bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inactivation of the Candidate Tumor Suppressor Par-4 in Endometrial Cancer
Authors: Moreno-Bueno Gema , Fernandez-Marcos Pablo J. , Collado Manuel , Tendero Mercedes J. , Rodriguez-Pinilla Socorro M. , Garcia-Cao Isabel , Hardisson David , Diaz-Meco Maria T. , Moscat Jorge , Serrano Manuel , Palacios Jose 
Published: March 2007

Abstract
Recently, it has been shown that mice deficient in the proapoptotic protein prostate apoptosis response 4 (Par-4) are specifically prone to develop endometrial carcinomas. Based on this, we have examined here the possible role of Par-4 as a tumor suppressor gene in human endometrial cancer. Using cDNA arrays, quantitative reverse transcription-PCR, and immunohistochemistry, we detected Par-4 down-regulation in ∼40% of endometrial carcinomas. This alteration was not associated with phosphatase and tensin homologue (PTEN), K-RAS, or β-catenin mutations, but was more frequent among tumors showing microsatellite instability (MSI) or among tumors that were estrogen receptor positive. Mutational analysis of the complete coding sequence of Par-4 in endometrial cancer cell lines (n = 6) and carcinomas (n = 69) detected a mutation in a single carcinoma, which was localized in exon 3 [Arg (CGA) 189 (TGA) Stop]. Interestingly, Par-4 promoter hypermethylation was detected in 32% of the tumors in association with low levels of Par-4 protein and was more common in MSI-positive carcinomas. Par-4 promoter hypermethylation and silencing was also detected in endometrial cancer cell lines SKUT1B and AN3CA, and reexpression was achieved by treatment with the demethylating agent 5′-aza-2′-deoxycytidine. Together, these data show that Par-4 is a relevant tumor suppressor gene in human endometrial carcinogenesis. [Cancer Res 2007;67(5):1927–34]
Engagement of Collagen-Binding Integrins Promotes Matrix Metalloproteinase-9–Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells
Authors: Symowicz Jaime , Adley Brian P. , Gleason Kara J. , Johnson Jeffrey J. , Ghosh Supurna , Fishman David A. , Hudson Laurie G. , Stack M. Sharon 
Published: March 2007

Abstract
Reversible modulation of cell-cell adhesion, cell-matrix adhesion, and proteolytic activity plays a critical role in remodeling of the neoplastic ovarian epithelium during metastasis, implicating cadherins, integrins, and proteinases in i.p. metastatic dissemination of epithelial ovarian carcinoma (EOC). Aberrant epithelial differentiation is an early event in ovarian carcinogenesis; thus, in contrast to most carcinomas that lose E-cadherin expression with progression, E-cadherin is abundant in primary EOC. Metastasizing EOCs engage in integrin-mediated adhesion to submesothelial interstitial collagens and express matrix metalloproteinases (MMP) that facilitate collagen invasion, thereby anchoring secondary lesions in the submesothelial matrix. As metalloproteinases have also been implicated in E-cadherin ectodomain shedding, the current study was undertaken to model the effects of matrix-induced integrin clustering on proteinase-catalyzed E-cadherin ectodomain shedding. Aggregation of collagen-binding integrins induced shedding of an 80-kDa E-cadherin ectodomain [soluble E-cadherin (sE-cad)] in a MMP- and Src kinase-dependent manner, and sE-cad was prevalent in ascites from ovarian cancer patients. Expression of MMP-9 was elevated by integrin aggregation, integrin-mediated ectodomain shedding was inhibited by a MMP-9 function blocking antibody, and incubation of cells with exogenous MMP-9 catalyzed E-cadherin ectodomain shedding. In contrast to other tumors wherein sE-cad is released into the circulation, EOC tumors maintain direct contact with sE-cad–rich ascites at high concentration, and incubation of EOC cells with physiologically relevant concentrations of recombinant sE-cad disrupted adherens junctions. These data support a novel mechanism for posttranslational modification of E-cadherin function via MMP-9 induction initiated by cell-matrix contact and suggest a mechanism for promotion of EOC metastatic dissemination. [Cancer Res 2007;67(5):2030–9]
Homeodomain-Interacting Protein Kinase 2 Is the Ionizing Radiation–Activated p53 Serine 46 Kinase and Is Regulated by ATM
Authors: Dauth Ilka , Krüger Jana , Hofmann Thomas G. 
Published: March 2007

Abstract
Phosphorylation of p53 at Ser46 is important to activate the apoptotic program. The protein kinase that phosphorylates p53 Ser46 in response to DNA double-strand breaks is currently unknown. The identification of this kinase is of particular interest because it may contribute to the outcome of cancer therapy. Here, we report that ionizing radiation (IR) provokes homeodomain-interacting protein kinase 2 (HIPK2) accumulation, activation, and complex formation with p53. IR-induced HIPK2 up-regulation strictly correlates with p53 Ser46 phosphorylation. Down-regulation of HIPK2 by RNA interference specifically inhibits IR-induced phosphorylation of p53 at Ser46. Moreover, we show that HIPK2 activation after IR is regulated by the DNA damage checkpoint kinase ataxia telangiectasia mutated (ATM). Cells from ataxia telangiectasia patients show defects in HIPK2 accumulation. Concordantly, IR-induced HIPK2 accumulation is blocked by pharmacologic inhibition of ATM. Furthermore, ATM down-regulation by RNA interference inhibited IR-induced HIPK2 accumulation, whereas checkpoint kinase 2 deficiency showed no effect. Taken together, our findings indicate that HIPK2 is the IR-activated p53 Ser46 kinase and is regulated by ATM. [Cancer Res 2007;67(5):2274–9]
Fractalkine (CX3CL1)– and Interleukin-2–Enriched Neuroblastoma Microenvironment Induces Eradication of Metastases Mediated by T Cells and Natural Killer Cells
Authors: Zeng Yan , Huebener Nicole , Fest Stefan , Weixler Silke , Schroeder Ulrike , Gaedicke Gerhard , Xiang Rong , Schramm Alexander , Eggert Angelika , Reisfeld Ralph A. , Lode Holger N. 
Published: March 2007

Abstract
Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Its function is mediated through CX3C receptor (CX3CR), which is expressed by TH1 immune cells including T cells and natural killer (NK) cells. FKN was shown to be expressed in &gt;90% of 68 neuroblastoma samples as determined by cDNA microarray analysis. Here, we characterized the effect of FKN in the neuroblastoma microenvironment using a syngeneic model genetically engineered to secrete FKN. We show FKN-mediated migration, adhesion, and IFN-γ secretion of immune effector cells, but limited antineuroblastoma activity, in vitro and in vivo. Therefore, we tested the hypothesis that a combined increase of FKN and interleukin-2 (IL-2) in the neuroblastoma microenvironment induces an effective antitumor immune response. For this purpose, IL-2 was targeted to ganglioside GD2, which is highly expressed on neuroblastoma tissue, using an anti-GD2 antibody IL-2 immunocytokine (ch14.18-IL-2). Only mice bearing FKN- and IL-2–enriched neuroblastoma tumors exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases. The depletion of T cells and NK cells in vivo abrogated the effect, and these effector cells showed the highest cytolytic activity in vitro. Finally, only the FKN- and IL-2–enriched neuroblastoma microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. In summary, we showed for the first time the immunologic mechanisms by which targeted IL-2 treatment of neuroblastoma with an FKN-rich microenvironment induces an effective antitumor response. [Cancer Res 2007;67(5):2331–8]
Targeting the Oligomerization Domain of ETO Interferes with RUNX1/ETO Oncogenic Activity in t(8;21)-Positive Leukemic Cells
Authors: Wichmann Christian , Chen Linping , Heinrich Markus , Baus Daniela , Pfitzner Edith , Zörnig Martin , Ottmann Oliver G. , Grez Manuel 
Published: March 2007

Abstract
About 12% of all de novo acute myeloid leukemias are characterized by the translocation t(8;21), which generates the oncogenic fusion protein RUNX1/ETO. RUNX1/ETO has a modular structure and contains several docking sites for heterologous proteins, including transcriptional corepressors like N-CoR, SMART, and mSIN3A. RUNX1/ETO is found in high molecular weight complexes, which are crucial for the block in myeloid differentiation observed in RUNX1/ETO–transformed cells. Essential for high molecular weight complex formation is the nervy homology region 2 (NHR2) within ETO, which serves as interacting surface for oligomerization as well as association with members of the ETO protein family. Here, we show that the expression of a fusion peptide consisting of 128 amino acids (NC128), including the entire NHR2 domain of ETO, disrupts the stability of the RUNX1/ETO high molecular weight complexes, restores transcription of RUNX1/ETO target genes, and reverts the differentiation block induced by RUNX1/ETO in myeloid cells. In the presence of NC128, RUNX1/ETO–transformed cells lose their progenitor cell characteristics, are arrested in cell cycle progression, and undergo cell death. Our results indicate that selective interference with the oligomerization domain of ETO could provide a promising strategy to inhibit the oncogenic properties of the leukemia-associated fusion protein RUNX1/ETO. [Cancer Res 2007;67(5):2280–9]
The p53 Isoform Δp53 Lacks Intrinsic Transcriptional Activity and Reveals the Critical Role of Nuclear Import in Dominant-Negative Activity
Authors: Chan Wan Mui , Poon Randy Y.C. 
Published: March 2007

Abstract
The transcription factor p53 is one of the most frequently mutated tumor suppressors. Recent progress has unraveled several novel isoforms of p53. Intriguingly, one of the p53 isoform, Δp53, which lacks part of the DNA binding domain, was reported to be transcriptionally active toward some p53 target genes and is critical for the intra–S phase checkpoint. Here, we show that, in contrast to full-length p53, ectopically expressed Δp53 neither transactivated the promoters of p21CIP1/WAF1 or murine double minute-2 (MDM2) nor repressed the cyclin B1 promoter in unstressed H1299 cells. Due to the deletion of a nuclear localization signal, Δp53 was not imported into the nucleus. Engineering of nuclear localization signals to Δp53 restored nuclear accumulation. However, the nuclear-targeting Δp53 remained inactive, indicating that the lack of intrinsic activity of Δp53 was not simply due to subcellular localization but to its incomplete DNA binding domain. Similar to p53, Δp53 was subjected to MDM2-mediated ubiquitination/proteolysis. The cytoplasmic localization of Δp53 correlated with the instability of the protein because forcing Δp53 into the nucleus increased its stability. Although Δp53 could form a complex with p53 and stimulated the cytoplasmic retention of p53, it was not a robust inhibitor of p53. Targeting Δp53 into the nucleus enhanced the dominant-negative activity of Δp53. These observations underscore the critical role of subcellular localization in the dominant-negative action of p53. [Cancer Res 2007;67(5):1959–69]
Osteopontin Promotes Integrin Activation through Outside-In and Inside-Out Mechanisms: OPN-CD44V Interaction Enhances Survival in Gastrointestinal Cancer Cells
Authors: Lee Jia-Lin , Wang Mei-Jung , Sudhir Putty-Reddy , Chen Gen-Der , Chi Chin-Wen , Chen Jeou-Yuan 
Published: March 2007

Abstract
Osteopontin (OPN) and splice variants of CD44 (CD44V) have independently been identified as markers for tumor progression. In this study, we show that both OPN and CD44V are frequently overexpressed in human gastric cancer and that OPN-engaged CD44V ligation confers cells an increased survival mediated through integrin activation. First, we show that OPN treatment confers cells an increased resistance to UV-induced apoptosis. The OPN-mediated antiapoptosis is dependent on the expression of the variant exon 6 (V6)- or V7-containing CD44 as shown by overexpression of individual CD44V in gastric AZ521 cells that express no or very low level of endogenous CD44 and by knockdown of the constitutively expressed V6-containing CD44 isoforms in colon HT29 cells. Although OPN also interacts with RGD integrins, OPN-RGD sequence is dispensable for OPN-mediated antiapoptosis. OPN-induced antiapoptosis is mainly attributed to the engagement of CD44V isoforms and the relay of an inside-out signaling via Src activity, leading to robust integrin activation. Furthermore, OPN-elicited antiapoptosis was observed when cells were plated on fibronectin but not on poly-d-lysin, and preincubation of cells with anti-integrin β1 antibody to block integrin-extracellular matrix (ECM) interaction or ectopic expression of the dominant-negative forms of focal adhesion kinase to block ECM-derived signal abolished OPN-induced survival, suggesting that OPN-elicited antiapoptotic function is propagated from matrix transduced by integrin. Taken together, we showed that OPN-CD44V interaction promotes ECM-derived survival signal mediated through integrin activation, which may play an important role in the pathogenic development and progression of gastric cancer. [Cancer Res 2007;67(5):2089–97]
Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection
Authors: Huang Fei , Reeves Karen , Han Xia , Fairchild Craig , Platero Suso , Wong Tai W. , Lee Francis , Shaw Peter , Clark Edwin 
Published: March 2007

AbstractDasatinib is a multitargeted kinase inhibitor that was recently approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. It is also in clinical trials for treating patients with solid tumors. The identification of molecular markers predictive of response to dasatinib could assist in clinical development by selecting patients most likely to derive clinical benefit. Using baseline gene expression profiling of a panel of 23 breast cancer cell lines, we identified genomic signatures highly correlated with in vitro sensitivity to dasatinib. The ability of these signatures to predict dasatinib sensitivity was further confirmed and validated in independent test cell lines. A six-gene model was used to correctly predict dasatinib sensitivity in 11 out of 12 (92%) additional breast and 19 out of 23 (83%) lung cancer cell lines. Quantitative real-time PCR and immunohistochemical assays further confirmed the differential expression pattern of selected markers. Finally, these gene signatures were observed in a subset of primary breast, lung, and ovarian tumors suggesting potential utility in patient selection. The subset of breast cancer patients expressing the dasatinib-sensitive signature includes a distinct clinical and molecular subgroup: the so-called “triple negative” (i.e., estrogen receptor–negative, progesterone receptor–negative, and HER2-negative) or “basal” breast cancer subtype. This patient population has a poor prognosis and currently has few effective treatment options. Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients. [Cancer Res 2007;67(5):2226–38]
The Possible Role of Cytokeratin 8 in Cadmium-Induced Adaptation and Carcinogenesis
Authors: Lau Andy T.Y. , Chiu Jen-Fu 
Published: March 2007

Abstract
Chronic exposures to cadmium compounds are carcinogenic. It was hypothesized that the development of resistance to cadmium may drive carcinogenesis. This is achieved by selection of resistant cells in which the apoptotic response is significantly attenuated. The induction of cadmium resistance in rat lung epithelial cells (LEC) was used to explore the mechanisms of cadmium-induced adaptation and carcinogenesis. Our previous results showed that LECs developed resistance to apoptosis during cadmium adaptation possibly due to perturbation of the c-Jun NH2-terminal kinase pathway. Here, we further study these cells by comparative proteomics. Interestingly, we showed that two intermediate filament proteins, cytokeratin 8 (CK8) and cytokeratin 14 (CK14), were increased significantly and stably maintained only in the adapted cells but not in cadmium-treated parental cells. It has been documented that CK8/cytokeratin 18 provided resistance to tumor necrosis factor (TNF)–induced apoptosis and CK14 may function as an inhibitor of TNF-TNF receptor 1 (TNFR1) signaling through an association with TNFR1-associated death domain protein, suggesting that up-regulation of CK8 and CK14 may be responsible for apoptotic resistance. Finally, we showed that small interfering RNA–specific knockdown of CK8 in cadmium-adapted cells attenuated the cadmium resistance, indicating the potential role of CK8 in cadmium resistance. This acquired self-resistance to apoptosis could account for cadmium-induced carcinogenesis, as this promotes neoplastic cell survival as well as subsequent clonal expansion and then progression of tumor development. Thus, increased expression of these cytokeratins represents an adaptive survival mechanism that resists cadmium-induced apoptosis and it is unprecedented that cells respond to long-term cadmium exposure by modulating keratin dynamics. [Cancer Res 2007;67(5):2107–13]
Notch Signaling, γ-Secretase Inhibitors, and Cancer Therapy
Authors: Shih Ie-Ming , Wang Tian-Li 
Published: March 2007

Abstract
The Notch signaling pathway represents a critical component in the molecular circuits that control cell fate during development. Aberrant activation of this pathway contributes to tumorigenesis. The role of Notch in human cancer has been highlighted recently by the presence of activating mutations and amplification of Notch genes in human cancer and by the demonstration that genes in the Notch signaling pathway could be potential therapeutic targets. It has become clear that one of the major therapeutic targets in the Notch pathway are the Notch receptors, in which γ-secretase inhibitors prevent the generation of the oncogenic (intracellular) domain of Notch molecules and suppress the Notch activity. This review article summarizes the biological roles of Notch molecules in cancer development with special emphasis on the promise and challenges in applying γ-secretase inhibitors as a new line of targeted therapeutic agents. [Cancer Res 2007;67(5):1879–82]
Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer
Authors: Huang Yu-Chuen , Lee Cheng-Ming , Chen Marcelo , Chung Ming-Yi , Chang Yen-Hwa , Huang William Ji-Shian , Ho Donald Ming-Tak , Pan Chin-Chen , Wu Tony T. , Yang Stone , Lin Ming-Wei , Hsieh Jer-Tsong , Chen Yi-Ming Arthur 
Published: March 2007

Abstract
Purpose: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer.
Experimental Design: Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients.
Results: Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P &lt; 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues.
Conclusions: Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.
Antibody-Dependent Cellular Cytotoxicity Mediated by Cetuximab against Lung Cancer Cell Lines
Authors: Kurai Jun , Chikumi Hiroki , Hashimoto Kiyoshi , Yamaguchi Kosuke , Yamasaki Akira , Sako Takanori , Touge Hirokazu , Makino Haruhiko , Takata Miyako , Miyata Masanori , Nakamoto Masaki , Burioka Naoto , Shimizu Eiji 
Published: March 2007

AbstractPurpose: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines.Experimental Design: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h 51Cr release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells.Results: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 μg/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients.Conclusions: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.