bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan
Authors: Hu Yongzhen , Kirito Keita , Yoshida Kozue , Mitsumori Toru , Nakajima Kei , Nozaki Yumi , Hamanaka Satoshi , Nagashima Takahiro , Kunitama Masae , Sakoe Kumi , Komatsu Norio 
Published: August 2009

AbstractAbnormal activation of hypoxia-inducible factor-1 (HIF-1), one of the most important transcription factors for the adaptation of cells to hypoxia, is frequently observed in numerous types of solid tumors. Dysregulation of HIF-1 induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins and glycolysis-associated enzymes in cancer cells, which in turn leads to the promotion of tumor growth. In the present study, we examined the pathophysiologic role of HIF-1 in multiple myeloma. Furthermore, we explored the possibility that HIF-1 may be a molecular target for myeloma therapy. We identified constitutive expression of the hypoxia-inducible factor-1 α (HIF-1α)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1α expression through activation of the AKT and mitogen-activated protein kinase signaling pathways. Inhibition of HIF-1 function either by echinomycin, a specific HIF-1 inhibitor, or a siRNA against HIF-1α resulted in enhanced sensitivity to melphalan in myeloma cells. This inhibition of HIF-1 also reversed the protective effect of IGF-1 on melphalan-induced apoptosis. Inhibition of HIF-1 drastically reduced both basal and IGF-1–induced expression of survivin, one of the most important anti-apoptotic proteins in myeloma cells. We conclude that HIF-1 inhibition may be an attractive therapeutic strategy for multiple myeloma. [Mol Cancer Ther 2009;8(8):2329–38]
Targeting Migration inducting gene-7 inhibits carcinoma cell invasion, early primary tumor growth, and stimulates monocyte oncolytic activity
Authors: Petty Aaron P. , Wright Stephen E. , Rewers-Felkins Kathleen A. , Yenderrozos Michelle A. , Vorderstrasse Beth A. , Lindsey J. Suzanne 
Published: August 2009

Abstract
Expression of Migration inducting gene-7 (Mig-7) is limited to tumor cells and to date not found in normal tissues. Multiple tumor microenvironment factors, such as epidermal and hepatocyte growth factors, in concert with αvβ5 integrin ligation, induce Mig-7 mRNA expression. Gain or loss of Mig-7 protein studies shows that Mig-7 promotes invasion of colon and endometrial carcinoma cells. These data led us to hypothesize that targeting Mig-7 through various methods could decrease invasion, enhance monocyte cell killing of tumor cells, and inhibit disease progression. To begin testing this hypothesis, an in vitro chemoinvasion assay of endometrial carcinoma cells treated with Mig-7–specific or control antibodies was used. Mig-7 antibody significantly reduced invasion by &gt;60% compared with controls. In another approach to test this hypothesis, an in vitro analysis of peptide-stimulated human peripheral blood monocyte cells and their killing of MCF-7 breast carcinoma cells was used. Mig-7 peptide treatment increased monocyte cell tumor necrosis factor expression and killing of MCF-7 cells 30-fold over no peptide stimulation and 3-fold over MUC-1 or control peptide treatments. Furthermore, stably expressing Mig-7–specific short hairpin RNA resulted in significantly reduced Mig-7 protein levels and early primary tumor growth in a xenograft nude mouse model. Reduced phosphorylation of ERK1/2, Akt, and S6 kinase as well as decreased membrane-type 1 matrix metalloproteinase activity were mechanisms through which Mig-7 protein caused these effects. Based on these collective data, Mig-7 expression could be a potential candidate for future targeted cancer therapies. [Mol Cancer Ther 2009;8(8):2412–23]
Gene expression signatures and response to imatinib mesylate in gastrointestinal stromal tumor
Authors: Rink Lori , Skorobogatko Yuliya , Kossenkov Andrew V. , Belinsky Martin G. , Pajak Thomas , Heinrich Michael C. , Blanke Charles D. , von Mehren Margaret , Ochs Michael F. , Eisenberg Burton , Godwin Andrew K. 
Published: August 2009

Abstract
Despite initial efficacy of imatinib mesylate in most gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of tumors before and after imatinib mesylate treatment. As part of a recent phase II trial of neoadjuvant/adjuvant imatinib mesylate treatment for advanced primary and recurrent operable GISTs (Radiation Therapy Oncology Group S0132), gene expression profiling using oligonucleotide microarrays was done on tumor samples obtained before and after imatinib mesylate therapy. Patients were classified according to changes in tumor size after treatment based on computed tomography scan measurements. Gene profiling data were evaluated with Statistical Analysis of Microarrays to identify differentially expressed genes (in pretreatment GIST samples). Based on Statistical Analysis of Microarrays [False Discovery Rate (FDR), 10%], 38 genes were expressed at significantly lower levels in the pretreatment biopsy samples from tumors that significantly responded to 8 to 12 weeks of imatinib mesylate, that is, &gt;25% tumor reduction. Eighteen of these genes encoded Krüppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Importantly, 10 KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to imatinib mesylate–based therapy in a naïve panel of GIST. Furthermore, we found that modifying expression of genes within this predictive signature can enhance the sensitivity of GIST cells to imatinib mesylate. Using clinical pretreatment biopsy samples from a prospective neoadjuvant phase II trial, we have identified a gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short-term imatinib mesylate treatment. [Mol Cancer Ther 2009;8(8):2172–82]
Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy
Authors: Wang Yingqun 
Published: August 2009

Abstract
The evolutionarily conserved and developmentally important Wnt signaling pathway has traditionally been regarded as a critical player in tumorigenesis through the canonical Wnt/β-catenin cascade. Nevertheless, accumulating evidence based on recent research has revealed the previously unacknowledged role of noncanonical Wnt/planar cell polarity (PCP) signaling in cancer progression, invasion and metastasis, and angiogenesis. This review describes the PCP signaling pathway and its ever-expanding components and modulators, highlights the most recent studies that provide insight into the link between PCP signaling and cancer, and, finally, proposes a model by which PCP signaling may promote cancer development. This review underscores the emerging theme that deregulated PCP signaling contributes to tumorigenesis, providing new potential targets for cancer therapy. [Mol Cancer Ther 2009;8(8):2103–9]
Induction of endoplasmic reticulum stress response by TZD18, a novel dual ligand for peroxisome proliferator-activated receptor α/γ, in human breast cancer cells
Authors: Zang Chuanbing , Liu Hongyu , Bertz Janina , Possinger Kurt , Koeffler H. Phillip , Elstner Elena , Eucker Jan 
Published: August 2009

Abstract
Previously we reported that the peroxisome proliferator-activated receptor α/γ dual ligand TZD18 inhibited growth and induced apoptosis of leukemia and glioblastoma cells. Now we show that TZD18 also has the same effects against six human breast cancer cell lines. To obtain insights into the mechanism involved in TZD18-induced growth inhibition and apoptosis in breast cancer, the gene expression profiles of TZD18-treated and untreated MCF-7 and MDA-MB-231 cells were compared by microarray analysis. Results reveal that many genes implicated in endoplasmic reticulum stress signaling, such as CHOP (also known as DDIT3 or GADD153), GRP78 (HSPA5), and ATF4, are highly up-regulated, suggesting endoplasmic reticulum stress is induced. This is supported by our data that treatment of MCF-7 and MDA-MB-231 cells with TZD18 induces phosphorylation of PERK and the α subunit of eukaryotic initiation factor 2 (eIF2α), as well as an up-regulation of GRP78 and an activation of ATF6, all of which are specific markers for endoplasmic reticulum stress. Furthermore, this ligand increases the endoplasmic reticulum stress–related cell death–regulators such as CHOP, DR5, GADD34, Bax, and Bak in these cells. Importantly, knockdown of CHOP by small interference RNA antagonizes the TZD18-induced apoptosis, indicating a crucial role of CHOP in the apoptotic process triggered by TZD18. In addition, TZD18 also activates stress-sensitive mitogen-activated protein kinase (MAPK) pathways including p38, ERK, and JNK. The specific inhibitors of these MAPKs attenuated the TZD18-induced growth inhibition in these cells. These results clearly show that activation of these MAPKs is important for TZD18-induced growth inhibition. In summary, TZD18-treatment leads to the activation of endoplasmic reticulum stress response and, subsequently, growth arrest and apoptosis in breast cancer cells. [Mol Cancer Ther 2009;8(8):2296–307]
Oncolytic adenoviruses targeted to cancer stem cells
Authors: Short Joshua J. , Curiel David T. 
Published: August 2009

Abstract
Cancer stem cells (CSC) represent a distinct subpopulation of cancer cells of integral importance. CSCs embody the refractory nature observed among many cancers: very competent initial tumor establishment and extremely aggressive metastatic nature. Recent discoveries indicate that CSCs embody chemo- and radioresistance and have been correlated with advanced disease and resistance to current therapies, and thus help explain the treatment resistance of many cancers. As CSCs are critical for tumor initiation, progression, persistence, and the development of metastasis, the success or failure of treatment approaches may be influenced greatly by the presence and treatment sensitivity of these cells. There also seems to be a direct link between epithelial-mesenchymal transition phenomena and CSCs. Cancer cure is predicated upon effectively targeting and eradicating the CSC population. Oncolytic viruses have undergone many developments and through multiple generations offer an effective way to specifically target and eradicate CSCs, while still maintaining the ability to affect the general tumor cell population. Conditionally replicative adenoviruses (CRAd) are one virotherapy that is especially promising. Multiple advanced targeting and infectivity enhancement schemes have been developed to allow the necessary specificity and transduction efficiency required for an effective therapy. Furthermore, these advanced generation CRAds can be armed with therapeutic transgenes to generate greater antitumor effects. Although ultimately, the rewards of targeting and eradicating CSCs will be evaluated in clinical trials, there are numerous methods for isolating primary CSCs based on surface marker expression and multiple established cell lines representative of CSCs for preliminary evaluation.[Mol Cancer Ther 2009;8(8):2096–102]
Molecular predictors of response to a humanized anti–insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer
Authors: Zha Jiping , O'Brien Carol , Savage Heidi , Huw Ling-Yuh , Zhong Fiona , Berry Leanne , Lewis Phillips Gail D. , Luis Elizabeth , Cavet Guy , Hu Xiaolan , Amler Lukas C. , Lackner Mark R. 
Published: August 2009

Abstract
The insulin-like growth factor-I receptor (IGF-IR) pathway is required for the maintenance of the transformed phenotype in neoplastic cells and hence has been the subject of intensive drug discovery efforts. A key aspect of successful clinical development of targeted therapies directed against IGF-IR will be identification of responsive patient populations. Toward that end, we have endeavored to identify predictive biomarkers of response to an anti-IGF-IR-targeting monoclonal antibody in preclinical models of breast and colorectal cancer. We find that levels of the IGF-IR itself may have predictive value in these tumor types and identify other gene expression predictors of in vitro response. Studies in breast cancer models suggest that IGF-IR expression is both correlated and functionally linked with estrogen receptor signaling and provide a basis for both patient stratification and rational combination therapy with antiestrogen-targeting agents. In addition, we find that levels of other components of the signaling pathway such as the adaptor proteins IRS1 and IRS2, as well as the ligand IGF-II, have predictive value and report on the development of a pathway-focused panel of diagnostic biomarkers that could be used to test these hypotheses during clinical development of IGF-IR-targeting therapies. [Mol Cancer Ther 2009;8(8):2110–21]
Activity of dasatinib againstL576P KITmutant melanoma: Molecular, cellular, and clinical correlates
Authors: Woodman Scott E. , Trent Jonathan C. , Stemke-Hale Katherine , Lazar Alexander J. , Pricl Sabrina , Pavan Giovanni M. , Fermeglia Maurizio , Gopal Y.N. Vashisht , Yang Dan , Podoloff Donald A. , Ivan Doina , Kim Kevin B. , Papadopoulos Nicholas , Hwu Patrick , Mills Gordon B. , Davies Michael A. 
Published: August 2009

AbstractPoint mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma (∼30-40%). In vitro testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other KIT mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (P = 0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (ΔΔGbind = −2.52 kcal/mol) but not for dasatinib (ΔΔGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (&gt;50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography (PET) imaging after dasatinib treatment. These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas. [Mol Cancer Ther 2009;8(8):2079–85]
Regulation of Bcl-2 Expression by HuR in HL60 Leukemia Cells and A431 Carcinoma Cells
Authors: Ishimaru Daniella , Ramalingam Sivakumar , Sengupta Tapas K. , Bandyopadhyay Sumita , Dellis Stephanie , Tholanikunnel Baby G. , Fernandes Daniel J. , Spicer Eleanor K. 
Published: August 2009

Abstract
Overexpression of the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis. Expression of bcl-2 is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA. Elements in the 3′-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of the message. Previously, it was found that the RNA binding proteins nucleolin and Ebp1 have a role in stabilizing bcl-2 mRNA in HL60 cells. Here, we have identified HuR as a component of bcl-2 messenger ribonucleoprotein (mRNP) complexes. RNA coimmunoprecipitation assays showed that HuR binds to bcl-2 mRNA in vivo. We also observed an RNA-dependent coprecipitation of HuR and nucleolin, suggesting that the two proteins are present in common mRNP complexes. Moreover, nucleolin and HuR bind concurrently to bcl-2 AU-rich element (ARE) RNA in vitro, suggesting separate binding sites for these proteins on bcl-2 mRNA. Knockdown of HuR in A431 cells leads to down-regulation of bcl-2 mRNA and protein levels. Observation of a decreased ratio of bcl-2 mRNA to heterogeneous nuclear RNA in HuR knockdown cells confirmed a positive role for HuR in regulating bcl-2 stability. Recombinant HuR retards exosome-mediated decay of bcl-2 ARE RNA in extracts of HL60 cells. This supports a role for HuR in the regulation of bcl-2 mRNA stability in HL60 cells, as well as in A431 cells. Addition of nucleolin and HuR to HL60 cell extracts produced a synergistic protective effect on decay of bcl-2 ARE RNA. HuR knockdown also leads to redistribution of bcl-2 mRNA from polysomes to monosomes. Thus, HuR seems to play a positive role in both regulation of bcl-2 mRNA translation and mRNA stability. (Mol Cancer Res 2009;7(8):1354–66)
miR-93, miR-98, and miR-197 Regulate Expression of Tumor Suppressor Gene FUS1
Authors: Du Liqin , Schageman Jeoffrey J. , Subauste Maria C. , Saber Barbara , Hammond Scott M. , Prudkin Ludmila , Wistuba Ignacio I. , Ji Lin , Roth Jack A. , Minna John D. , Pertsemlidis Alexander 
Published: August 2009

Abstract
FUS1 is a tumor suppressor gene located on human chromosome 3p21, and expression of Fus1 protein is highly regulated at various levels, leading to lost or greatly diminished tumor suppressor function in many lung cancers. Here we show that selected microRNAs (miRNA) interact with the 3′-untranslated region (3′UTR) of FUS1, leading to down-regulation of protein expression. Using computational methods, we first predicted that FUS1 is a target of three miRNAs, miR-93, miR-98, and miR-197, and then showed that exogenous overexpression of these miRNAs inhibited Fus1 protein expression. We then confirmed that the three miRNAs target the 3′UTR region of the FUS1 transcript and that individual deletion of the three miRNA target sites in the FUS1 3′UTR restores the expression level of Fus1 protein. We further found that miR-93 and miR-98 are expressed at higher levels in small-cell lung cancer cell lines (SCLC) than in non–small-cell lung cancer cell lines (NSCLC) and immortalized human bronchial epithelial cells (HBEC), and that miR-197 is expressed at higher levels in both SCLCs and NSCLCs than in HBECs. Finally, we found that elevated miR-93 and miR-197 expression is correlated with reduced Fus1 expression in NSCLC tumor specimens. These results suggest that the three miRNAs are negative regulators of Fus1 expression in lung cancers. (Mol Cancer Res 2009;7(8):1234–43)
Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α
Authors: Mori Akira , Moser Christian , Lang Sven A. , Hackl Christina , Gottfried Eva , Kreutz Marina , Schlitt Hans J. , Geissler Edward K. , Stoeltzing Oliver 
Published: August 2009

Abstract
Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk–mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1β or hypoxia. The IL-1 β–mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1α (HIF-1α) and HIF-1αsiRNA reduced constitutive KLF5. Similarly, KLF5siRNA reduced the expression of the HIF-1α target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/MAPK/Erk signaling, but involves the IL-1β/IL-1R system, p38, and the transcription factor HIF-1α. (Mol Cancer Res 2009;7(8):1390–8)
Oncogenic Activating Mutations Are Associated with Local Copy Gain
Authors: Modrek Barmak , Ge Lin , Pandita Ajay , Lin Eva , Mohan Sankar , Yue Peng , Guerrero Steve , Lin William M. , Pham Thinh , Modrusan Zora , Seshagiri Somasekar , Stern Howard M. , Waring Paul , Garraway Levi A. , Chant John , Stokoe David , Cavet Guy 
Published: August 2009

Abstract
Although activating mutations and gains in copy number are key mechanisms for oncogene activation, the relationship between the two is not well understood. In this study, we focused on KRAS copy gains and mutations in non–small cell lung cancer. We found that KRAS copy gains occur more frequently in tumors with KRAS activating mutations and are associated with large increases in KRAS expression. These copy gains tend to be more focal in tumors with activating mutations than in those with wild-type KRAS. Fluorescence in situ hybridization analysis revealed that some tumors have homogeneous low-level gains of the KRAS locus, whereas others have high-level amplification of KRAS, often in only a fraction of tumor cells. Associations between activating mutation and copy gains were also observed for other oncogenes (EGFR in non–small cell lung cancer, BRAF and NRAS in melanoma). Activating mutations were associated with copy gains only at the mutated oncogene locus but not other oncogene loci. However, KRAS activating mutations in colorectal cancer were not associated with copy gains. Future work is warranted to clarify the relationship among the different mechanisms of oncogene activation. (Mol Cancer Res 2009;7(8):1244–52)