bluuebunny/crossref_metadata_2025_split huggingface dataset:
Male Germ Cell–Associated Kinase, a Male-Specific Kinase Regulated by Androgen, Is a Coactivator of Androgen Receptor in Prostate Cancer Cells
Authors: Ma Ai-Hong , Xia Liang , Desai Sonal J. , Boucher David L. , Guan Yi , Shih Hsiu-Ming , Shi Xu-Bao , deVere White Ralph W. , Chen Hong-Wu , Tepper Cliff G. , Kung Hsing-Jien 
Published: September 2006

Abstract
Androgen receptor (AR) is a ligand-induced transcriptional factor, which plays an important role in the normal development of prostate as well as in the progression of prostate cancer. Numerous coactivators, which associate with AR and function to remodel chromatin and recruit RNA polymerase II to enhance the transcriptional potential of AR, have been identified. Among these coactivators, few are protein kinases. In this study, we describe the characterization of a novel protein kinase, male germ cell–associated kinase (MAK), which serves as a coactivator of AR. We present evidence, which indicates that (a) MAK physically associates with AR (MAK and AR are found to be coprecipitated from cell extracts, colocalized in nucleus, and corecruited to prostate-specific antigen promoter in LNCaP as well as in transfected cells); (b) MAK is able to enhance AR transactivation potential in an androgen- and kinase-dependent manner in several prostate cancer cells and synergize with ACTR/steroid receptor coactivator-3 coactivator; (c) small hairpin RNA (shRNA) knocks down MAK expression resulting in the reduction of AR transactivation ability; (d) MAK-shRNA or kinase-dead mutant, when introduced into LNCaP cells, reduces the growth of the cells; and (e) microarray analysis of LNCaP cells carrying kinase-dead MAK mutant showed a significant impediment of AR signaling, indicating that endogenous MAK plays a general role in AR function in prostate cancer cells and likely to be a general coactivator of AR in prostate tissues. The highly restricted expression of this kinase makes it a potentially useful target for intervention of androgen independence. (Cancer Res 2006; 66(17): 8439-47)
p53 Is Preferentially Recruited to the Promoters of Growth Arrest Genes p21 and GADD45 during Replicative Senescence of Normal Human Fibroblasts
Authors: Jackson James G. , Pereira-Smith Olivia M. 
Published: September 2006

Abstract
Replicative senescence is the terminal growth arrest that most normal human cells enter into after a fixed number of divisions in vitro, limiting the proliferative potential of a cell and preventing genomic instability caused by critically short telomeres. Thus, senescence presents a tumor-suppressive mechanism and a barrier to tumor formation. However, senescent cells are inherently resistant to apoptosis and, as they accumulate in aging tissues, may contribute to organ dysfunction and promote tumor progression as part of the stromal environment. Replicative life span in normal human cells can be extended by inactivation of the tumor suppressor gene p53 or its direct target, the cyclin-dependent kinase inhibitor p21, suggesting a direct role for this pathway in senescence. However, p53 recruitment to promoters of target genes during replicative senescence has not been shown in live cells. In this study, we used chromatin immunoprecipitation to determine that p53 preferentially occupied the promoters of growth arrest genes p21 and GADD45 in senescent normal human diploid fibroblasts but not the promoters of other target genes that recruited p53 following doxorubicin-induced DNA damage, such as apoptosis regulators TNFRSF10b, TNFRSF6, and PUMA. This differential recruitment of p53 in senescent versus doxorubicin-treated fibroblasts was accompanied by differences in post-translational modification of p53. These data provide mechanisms for both the growth arrest mediated by p53 and the resistant nature of senescent cells to apoptosis despite p53 activity. (Cancer Res 2006; 66(17): 8356-60)
Breast Cancer in African-American Women: Differences in Tumor Biology from European-American Women
Authors: Amend Kandace , Hicks David , Ambrosone Christine B. 
Published: September 2006

Abstract
Disparities exist between African-American and European-American women in the incidence and nature of breast cancer. African-American women are more often diagnosed with breast cancer at an earlier age and with more aggressive disease, characterized by higher grade and negative estrogen and progesterone receptor status. Recent findings reveal specific gene expression patterns associated with the more aggressive breast cancers observed in African-American women. An overview of the current literature about racial differences in breast cancer prompts questions for future research to elucidate causes for the apparent disparities in tumor biology. (Cancer Res 2006; 66(17): 8327-30)
A Profile of Methyl-CpG Binding Domain Protein Occupancy of Hypermethylated Promoter CpG Islands of Tumor Suppressor Genes in Human Cancer
Authors: Lopez-Serra Lidia , Ballestar Esteban , Fraga Mario F. , Alaminos Miguel , Setien Fernando , Esteller Manel 
Published: September 2006

Abstract
Methyl-CpG binding domain (MBD) proteins have been shown to couple DNA methylation to transcriptional repression. This biological property suggests a role for MBD proteins in the silencing of tumor suppressor genes that are hypermethylated at their promoter CpG islands in cancer cells. Despite the demonstration of the presence of MBDs in the methylated promoter of several genes, we still ignore how general and specific is this association. Here, we investigate the profile of MBD occupancy in a large panel of tumor suppressor gene promoters and cancer cell lines. Our study shows that most hypermethylated promoters are occupied by MBD proteins, whereas unmethylated promoters are generally devoid of MBDs, with the exception of MBD1. Treatment of cancer cells with the demethylating agent 5-aza-2′-deoxycytidine results in CpG island hypomethylation, MBD release, and gene reexpression, reinforcing the notion that association of MBDs with methylated promoters is methylation-dependent. Whereas several promoters are highly specific in recruiting a particular set of MBDs, other promoters seem to be less exclusive. Our results indicate that MBDs have a great affinity in vivo for binding hypermethylated promoter CpG islands of tumor suppressor genes, with a specific profile of MBD occupancy that it is gene and tumor type specific. (Cancer Res 2006; 66(17): 8342-6)
Gadd45a Suppresses Ras-Driven Mammary Tumorigenesis by Activation of c-Jun NH2-Terminal Kinase and p38 Stress Signaling Resulting in Apoptosis and Senescence
Authors: Tront Jennifer S. , Hoffman Barbara , Liebermann Dan A. 
Published: September 2006

Abstract
The Gadd45 family of proteins is known to play a central role as cellular stress sensors that modulate the response of mammalian cells to stress inflicted by physiologic and environmental stressors. Gadd45a was shown to be a direct target to the p53 and BRCA1 tumor suppressor genes, whose loss of function is known to play a vital role in breast carcinogenesis; however, the role of Gadd45a in the suppression of breast cancer remains unclear. To address this issue, Gadd45a-deficient mice were crossed with breast cancer prone mouse mammary tumor virus–Ras mice to generate mice that express activated Ras and differ in their Gadd45a status. Using this mouse model, we show that the loss of Gadd45a accelerates Ras-driven mammary tumor formation, exhibiting increased growth rates and a more aggressive histologic phenotype. Moreover, it is shown that accelerated Ras-driven tumor formation in the absence of Gadd45a results in both a decrease in apoptosis, which is linked to a decrease in c-Jun NH2-terminal kinase (JNK) activation, and a decrease in Ras-induced senescence, which is correlated with a decrease in p38 kinase activation. Altogether, these results provide a novel model for the tumor-suppressive function of Gadd45a in the context of Ras-driven breast carcinogenesis, showing that Gadd45a elicits its function through activation of the stress-induced JNK and p38 kinases, which contribute to increase in apoptosis and Ras-induced senescence. (Cancer Res 2006; 66(17): 8448-54)
Expression of ΔDNMT3B Variants and Its Association with Promoter Methylation of p16 and RASSF1A in Primary Non–Small Cell Lung Cancer
Authors: Wang Jie , Walsh Garret , Liu Diane D. , Lee J. Jack , Mao Li 
Published: September 2006

Abstract
Despite the role of DNMT3B in de novo DNA methylation, a correlation between DNMT3B expression and promoter DNA methylation has not being established in tumors. We recently reported ΔDNMT3B, a subfamily of DNMT3B, with seven variants, as the predominant expression forms in non–small cell lung cancer (NSCLC). We hypothesized that expression of the ΔDNMT3B variants plays a role in promoter methylation formation during lung tumorigenesis. Expression of seven ΔDNMT3B variants was measured in 119 NSCLCs and the corresponding normal lungs using reverse transcription-PCR. The expression patterns of ΔDNMT3B variants were analyzed with the status of p16 and RASSF1A promoter methylation in the tumors as well as in patients' clinical variables, including outcomes. Expression of ΔDNMT3B variants was detected in 94 of 119 (80%) tumors but in only 22 (18%) of the corresponding normal lungs (P &lt; 0.0001). ΔDNMT3B1, ΔDNMT3B2, and ΔDNMT3B4 were the most frequently detected transcripts in the tumors (62%, 76%, and 46%, respectively). The expression of ΔDNMT3B variants was associated with p16 and RASSF1A promoter methylation in the tumors, but the strongest association was between ΔDNMT3B4 and RASSF1A. Forty-two of 46 (91%) tumors with RASSF1A promoter methylation expressed ΔDNMT3B4 compared with only 13 of 73 (18%) tumors without the promoter methylation (P &lt; 0.0001). Strong associations were also observed between expression of the variants in the tumors and in patients' clinical outcomes. Expression of ΔDNMT3B variants is common in NSCLC and may play an important role in the development of promoter methylation. (Cancer Res 2006; 66(17): 8361-6)
Aurora Kinase A Messenger RNA Overexpression Is Correlated with Tumor Progression and Shortened Survival in Head and Neck Squamous Cell Carcinoma
Authors: Reiter Rudolf , Gais Peter , Jütting Uta , Steuer-Vogt Miriam K. , Pickhard Anja , Bink Karin , Rauser Sandra , Lassmann Silke , Höfler Heinz , Werner Martin , Walch Axel 
Published: September 2006

Abstract
Purpose: Aurora kinase A (AURKA/STK15/BTAK) encodes a serine/threonine kinase associated with chromosomal distribution and its up-regulation induces chromosomal instability, thereby leading to aneuploidy and cell transformation in several types of cancer. In this study, we investigated the role of AURKA in head and neck squamous cell carcinoma (HNSCC).
Experimental Design: The mRNA expression levels of AURKA were compared in tumor tissues of 66 HNSCC patients with those in corresponding normal squamous epithelium by real-time quantitative reverse transcriptase-PCR. In addition, the association between AURKA mRNA and protein expression, centrosome abnormalities, and aneuploidy was studied in a subset of cases (n = 34). All molecular variables were correlated to histomorphologic findings and clinical follow-up data of the patients.
Results: AURKA mRNA up-regulation was significantly associated with tumor stage and the occurrence of regional lymph node, as well as distant metastasis (P &lt; 0.0001 for all). Similarly, a correlation was found for protein expression and the occurrence of regional lymph node (P = 0.0183) and distant metastasis (P = 0.03). The mRNA was positively associated with protein expression (P = 0.003) and centrosome abnormalities (P = 0.03). Cox regression analysis revealed that AURKA mRNA up-regulation correlated with disease-free survival of the patients (P = 0.03) as well as shorter overall survival (P &lt; 0.001).
Conclusions: We conclude that the up-regulation of AURKA mRNA may play a critical role in the tumor progression of HNSCC and provides useful information as a prognostic factor for HNSCC patients.
Microsatellite DNA Alterations of Gastrointestinal Stromal Tumors Are Predictive for Outcome
Authors: Schurr Paulus , Wolter Stefan , Kaifi Jussuf , Reichelt Uta , Kleinhans Helge , Wachowiak Robin , Yekebas Emre , Strate Tim , Kalinin Viacheslav , Simon Ronald , Sauter Guido , Schaefer Hansjoerg , Izbicki Jakob 
Published: September 2006

AbstractPurpose: In gastrointestinal stromal tumors (GIST), loss of heterozygosity (LOH) on chromosome 22 and its presumptive biological function has been described. The prognostic value of these and other DNA regions for patient survival remains unclear.Experimental Design: Sixty patients who underwent surgery at our institution between 1992 and 2003 for GIST were histopathologically reclassified by immunohistochemistry and the GIST consensus group criteria 2001. Twenty-one microsatellite loci on chromosomes 3, 9, 13, 17, 18, and 22 were screened for alterations in tumor and healthy DNA. Survival was calculated by Kaplan-Meier plots.Results: Eleven (18.3%) of 60 patients showed metastases at presentation. Thirteen (21.7%) of 60 were high-risk GISTs. LOH was found in all tumors. Twenty-eight (46.7%) of 60 showed more than two LOH in 21 microsatellite marker sites. The frequency of single marker LOH varied from 1.7% to 28.3% among tumors. Frequent LOH was found on chromosomes 22 and 17. The correlation of LOH positivity and the consensus scoring was significant (P = 0.005, χ2 test). After a median observation time of 33.3 months (95% confidence interval, 23.9-42.6), overall survival was best for patients with tumors of very low, low, and intermediate risks with only 6 of 36 death events, whereas 14 of 24 high-risk and metastasized patients had died (P &lt; 0.001, log-rank test). Likewise, LOH significantly predicted survival (P = 0.013) and the effect was particularly detrimental for LOH on chromosome 17 (P &lt; 0.001).Conclusions: LOH is a useful phenomenon for the prognosis of GIST. Rather than chromosome 22 markers, chromosome 17 markers independently predict survival.
Overexpression of Hypoxia-Inducible Factor 1α and p53 Is a Marker for an Unfavorable Prognosis in Gastric Cancer
Authors: Sumiyoshi Yasushi , Kakeji Yoshihiro , Egashira Akinori , Mizokami Ken , Orita Hiroyuki , Maehara Yoshihiko 
Published: September 2006

Abstract
Purpose: To investigate the effects of the expression of hypoxia-inducible factor 1α (HIF-1α) and p53 on the prognosis of human gastric cancer, the clinicopathologic characteristics of the tumors and the clinical outcome were analyzed.
Experimental Design: The expressions of HIF-1α and p53 proteins were studied by immunohistochemistry in 216 specimens of primary gastric cancer.
Results: HIF-1α(+)/p53(+) tumors more frequently showed an undifferentiated type, an infiltrative growth appearance, and an invasive lymphatic involvement compared with HIF-1α(−)/p53(−) tumors. HIF-1α(+)/p53(+) tumors also had more lymph node metastasis compared with HIF-1α(−)/p53(−) tumors. When stratified for HIF-1α and p53 positivity, the patients who were p53-negative and HIF-1α-negative had the most favorable prognosis, whereas patients who were p53-positive and HIF-1α-positive had the worst prognosis (P = 0.0018). Using a multivariate Cox regression analysis, the depth of invasion, lymph node metastasis, and HIF-1α positivity were all found to be independent prognostic factors in patients with gastric cancer.
Conclusion: Thus, HIF-1α is considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1α protein overexpression with nonfunctional p53 tends to indicate a dismal prognosis.
Unique Tumor Antigens: Evidence for Immune Control of Genome Integrity and Immunogenic Targets for T Cell–Mediated Patient-Specific Immunotherapy
Authors: Sensi Marialuisa , Anichini Andrea 
Published: September 2006

AbstractThe molecular identification and characterization of antigenic epitopes recognized by T cells on human cancers has rapidly evolved since the cloning in 1991 of MAGEA1, the first gene reported to encode a CTL-defined human tumor antigen. In the expanding field of human tumor immunology, unique tumor antigens constitute a growing class of T cell–defined epitopes that exhibit strong immunogenicity. Some of these antigens, which often derive from mutation of genes that have relevant biological functions, are less susceptible to immunoselection and may be retained even in advanced tumors. Immunogenicity and constitutive expression of the unique tumor antigens provide a strong rationale for the design of novel, patient-tailored therapies that target such determinants. Here we discuss the immunologic relevance of unique tumor antigens in the light of the prospects for exploiting such epitopes as targets for patient-specific immune intervention strategies.
Rac Activation Is Associated with Hepatocellular Carcinoma Metastasis by Up-regulation of Vascular Endothelial Growth Factor Expression
Authors: Lee Terence K. , Poon Ronnie T.P. , Yuen Anthony P. , Man Kwan , Yang Zhen Fan , Guan Xin Yuan , Fan Sheung Tat 
Published: September 2006

Abstract
Purpose: Hepatocellular carcinoma (HCC) is associated with a propensity for vascular invasion and metastasis, which contribute to poor prognosis. Angiogenesis is a crucial process contributing to tumor growth and metastasis. Recently, Rac has been suggested to play a role in angiogenesis. However, the actual role of Rac in HCC angiogenesis remains unclear. Given that vascular endothelial growth factor (VEGF) is an important angiogenic factor in HCC, the purpose of this study was to evaluate the possible correlation between Rac activation and VEGF expression in HCC tumor samples, as well as the mechanism involved in Rac-induced HCC angiogenesis.
Experimental Design: We evaluated Rac and VEGF expression in the HCC tissue microarray of paired primary and metastatic HCC samples using immunohistochemical staining. The role of Rac-induced HCC angiogenesis was also evaluated in vitro in HCC cell lines.
Results: We first showed that activation of Rac was correlated with HCC metastasis (P &lt; 0.001), and its expression was significantly correlated with VEGF expression by tissue microarray. Ectopic Rac-dominant active transfection in Hep3B cells increased VEGF secretion, which induced the morphologic change and proliferation of human umbilical vein endothelial cells, resulting in the promotion of angiogenesis. Rac induced the transcriptional activation of VEGF by direct interaction with hypoxia-inducible factor-1α (HIF-1α) expression. In hypoxic conditions, Rac promoted angiogenesis through an increase in HIF-1α stabilization.
Conclusion: This study shows that Rac is a novel angiogenic factor for HCC through the enhancement of HIF-1α protein stability, which provides a possible therapeutic target in the development of inhibitors of angiogenesis.
The Biological Role of the Low-Affinity p75 Neurotrophin Receptor in Esophageal Squamous Cell Carcinoma
Authors: Okumura Tomoyuki , Tsunoda Shigeru , Mori Yukiko , Ito Tetsuo , Kikuchi Keiji , Wang Timothy Cragin , Yasumoto Shigeru , Shimada Yutaka 
Published: September 2006

Abstract
In this study, we investigated the clinicopathologic significance of the low-affinity p75 neurotrophin receptor (p75NTR; which is expressed in the stem/progenitor cell fraction of normal esophageal epithelial cells) in 187 resected esophageal squamous cell carcinoma (ESCC) specimens and found that ∼50% of ESCC expressed p75NTR. Our investigation using ESCC cell lines showed that p75NTR was intensely expressed in the cells with high colony-forming capacity but they were sensitive to cell death on inhibition of p75NTR expression with transient transfection of small interfering RNA (siRNA). These findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies.
Purpose: p75NTR is expressed in a stem/progenitor cell fraction of human normal esophageal epithelial cells. In this study, we investigated the expression and biological role of p75NTR in ESCC.
Experimental Design: The expression of p75NTR in 187 resected ESCC specimens was immunohistochemically investigated. The expression of p75NTR in 30 ESCC cell lines (KYSEs) was assessed by reverse transcription-PCR, immunocytochemistry, and flow cytometry. The p75NTR-bright and p75NTR-dim/negative cells were isolated from KYSE150 by magnetic beads and colony formation was investigated. The role of p75NTR in KYSEs was assessed by transient transfection of siRNA.
Results: p75NTR was expressed in 92 of 187 (49.2%) tumors. In well-differentiated tumors, positive staining was apparent in the first one to two layers from infiltrative margin of the tumors where most of the cells were actively proliferating. In moderately differentiated tumors, p75NTR was expressed in wider range from the margin of the tumors whereas p75NTR was diffusely distributed in poorly differentiated tumors. p75NTR was expressed in all examined KYSEs and the mean proportion of the p75NTR-bright fraction was 30.1%. The size of p75NTR-positive colonies was larger than that of p75NTR-negative colonies derived from KYSE150 (P &lt; 0.0001). The purified p75NTR-bright cells formed p75NTR-positive large colonies more frequently than the p75NTR-dim/negative cells (P &lt; 0.0001). Down-regulation of p75NTR expression by siRNA resulted in marked growth inhibition with induction of apoptosis.
Conclusions: Our findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies.
Promoter Hypermethylation Profile of Kidney Cancer with New Proapoptotic p53 Target Genes and Clinical Implications
Authors: Christoph Frank , Weikert Steffen , Kempkensteffen Carsten , Krause Hans , Schostak Martin , Köllermann Jens , Miller Kurt , Schrader Mark 
Published: September 2006

AbstractPurpose: Risk stratification of renal cell carcinoma is based on the histopathologic classification. Promoter hypermethylation as a mechanism of gene inactivation in renal cell carcinoma has been shown for only a small number of genes. We examined the usefulness of quantitative methylation analysis with a new set of p53 target genes for determining the clinical outcome and aggressiveness of the tumor disease.Experimental Design: The genes selected were APAF-1, CASPASE-8, DAPK-1, IGFBP-3, and PML. The tissue samples analyzed were taken from tumor specimens obtained from 90 consecutive patients with clear cell renal carcinoma and from 20 normal kidney specimens. Quantitative methylation analysis of CpG sites in the promoter region was done by methylation-specific real-time PCR and the normalized index of methylation (NIM) was determined for each sample.Results: Hypermethylation of the promoter region was common for APAF-1 (97%) and DAPK-1 (41%) but not for IGFBP-3 (3%), PML (3%), or CASP-8 (0%). The tumor patients had a median follow-up of 55 months. A correlation was found between the methylation level of APAF-1 and tumor size and nodal status, but not for tumor stage, grade, and age of patient. Kaplan-Meier analysis was able to identify patients with a higher risk of recurrence and tumor-related death by using APAF-1 (≥56% NIM) and DAPK-1 (≥10% NIM) methylation levels. In multivariate analysis, APAF-1 and DAPK-1 methylation levels were independent prognostic markers for metastatic disease and death from renal cell carcinoma.Conclusions: Our findings indicate that promoter hypermethylation of APAF-1 and DAPK-1 is a marker of aggressive renal cell carcinoma and provides independent prognostic information on disease outcome.