bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 203: The histone deacetylase inhibitor LBH589 sensitizes pancreatic cancer cells to TRAIL-induced apoptosis through induction of c-FLIP degradation
Authors: Kauh John , Fan Songqing , Yang Lily , Khuri Fadlo R. , Sun Shi-Yong 
Published: February 2011

Abstract
Great efforts have been made to develop novel and efficacious therapeutics against pancreatic cancer to improve the treatment outcomes. Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is such a therapeutic cytokine with selective killing effect toward malignant cells. However, some human pancreatic cancers are intrinsically resistant to TRAIL-mediated apoptosis or therapy. We are interested in overcoming TRAIL-resistance. In this study, we have shown that the histone deacetylase inhibitor LBH589 can cooperate with TRAIL to augment apoptosis even in TRAIL-resistant cells. LBH589 decreased c-FLIP levels in every tested cell line and survivin levels in some of the tested cell lines with minimal modulatory effects on the expression of death receptor 5 and XIAP. Enforced expression of ectopic c-FLIP, but not survivin, abolished the cooperative induction of apoptosis by the combination of LBH589 and TRAIL, indicating that c-FLIP downregulation plays a critical role in LBH sensitization of pancreatic cancer cells to TRAIL. Moreover, we found that LBH589 decreased c-FLIP stability and the presence of the proteasome inhibitor MG132 prevented c-FLIP from reduction by LBH589. Correspondingly, we detected increased levels of ubiqutinated c-FLIP in LBH589-treated cells. These data thus indicate that LBH589 promotes ubiqutin/proteasome-mediated degradation of c-FLIP, leading to downregulation of c-FLIP. Collectively, LBH589 induces c-FLIP degradation and accordingly sensitizes pancreatic cancer cells to TRAIL-induced apoptosis, highlighting a novel therapeutic regimen against pancreatic cancer. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award. F. R. K. and S-Y. S. are Georgia Cancer Coalition Distinguished Cancer Scholars)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 203.
Abstract 2031: Regulation of glucocorticoid receptor in multiple myeloma by microRNA
Authors: Tessel Michael , Krett Nancy L. , Rosen Steven T. , Gunaratne Preethi 
Published: February 2011

Abstract
Resistance to glucocorticoid-based therapies affects the treatment options of many diseases including Multiple Myeloma (MM). Glucocorticoids (GCs) are the most successful treatment for MM, causing apoptosis in the malignant cells. Unfortunately, patients ultimately become resistant to this therapy and despite the application of novel therapeutics, this disease is ultimately fatal. Expression of glucocorticoid receptor (GR) is required for response to therapy and patients who express higher levels of GR have improved survival. To examine the regulation of GR, our lab has previously established tissue culture cell lines from a myeloma patient who had been treated with GCs and become resistant to that treatment. From the initial patient isolate, we established a cell line that is sensitive to GCs (MM.1S) and two phenotypes of GC resistance (MM.1Re and MM.1RL). We hypothesize that miRNA expression in the GC resistant cells cause a decrease in GR expression. To test this hypothesis, we transfected both GC-sensitive and -resistant MM cells with a luciferase reporter construct containing the GR 3′UTR. We measured a decrease in luciferase activity in the GC resistant cells indicating that miRNAs are most likely involved in GR regulation. To identify which miRNAs may be responsible for this regulation, we used deep sequencing miRNAome analysis of the MM.1S, MM.1Re and MM.1RL cell lines. miRNAs more highly expressed in the GC-resistant cells and containing seed sequences which could target the GR 3′UTR were considered candidates. Expression of the candidate miRNAs was validated by Taqman qRT-PCR. GR regulation by candidate miRNAs was tested by transfection of MM.1S cells with miRNA mimics and the luciferase reporter expressing the GR 3′UTR. When exogenously expressed with the luciferase reporter, miR-130b is able to significantly decrease luciferase activity compared to controls as well as reducing the endogenous GR protein expression. In addition, miR-130b over expression partially blocks GC induced cell death, suggesting a role for this miRNA in the regulation of GR and in GC resistance in MM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2031.
Abstract 2033: Regulatory role of miR-203 in prostate cancer
Authors: Saini Sharanjot , Majid Shahana , Deng Guoren , Yamamura Soichiro , Ueno Koji , Chen Yi , Zaman Saif , Dahiya Rajvir 
Published: February 2011

Abstract
MicroRNAs (miRNAs) constitute an evolutionarily conserved class of small non-coding RNAs that primarily regulate gene expression at the post-transcriptional level via sequence-specific interaction with the 3’-untranslated regions (UTRs) of cognate mRNA targets. It is being increasingly recognized that miRNAs play roles in the establishment and progression of human malignancies. Several recent studies have shown that microRNAs are significantly altered in prostate cancer. Here we explored the role of miR-203 in prostate cancer progression and metastasis. RT-PCR analysis of prostate carcinoma cell lines showed that miR-203 expression is attenuated in prostate cancer. This attenuation was validated by in situ hybridization analysis of miR-203 in clinical specimens. To evaluate the functional significance of miR-203, miR-203 was reintroduced in prostate cancer cell lines followed by functional assays. Overexpression of miR-203 in prostate cancer cell line leads to decreases in cell growth, clonability, invasiveness and migratory properties. miR-203 reexpression in prostate carcinoma cell line induces cell cycle arrest at the G0-G1 phase of the cell cycle with a concomitant alteration of cell cycle regulators such as p21, p27, cyclin E and cdk2. Also, miR-203 transfection leads to a significant increase in apoptosis in prostate cancer cells pointing to the pleiotropic roles of this miR in prostate cancer. Further, analysis of putative miR-203 targets showed that miR-203 regulates the expression of survivin, a small inhibitor of apoptosis (IAP) protein that plays a key role in prostate cancer progression. In conclusion, our data suggests a crucial tumor suppressive role for miR-203 in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2033.
Abstract 2034: Tumor suppressive activity of Smad3 by regulation of microRNAs in gastric cancer
Authors: Kim Jooyoung , Park Dong-Kyun , Ahn Sung-Min , Cha Jiyoung , Hong Suntaek 
Published: February 2011

Abstract
Loss of the tumor suppressive effect of transforming growth factor-β (TGF-β) has been commonly found at later stages in carcinogenic progression. It was recently found that Smad3 expression is lost in more than a third of cancers and the introduction of Smad3 into Smad3 null gastric cancer cell line restores TGF-β-mediated growth inhibitory and tumor suppressive activity. Interestingly, expression of Smad3 induced the expression of E-cadherin. Since there is accumulating evidence that microRNAs (miRNAs) regulate transcriptional repressors of E-cadherin such as ZEB1 and ZEB2, thus affecting the expression of E-cadherin, we aimed to compare miRNA profiles of Smad3-negative gastric cell line (SNU484-LPCX) and Smad3-overexpressed one (SNU484-Smad3). To investigate global changes of miRNA profiles associated with Smad3 restoration, we applied massively parallel sequencing (MPS) to miRNA profiling. Using this approach, we identified more than 150 known miRNAs, and at least 10 miRNAs including miR200 show statistical significance in expression between two cell lines. To further confirm these findings, we applied qRT-PCR analysis of selected miRNAs and mRNAs. Using Smad3 specific siRNAs, we also proved that Smad3 is involved in the E-cadherin expression through the regulation of specific miRNAs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2034.
Abstract 2036: MicroRNA-137 reverse the malignant phenotypes of colorectal cancer cells by targeting small GTPase Cdc42
Authors: BI FENG , Liu Ming , Lang Nan , Tang Qiuling 
Published: February 2011

Abstract
MicroRNAs have emerged as post-transcriptional regulators that are critically involved in the pathogenesis of a number of human cancers. Cdc42, one of the best characterized members of the Rho GTPase family, is found to be up-regulated in several types of human tumors, and has been implicated in cancer initiation and progression. In the present studies, we have identified miR-137 as a potential regulator of Cdc42 expression. A bioinformatics search revealed a target-site for miR-137 within the Cdc42 3’ UTR at nt 792-798, which is highly conserved across different species. Expression of miR-137 in colorectal cancer cell lines was found inversely correlated with Cdc42 expression. MiR-137 could significantly suppress Cdc42 3’ UTR luciferase-reporter activity, while this effect was not detectable when the putative target-site for miR-137 was mutated. Consistent with the results of reporter assay, ectopic expression of miR-137 reduced both mRNA and protein expression levels of Cdc42 and mimicked the effect of Cdc42 knockdown in inhibiting proliferation, inducing G1 cell cycle arrest, and blocking invasion of the colorectal cancer cells. Furthermore, expression of miR-137 suppressed the immediate downstream effector of Cdc42, PAK signaling in colorectal cancer cell lines. Our results suggest that miR-137 may have a tumor suppressor function by directly targeting the Rho GTPase Cdc42 to inhibit the proliferation and invasion activities of colorectal cancer cells. They raise an interesting possibility that Cdc42 activity and function can be controlled by microRNAs in addition to the classic regulators such as guanine nucleotide exchange factors and GTPase-activating proteins.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2036.
Abstract 2042: Aberrant expression of miR-21 triggers malignancy of human gliomas by disrupting negative feedback regulator, Spry2
Authors: Kim Youn-Jae , Kwak Hee-Jin , Park Jong Bae , Lee Seung-Hoon 
Published: February 2011

Abstract
The malignant progression of glioma is accompanied by diffuse infiltration. Recent evidences suggest the significant role of microRNAs in cancer cell migration and invasion. Therefore, we hypothesized that deregulation of microRNA may be important for the malignant progression of glioma. We found that aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional PTEN, but not wild-type PTEN-harboring glioma cells. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues as well as cancer stem cell-derived tumor models, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, although they were inversely correlated with miR-21. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 plays an essential role on the malignant progression of human gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2042.
Abstract 2056: MicroRNA-126 inhibits SOX2 expression in gastric cancer cells
Authors: Otsubo Takeshi , Akiyama Yoshimitsu , Hashimoto Yutaka , Yuasa Yasuhito 
Published: February 2011

Abstract
A transcription factor SOX2 is essential for embryonic development and play critical roles in the maintenance of embryonic stem cell's pluripotency. We previously reported that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis, and SOX2 expression was frequently down-regulated in gastric cancers, some of which were due to aberrant DNA methylation. However, the mechanisms underlying loss of SOX2 expression and its target genes involved in gastric carcinogenesis remain largely unknown. In this study, we initially assessed whether microRNAs, small noncoding RNAs, control SOX2 expression in gastric cancers. In silico analysis revealed that microRNA-126 (miR-126) has two predictive target sites in the 3′-UTR of the SOX2 mRNA. Gain- and loss-of function experiments demonstrated that miR-126 inhibited SOX2 expression in gastric cancer cell lines. Luciferase reporter assays with a pGL4-SOX2 3′-UTR vector revealed that miR-126 directly inhibits SOX2 expression by targeting two binding sites in the 3′-UTR of the SOX2 mRNA independently. Some primary gastric cancer tissues with low expression of SOX2 exhibited markedly high levels of miR-126 expression compared with paired non-cancerous mucosae. To further understand the potential effects of miR-126-induced down-regulation of SOX2 on gastric carcinogenesis, we next attempted to identify the downstream target genes of SOX2 in gastric cancer cells. The microarray analysis after SOX2 over-expression in a gastric cancer cell line showed that 437 genes were up-regulated (&gt;2-fold) and 447 genes were down-regulated (&lt;0.5-fold), some of which were cancer-related genes. Taken together, we identified miR-126 as a novel microRNA which inhibits SOX2 expression in gastric cancer cells, and suggest that aberrant miR-126 expression and consequent SOX2 down-regulation may contribute to gastric carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2056.
Abstract 2057: Cigarette smoke enhances pulmonary carcinogenesis via downregulation of has-miR-487b in respiratory epithelial cells
Authors: Xi Sichuan , Yang Maocheng , Tao Yong-Guang , Shan Jiqui , Xu Hong , Zhang Mary , Schrump David S. 
Published: February 2011

Abstract
Limited information is available regarding the mechanisms by which miRNA alternations contribute to initiation and progression of lung cancer. In order to examine this issue, array techniques were used to assess miRNA expression profiles in short term normal human bronchial epithelia (NHBE) and small airway epithelial cells (SAEC), as well as A549 and Calu-6 lung cancer cells cultured in normal media (NM) with or without cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC consistently mediated a 3.4 − 5.5 fold decrease in has-miR-487b expression in cultured normal as well as lung cancer cells. Quantitative RT-PCR experiments demonstrated that expression levels of has-miR-487b were significantly downregulated (2.9 − 21 fold) in a panel of resected lung cancers relative to adjacent normal tissues. Software-guided analysis revealed numerous potential targets for has-miR-487b including H2AZ, encoding a histone variant modulating expression of developmentally regulated genes as well as SUZ12, which encodes a component of polycomb repressor complexes implicated in aberrant silencing of tumor suppressor genes such as Dickkopf-1 (Dkk-1) in lung cancer cells. Quantitative RT-PCR experiments revealed that constitutive over-expression of has-miR-487b mediated 3-35 fold reductions in H2AZ and SUZ12 expression in SAEC, A549, and Calu-6 cells. RNA cross-link immunoprecipitation (CLIP) experiments confirmed direct interference of has-miR-487b with H2AZ and SUZ12 transcripts. Overexpression of has-miR-487b enhanced sensitivity to cisplatin in lung cancer cells. Collectively, these data suggest that CSC-mediated downregulation of has-miR-487b promotes pulmonary carcinogenesis, in part, via activation of genes encoding proteins implicated in epigenetic regulation of stem cell gene expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2057.
Abstract 2061: Vitamin D-regulates microRNAs in primary cultures of normal prostatic epithelial cells
Authors: Antonio Angeline , Vaishnav Avani , Nonn Larisa 
Published: February 2011

Abstract
Recent discoveries in cancer find that endogenous non-coding RNAs, microRNAs (miRNA), bind to the 3’ untranslated region of target mRNAs and function to translationally repress or decrease mRNA stability. Additionally, a number of studies show that aberrant miRNA expression is linked to various cancers, such as prostate cancer. Cancer-related changes in miRNA levels may result in either repression of tumor suppressor genes and/or activation of oncogenes. MiRNAs pose a potential role as targets in the treatment of cancers. In prostate cancer research, studies suggest a role of vitamin D as a chemopreventive agent. Vitamin D inhibits the growth and differentiation of malignant prostate cells and tumors. Studies show that a reduction in serum levels of vitamin D metabolites is linked to PC occurrence. Research from our laboratory shows that vitamin D treatment alters mRNA stability. This suggests a potential role for miRNAs in the vitamin D prevention of prostate cancer. We hypothesize that vitamin D's prevention of prostate cancer involves up-regulating tumor suppressive miRNAs and down-regulating oncogenic miRNAs. Using normal human prostatic epithelial cells as a model, we investigated the miRNA expression profile changes in cells that were treated with 1,25-dihydroxyvitamin D for time points ranging from 30 min to 24 hours. Our results demonstrated that approximately 50% of the miRNAs are expressed in the normal epithelial cells. A smaller percentage of miRNAs, approximately 10%, were changed by vitamin D treatment. We found that vitamin D down-regulated a small number of miRNAs (&lt;0.5 fold) commonly up-regulated in cancer (miR-181d, miR-378) and up-regulated miRNAs that are down-regulated in cancer (miR-29a, miR-16). Of the miRNAs altered by vitamin D, we observed an interesting down-regulation of the let-7 family of tumor suppressor miRNAs. Six of the seven let-7 family members present on the array (let-7 a-g) were down-regulated across the time points with four of the let-7 miRNAs downregulated as early as 30 minutes. This is a somewhat discrepant finding since let-7 is known as a tumor suppressor miRNA that is decreased in many cancers and we know that vitamin D is a cancer preventive agent. Further studies will determine the role of vitamin D on let-7 in the prostatic epithelial cells and the implications in cancer. Ongoing research will also determine the mechanism of vitamin D regulation of miRNAs to help further understand the chemopreventive role of vitamin D in prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2061.
Abstract 2064: Down-regulation of miR-31 is associated with metastatic potential of human and canine osteosarcoma
Authors: Melkamu Tamene , Carlson Daniel F. , Farese James P. , Kassie Fekadu 
Published: February 2011

Abstract
Osteosarcoma is the most common primary bone tumor in humans and dogs. The primary cause for the poor survival of patients with osteosarcoma in both species is the emergence of metastases in organs distant from the primary tumor, especially in the lung. Therefore, identification of molecular determinants of osteosarcoma metastasis is highly warranted. In order to identify microRNAs (miRNAs) that regulate osteosarcoma metastasis, we examined, using qRT-PCR, levels of 10 miRNAs commonly associated with cancer metastasis (miR-10b, miR-146a, miR182, miR183, miR-206, miR-335, miR373, miR-520c-5p, miR-21 and miR-31) in total RNA samples prepared from canine parental osteosarcoma (POS) and highly metastatic POS (HMPOS) cells. Of the 10 miRNAs, only miR-31 showed differential expression between the two cell lines (reduced by 7.8-fold in HMPOS cells versus POS cells). Exposure of HMPOS cells to various chemopreventive agents (myo-inositol, indole-3-carbinol, diindolylmethane, deguelin, phenethyl isothiocyanate, cisplatin, and aza-2′-deoxycytidine) increased the level of miR-31 at least by two-fold, the most potent agents being deguelin and phenethyl isothiocyanate. Subsequently, we assessed the expression of miR-31 in additional canine osteosarcoma cell lines (three cell lines established from primary tumors and three cell lines developed from pulmonary metastases) and human osteosarcoma cell lines differing in metastatic potential (parental SaOS2, low- (LM2), and high- (LM7) metastatic cells). miR-31 levels decreased by 18-fold in canine cell lines derived from pulmonary metastatic tumors relative to that obtained from primary tumors and by 2-fold and 3-fold in LM2 and LM7 cells, respectively, compared to the expression in parental Saos-2 cells. Also, analysis of 3 primary human osteosarcoma tissues and 3 pulmonary metastatic tissues revealed a 13-fold reduction of miR-31 in metastatic tissues relative to primary tumor tissues. In preliminary experiments where attempts were made to identify potential targets of miR-31, exogenous over-expression of a synthetic miR-31 cassette in HMPOS cells negatively regulated a tight junction protein claudin-2, which is incriminated in cancer metastasis. In summary, our studies indicate that miR-31 is a promising marker for the metastatic potential of osteosarcoma and for disease prognosis. Moreover, reactivation of silenced miR-31 by chemopreventive/chemotherapeutic agents could reverse osteosarcoma metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2064.