published: June 2012

Abstract
Brain metastases occur in 10-20% of metastatic breast cancer patients. The one year survival rate is approximately 20%. Brain metastasis is typically diagnosed late in breast cancer progression; however, studies suggest that the incidence of brain metastasis may be increasing under current chemotherapeutic regimens. We have investigated changes in gene expression associated with the acquisition of brain metastatic potential by breast cancer. A DNA microarray analysis comparing human brain metastases and a cohort of unlinked primary breast carcinomas identified Pigment Epithelium-Derived Factor (PEDF) as down-regulated in the brain metastases relative to the primary tumors (mean ∼14X lower by QPCR validation). The data suggest the hypothesis that PEDF may have a negative impact on brain metastatic progression. PEDF, a secreted factor, has been shown to act as a tumor suppressor, has strong anti-angiogenic activity, but supports the proliferation/viability/ differentiation of neural tissue. We hypothesize that the multiple roles of PEDF make it a potent agent which targets not only tumor cells, but also the microenvironment of the brain. In vitro experiments demonstrated that PEDF can promote death of breast cancer cells. Conversely, PEDF promoted neuronal survival, in vitro. In a xenograft model system (231BR, a brain-tropic derivative of human MDA-MB-231 breast cancer cells) PEDF overexpression inhibited formation of large brain metastases (∼2-fold, p=0.001) and reduced proliferation of PEDF-expressing breast cancer cells in mouse brain metastases (11% Ki67-positive, PEDF-positive vs. &gt;56% Ki67-positive, PEDF-negative). In an intracranial implantation model, expression of PEDF by breast cancer cells lead to a rapid reduction in brain metastatic tumor volume. Histological examination suggests that PEDF reduces gliosis and protects neurons concomitant to suppression of metastatic growth. The data suggest the intriguing possibility that PEDF overexpression may concurrently inhibit brain metastasis of breast cancer cells but preserve neuronal function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2846. doi:10.1158/1538-7445.AM2011-2846
Abstract 2865: Cytoplasmic deacetylase HDAC6 confers tumor suppressive potential through autophagic cell death in human hepatocellular carcinoma
Authors: Jung Kwang Hwa , Noh Ji Heon , Eun Jung Woo , Kim Jeong Kyu , Bae Hyun Jin , Xie Hongjian , Nam Eliel , Park Won Sang , Lee Jung Young , Nam Suk Woo 
Published: June 2012

Abstract
The histone modification and acetylation by histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been associated with chromatin decondensation and transcriptional activation and silencing. HDAC6, one of class II HDAC isotypes, is a cytosolic protein and microtubule-associated deacetylase that interacts with non-histone protein, including α-tubulin. HDAC6 is involved in autophagic degradation of the cells, but the underlying mechanism associated with carcinogenesis in solid tumors remains unclear. In this study, we investigated the expression levels of HDAC6 in human liver cancer cell lines and tissues. HDAC6 expression was analyzed by Western blot analysis in nine selected hepatocellular carcinomas (HCCs) and immunohistochemical staining was performed in paraffin-embedded samples from 32 liver cancers. HDAC6 expression was significantly down-regulated in the HCCs compared to corresponding normal tissues in nine selected tissue samples. Immunohistochemical analysis also showed commonly down-regulated HDAC6 expression in the HCCs. Thus, to investigate the HDAC6-induced anti-neoplastic potentials on liver cancer progression, we restored HDAC6 expression using gene transfection in human Hep3B liver cancer cell line. Over-expression of HDAC6 suppressed proliferation of liver cancer cells with decreased acetylation status of α-tubulin and exhibited the characteristics of autophagic degradation (autophagosome formation and the LC3-II generation) in Western blot and Electron Microscopy (EM) analysis. In addition, we found that over-expression of HDAC6 induced expression of autophagy-related gene Beclin 1, a key molecule of autophagosome formation. In contrast, knock-down of HDAC6 over-expressed cells could reduce the expression level of increased Beclin 1 and LC3-II with restoration of acetylated α-tubulin. Furthermore, in the xenograft mouse models, over-expression of HDAC6 significantly suppressed tumor growth and incidence of tumor formation. In conclusion, our results suggest that HDAC6-indued autophagic cell death provide a novel mechanism for the regulation of beclin1 and LC3 expression in liver cancer development and progression providing new therapeutic intervention in human hepatocellular carcinoma
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2011-2865
Abstract 287: A SILAC proteomics analysis to identify bladder cancer metastasis-associated candidates
Authors: Grau Laura , Luque-García Jose L. , González-Peramato Pilar , Theodorescu Dan , Gil Marta , Palou Joan , Bellmunt Joaquin , Sanchez-Carbayo Marta 
Published: June 2012

Abstract
Bladder cancer is most clinically aggressive when metastases develop, associated with the shortest patient survival. To identify molecular pathways associated with the metastatic process in bladder cancer, we carried out a proteomic analysis of an invasive T24 and a metastatic derived T24T bladder cancer cell line using a SILAC (Stable Isotope Labelling by Amino acids in Cell culture) approach. Protein extracts were fractionated, separated by SDS-PAGE and analyzed by nanoflow LC-ESI-LTQ mass spectrometry (MS). Comparative analysis of the invasive and metastatic bladder cancer cells identified 831 proteins with high confidence (&gt;99%). Protein expression data from SILAC were compared with mRNA expression data obtained from oligonucleotide microarrays. Relatively weak correlations were observed, consistent with the poor associations between RNA and protein expression previously reported. The involvement of the proteins identified in biological networks served to propose how selected candidates may participate in molecular pathways associated with bladder cancer metastasis. Verification analyses included Western Blot using independent protein extracts. Immunohistochemistry analyses of proteins differentially expressed, such as Cul3, a protein involved in the ubiquitination and subsequent proteasomal degradation of target proteins, were performed on bladder tumours spotted onto tissue microarrays (n=284). Cul3 was associated with tumor staging, lymph node metastasis and disease-specific survival. Further functional analyses revealed that Cul3 silencing diminished the proliferative, migration and invasive rates of T24T cells, and restored the expression of other metastasis related cytoskeleton proteins identified by SILAC such as ezrin, moesin, filamin A or caveolin. Hence, this approach not only identified proteins and molecular mechanisms involved in bladder metastasis but also revealed a role for Cul3 in bladder cancer progression, metastasis and clinical outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 287. doi:10.1158/1538-7445.AM2011-287