bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5195: Kidney injury molecule-1: a novel therapeutic target in renal cell carcinoma.
Authors: Sabbisetti Venkata , Bhatt Rupal , Ramadesikan Swetha , Bonventre Joseph 
Published: August 2014

Abstract
Background. Renal cell carcinoma (RCC) is characterized by lack of early warning signs, diverse clinical manifestations, absence of a reliable diagnostic and predictive biomarker, and resistance to targeted therapy. Thus, novel approaches for diagnosis, management and treatment of RCC are urgently needed. Kidney Injury Molecule-1 (KIM-1) is not expressed in normal kidney tissues but markedly up-regulated in dedifferentiated proximal tubular epithelial cells following renal injury. We demonstrated that KIM-1 is expressed ubiquitoulsy by both primary and metastatic lesions of clear cell and papillary renal cell carcinoma, while barely detectable in other subtypes of RCC. Additionally, the ectodomain of KIM-1 is cleaved by matrix metalloproteinases and sheds into the surrounding milieu.
Methods. KIM-1 was stably transfected in immortalized renal tubular epithelial cells (LLC-PK1, gain-of-function) and KIM-1 was downmodulated in RCC cell lines (loss-of-function) using a siRNA lentiviral approach. KIM-1 function was assessed using these two systems.
Results. Stable expression of KIM-1 in non-malignant renal epithelial cells increased cell proliferation, migration and invasion potential, induced anchorage independent growth, and increased the secretion of tumor promoting and angiogenic factors including VEGF, Ang2, TGF beta and IL-6 (PK1-KIM-1); while depletion of KIM-1 in RCC cells led to G1 cell cycle arrest phase and senescence. Recently, we and others have demonstrated that KIM-1 is a phosphatildyl serine receptor and the expression of KIM-1 converts a normal epithelial cell into a “semi professional phagocyte” and facilitates the removal of apoptotic and necrotic cells by recognizing phosphotidyl serine (PS) on their cell surface. Our data suggests that during this process, tumor epithelial cells undergo reprogramming and secrete and activate cytokines involved in cell survival and angiogenesis programs.
Conclusions. The present study shows that KIM-1-expression promotes tumorigenesis primarily by two distinct mechanisms: i) by directly conferring oncogenic properties to renal epithelial cells; ii) by resulting in production of a variety of chemokines and cytokines that support tumor progression and angiogenesis. We believe that our findings can significantly contribute to the development of novel therapeutic apporaches and in the advancement of management strategies in RCC and help reduce associated mortality and morbidity.
Citation Format: Venkata Sabbisetti, Rupal Bhatt, Swetha Ramadesikan, Joseph Bonventre. Kidney injury molecule-1: a novel therapeutic target in renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5195. doi:10.1158/1538-7445.AM2013-5195
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5201: Elucidating distinct roles for NF1 in melanomagenesis.
Authors: Maertens Ophélia , Johnson Bryan , Hollstein Pablo , Frederick Dennie , Cooper Zachary , Messiaen Ludwine , Bronson Roderick , McMahon Martin , Granter Scott , Flaherty Keith , Wargo Jennifer , Marais Richard , Cichowski Karen 
Published: August 2014

Abstract
BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations tumor development is restricted by oncogene-induced senescence (OIS). Here we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both PI3K and ERK pathways. As such, Nf1/Braf mutant tumors are resistant to BRAF inhibitors but are sensitive to combined MEK/mTOR inhibition. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and demonstrate that NF1-inactivation may impact responses to targeted therapies.
Citation Format: Ophélia Maertens, Bryan Johnson, Pablo Hollstein, Dennie Frederick, Zachary Cooper, Ludwine Messiaen, Roderick Bronson, Martin McMahon, Scott Granter, Keith Flaherty, Jennifer Wargo, Richard Marais, Karen Cichowski. Elucidating distinct roles for NF1 in melanomagenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5201. doi:10.1158/1538-7445.AM2013-5201
Abstract 5204: Downregulation of PHLLP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells.
Authors: Wen Yang-an , Gao Tianyan 
Published: August 2014

Abstract
Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor by negatively regulating Akt signaling in colon cancer. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia in colon cancer cells. Hypoxia-induced decrease of PHLPP expression is attenuated by silencing HIF-1α but not HIF-2α, indicating that PHLPP downregulation is HIF-1α-dependent. Whereas the mRNA levels of PHLPP are not significantly altered in hypoxia, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased protein degradation. Specifically, hypoxia-induced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated levels of mTOR activity and protein synthesis. In addition, we show that hypoxia promotes PHLPP degradation by increasing the mRNA expression of USP46, a PHLPP-specific deubiquitinase, and resulting in upregulation of PHLPP ubiquitination. Functionally, downregulation of PHLPP plays an important role in hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understand the drug resistance in cancer treatment.
Citation Format: Yang-an Wen, Tianyan Gao. Downregulation of PHLLP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5204. doi:10.1158/1538-7445.AM2013-5204
Abstract 5222: Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach.
Authors: Kim Sangbae , Sohn Bo Hwa , Park Yun-Yong , Kim Ji-Hoon , Lee Sung Sook , Davies Micheal A. , Mills Gordon B. , Lee Ju-Seog 
Published: August 2014

Abstract
MicroRNAs(miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. Target predictions of miRNA based on sequence are limited due to too many candidates resulting in high false positives. To overcome this limitation functional target prediction approaches have been investigated with mRNA and miRNA expression data. These approaches can be used in the computational assessment of functional miRNA-target association. However, these approaches with miRNA-mRNA association were not enough to verify real functional targets at protein level, which could affect on cell signaling pathway. Therefore, in the present study to compensate this limitation, we developed a novel correlation based approach (sequence-independence) to predict potential miRNA targets with genomic and proteomic data, protein, miRNA and mRNA array data, in NCI-60 cells. To establish a prediction model for identifying the association of miRNA-cell signaling pathways by analyzing genomic and proteomic data, we performed a correlation based method among miRNA, mRNA and protein expression profile. Using this approach, we generated the Association score matrix (ASM) between miRNA and protein probes. Based on ASM, we finally generated the highly associated miRNAs with cell signaling pathways called miRNA-pathway association map (miRPM). To validate our approach, we used miR-500 as an example to investigate the hypothetical target regulation mechanisms predicted by miRPM. We confirmed in-vitro that mir-500 highly is associated with ERK/MAPK signaling pathway in melanoma and breast cancer cells. Furthermore, we found PP1/PP2 might be a direct target of miR-500 to regulate activating the ERK/MAPK pathway. In conclusion, we developed a novel expression profile based approach to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale. Our approach might be applied to investigate the unknown regulatory role of miRNAs in signaling pathways and gene regulatory networks.
Citation Format: Sangbae Kim, Bo Hwa Sohn, Yun-Yong Park, Ji-Hoon Kim, Sung Sook Lee, Micheal A. Davies, Gordon B. Mills, Ju-Seog Lee. Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5222. doi:10.1158/1538-7445.AM2013-5222
Abstract 5228: Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers.
Authors: Zapperi Stefano , Laporta Caterina Anna Maria 
Published: August 2014

Abstract
The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells.
Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.
Citation Format: Stefano Zapperi, Caterina Anna Maria Laporta. Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5228. doi:10.1158/1538-7445.AM2013-5228
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5255: The comparison between MAPK and PI3K signaling pathway inhibition in KRAS mutant NSCLC cell lines.
Authors: Dogan Irem , Cihan Ayla , Ekmekci Abdullah 
Published: August 2014

Abstract
Introduction: KRAS mutations are found 15-25% of patients with lung adenocarcinoma and they lead to constitutive activation of KRAS signaling pathway that results in sustained cell proliferation. Currently, there are no direct anti-KRAS therapies available. Therefore, it is rational to target the downstream molecules of KRAS signaling pathway. MAPK signaling pathway (RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR PI3K/Akt) are the activated pathways by KRAS signaling and crucial for cell survival and proliferation in non-small cell lung cancer (NSCLC). Here, we examined the inhibition of both these pathways combination and alone and analyzed the anti-proliferative and apoptotic events in KRAS mutant NCSLC cell lines, A549 and Calu-1.
Materials and Methods: Cytotoxicity was determined by MTT assay after the cells were treated with LY294002 (PI3K inhibitor), U0126 (MEK inhibitor) and RAD001 (mTOR inhibitor) for 24 hour. The expression levels of p-EGFR, EGFR, p-ERK, ERK, AKT, p-AKT, p53, cyclinD1, c-myc, p27kip1, BAX, BIM and GAPDH were detected by Western blot after 6 and 24 hour treatment.
Results: In proliferation assays, combination of RAD001 (100nM) with U0126 (10uM) and LY294002 (10uM) resulted in higher cytotoxic activity than single agents alone at 24 hour in both cell lines. Western blots revealed that U0126 directly inhibited the phosphorylation of ERK at 6 and 24 hour, followed by inhibiting the activations of its downstream molecules, including cyclinD1 and c-myc but increased the expression of p27kip1, BAX and BIM at 6 and 24 hour. On the other hand, LY294002 downregulated p-AKT signaling only at 6 hour, but not in 24 hour. However, LY294002 and RAD001 combination was effective on cyclinD1 and c-myc expression at 24 hour which can correlate with their cytotoxic effect. Although PI3K/mTOR inhibition is more effective in cytotoxicity, MEK/mTOR inhibition markedly decreases cell proliferation protein marker expressions.
Conclusion: These findings suggest that the combination of MEK and mTOR inhibitors and PI3K and mTOR inhibitors compared with either drug alone can inhibit cell proliferation, induce apoptosis and effect downstream signaling pathways. Also, in molecular level, U0126/RAD001 combination is a better option than LY294002/RAD001 combination in A549 and Calu-1 cells.
Citation Format: Irem Dogan, Ayla Cihan, Abdullah Ekmekci. The comparison between MAPK and PI3K signaling pathway inhibition in KRAS mutant NSCLC cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2013-5255
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5277: MicroRNA expression profile of astrocytoma in archived formalin-fixed paraffin-embedded brain tumor samples.
Authors: Rivera-Díaz Mónica , Quintero Mario , López Julio , Vivas-Mejia P E. 
Published: August 2014

Abstract
Astrocytomas, a tumor derived from astrocytic glial cells, are the most common type of adult primary central nervous system (CNS) neoplasms, representing around 76% of all primary brain tumors. The World Health Organization (WHO) classified astrocytomas into four histological grades spanning from grade I, a benign tumor, to grade IV, a highly malignant tumors. This classification is somewhat subjective and more reliable molecular markers for tumor grading are necessary. MicroRNAs (miRNAs) are small (≈22-nucleotide) noncoding RNAs that, in mammals, regulate genes at the translational level by binding to loosely complimentary sequences in the 3’-UTR of target mRNAs. There is increased in vitro and in vivo evidence that various miRNAs are deregulated in a variety of cancer including astrocytoma. The aim of this study was to assess miRNAs dysregulated in astrocytoma according to its grade using archived formalin-fixed paraffin-embedded (FFPE) samples. Total RNA was isolated, labeled, and hybridized to Affymetrix miRNA arrays. Images were analyzed using the PARTEK software. Eighty-five miRNAs were differentially regulated in grade II, 72 miRNAs in grade III and 118 miRNAs in GBM; compared with control samples. Several non-previously described miRNA in astrcoytoma were identified in this study. The most differentially expressed miRNAs in each tumor grade, were selected for further validation by TAqMan-based real-time PCR. Particularly, miR-92b was upregulated in all astrocytoma grades. Opposite, miR-548p, a miRNA regulating antiapoptotic molecules, was downregulated in GBM tumor tissues, and in well-established GBM cell lines. However, the role of these miRNAs in GBM cells has not been studied. We are currently performing in vitro studies to clarify the role of some of these microRNAs in the cell proliferation of GBM cells.
Citation Format: Mónica Rivera-Díaz, Mario Quintero, Julio López, P E. Vivas-Mejia. MicroRNA expression profile of astrocytoma in archived formalin-fixed paraffin-embedded brain tumor samples. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5277. doi:10.1158/1538-7445.AM2013-5277
Abstract 5293: Prognostic significance of miR-194 in endometrial cancer.
Authors: Zhai Haiyan , Karaayvaz Mihriban , Dong Peixin , Sakuragi Noriaki , Ju Jingfang 
Published: August 2014

Abstract
Endometrial cancer (EC) is the leading malignant tumor occurring in the female genital tract and some subtypes are highly invasive and metastatic. miRNAs are small non-coding RNAs that have a broad impact on cancer progression. In particular, miR-194 regulates epithelial to mesenchymal transition (EMT) by suppressing the expression of BMI-1 in EC. In this retrospective study, the clinical significance of miR-194 was investigated in archival EC specimens. We extracted total RNA from thirty-two EC samples and quantified the expression level of miR-194. We discovered that the expression level of miR-194 was significantly (P = 0.03) lower in type I EC patients with more advanced stage. In addition, patients with higher miR-194 levels have better prognosis than those with lower miR-194 levels (P = 0.0067; Cut-off value of miR-194 = 0.3). These results indicate that miR-194 has potential to serve as prognostic biomarker for EC patients.
Citation Format: Haiyan Zhai, Mihriban Karaayvaz, Peixin Dong, Noriaki Sakuragi, Jingfang Ju. Prognostic significance of miR-194 in endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5293. doi:10.1158/1538-7445.AM2013-5293
Abstract 5300: Identification and validation of novel autoantibodies for the detection of malignant mesothelioma.
Authors: Zhang Xufei , Zhao Lei , Shen Weike , Kernstine Kemp , Zhong Li 
Published: August 2014

Abstract
Malignant mesothelioma (MM) survival rate has been hampered by the lack of efficient and accurate early detection methods. The immune system may detect the early changes of tumor progression by responding with tumor-associated autoantibody production. Hence, in this study, we translated the humoral immune response to cancer proteins into a valuable blood test for MM. A T7 phage MM cDNA library was constructed using MM tumor tissues and biopanned for tumor-associated antigens (TAAs) using pooled MM patients and normal serum samples. About 1000 individual phage TAAs clones from the biopanned library were subjected for protein microarray construction and tested with 53 MM and 52 controls serum samples as a training group. The classifiers developed from the training group were further validated with 50 patient and 50 normal serum samples as an independent blind validation. Nine candidate autoantibody markers were selected by logistic regression and Treeview statistical analysis as a detecting panel. In the training set, sensitivity of 92.5% and specificity of 90.4% were reached with an AUC was 0.898 in Receiver Operating Characteristic analysis. For validation test, 86.5% sensitivity and 86.8% specificity were achieved with an AUC of 0.825. Among these 9 candidate markers, five were found to be strongly cancer associated proteins (PDIA6, MEG3, SDCCAG3, IGHG3, IGHG1). Our results achieved much greater accuracies than any other current biomarkers for MM detection and hence could be a useful tool to assess cancer risk in high-risk populations.
Citation Format: Xufei Zhang, Lei Zhao, Weike Shen, Kemp Kernstine, Li Zhong. Identification and validation of novel autoantibodies for the detection of malignant mesothelioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5300. doi:10.1158/1538-7445.AM2013-5300
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5338: MicroRNA-CGU promotes progression and metastasis through a negative regulation of ERM protein in human gastric cancer.
Authors: Wang Chia-Siu , Tsai Ming Ming , Kuo Liang-Mou , Lin Kwang-Huei 
Published: August 2014

Abstract
Background: miRNAs have an important role in tumor carcinogenesis. They may act either as oncogenes or tumor suppressor genes through their regulated-target genes. The aim of this study was to identify useful biomarkers from miRNAs that might regulate the tumorigenesis or progression of gastric cancer.
Materials and Methods:
Differential miRNA profile was analyzed with a 270 miRNAs-based qRT-PCR assay in a total of 6 pairs of tumor tissues and matched non-tumor mucosa from surgical specimens. One of the top strongest up-regulated miRNAs was selected, and it was validated by qRT-PCR in fresh frozen tissues of gastrectomized specimens from gastric cancer patients. The target gene was searched and identified. The clinicopathologic correlations of the candidate miRNA and target gene were evaluated for their clinical significance.
Results:
The miR-CGU significantly increases by more than 40.2-fold (p &lt; 0.001) in gastric cancer tissues compared with their matched adjacent nontumorous tissues (n = 109). Overexpression of miRNA was significantly associated with tumor progression that included serosal invasion, lymph node metastasis, distant metastasis and pathological stage (all p &lt; 0.001). Higher expression of miR-CGU was significantly associated with a worse 5-year survival outcome (log rank p &lt; 0.001, and p = 0.005, respectively). Functional assays showed that overexpression of this miRNA enhanced gastric cancer cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, a target gene, ERM protein, was identified for miR-CGU. Elevated expression of miRNA in gastric cancer cells could reduce the mRNA and protein levels of ERM protein, and vice versa. Luciferase assays confirmed that miR-CGU could directly bind to the 2-8 nucleotides of 3’ untranslated region of ERM protein. Moreover, an inverse correlation between miR-CGU and ERM protein expression was observed in gastric cancer tissues. The Interaction of miR-CGU and ERM protein expression was further studied in gastric cell lines.
Conclusion:
The miR-CGU is highly upreglated in gastric cancer tissues. It functions as a tumor metastasis enhancer in gastric cancer, and its overexpression contributes to lymph node metastasis and progression of gastric cancer. Overexpression of its target gene, ERM protein may have a therapeutic potential to suppress gastric cancer metastasis.
Citation Format: Chia-Siu Wang, Ming Ming Tsai, Liang-Mou Kuo, Kwang-Huei Lin. MicroRNA-CGU promotes progression and metastasis through a negative regulation of ERM protein in human gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5338. doi:10.1158/1538-7445.AM2013-5338