bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycolytic Enzymes Can Modulate Cellular Life Span
Authors: Kondoh Hiroshi , Lleonart Matilde E. , Gil Jesus , Wang Jing , Degan Paolo , Peters Gordon , Martinez Dolores , Carnero Amancio , Beach David 
Published: June 2022

Abstract
An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM). A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest. Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity and, conversely, depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence. Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells. Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.
A Mutation in the SDHC Gene of Complex II Increases Oxidative Stress, Resulting in Apoptosis and Tumorigenesis
Authors: Ishii Takamasa , Yasuda Kayo , Akatsuka Akira , Hino Okio , Hartman Philip S. , Ishii Naoaki 
Published: June 2022

Abstract
Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O2−) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.
Perinucleolar Compartment Prevalence Has an Independent Prognostic Value for Breast Cancer
Authors: Kamath Rajesh V. , Thor Ann D. , Wang Chen , Edgerton Susan M. , Slusarczyk Alicja , Leary D.J. , Wang J. , Wiley E.L. , Jovanovic B. , Wu Q. , Nayar R. , Kovarik P. , Shi F. , Huang Sui 
Published: June 2022

Abstract
The perinucleolar compartment (PNC) is a multicomponent nuclear structure enriched with RNAs transcribed by RNA pol III and RNA binding proteins. Studies in cultured cells showed an association between PNC and transformed phenotype. To evaluate the relationship between structure and malignancy in vivo, we examined PNC prevalence (the percentage of cells containing at least one PNC) in normal and cancerous paraffin-embedded breast tissues using immunohistochemistry against a PNC-associated protein. Five hundred nuclei in the most active area of each sample were scored for PNC prevalence. The results show that PNC prevalence significantly correlates with the progression of breast cancer (by the criteria of staging). PNC prevalence in primary tumors, lymph nodes, and distant metastases shows a stepwise increase from a median of 23% in primary tumors to ∼100% in distant metastases. In addition, univariate and multivariate (controlling for tumor size and grade) analyses show that early-stage patients with invasive ductal carcinomas containing a higher PNC prevalence have a significantly poorer prognosis. These findings link PNC prevalence with the progression of breast cancer in vivo and suggest that PNC-containing cells have metastatic advantages. These findings also show the potential of PNC prevalence as a prognostic marker for breast cancer.
Inactivation of Imprinted Genes Induced by Cellular Stress and Tumorigenesis
Authors: Pantoja Cristina , de los Ríos Laura , Matheu Ander , Antequera Francisco , Serrano Manuel 
Published: June 2022

Abstract
Cellular proliferation under stressful conditions may result in permanent genetic and epigenetic changes. Using primary mouse embryonic fibroblasts, we have completed a screening test to identify gene expression changes triggered when cells proliferate under stress. In this manner, we have discovered a novel phenomenon that consists of the rapid and coordinated silencing of genes subject to imprinting, including Cdkn1c, Igf2, H19, Ndn1, Grb10, and Meg3. This generalized silencing of imprinted genes is independent of the stress-responsive tumor suppressors p53, p19Arf, and p16Ink4a, and it is also independent of the oxidative culture conditions and the stress response known as “mouse embryonic fibroblast senescence”. In the case of Cdkn1c and H19, their silencing is associated with unscheduled de novo methylation of the normally expressed allele at their corresponding CpG island promoters, thus resulting in biallelic methylation. Finally, we provide evidence for frequent de novo methylation of Cdkn1c in a variety of murine cancer types. Altogether, our data support the concept that silencing of imprinted genes, including methylation of Cdkn1c, constitutes an epigenetic signature of cellular stress and tumorigenesis.
Oncogenic Transformation of Human Mammary Epithelial Cells by Autocrine Human Growth Hormone
Authors: Zhu Tao , Starling-Emerald B. , Zhang Xin , Lee Kok-Onn , Gluckman Peter D. , Mertani Hichem C. , Lobie Peter E. 
Published: June 2022

Abstract
The human growth hormone (hGH) gene is expressed in the normal human mammary epithelial cell and its expression increases concomitant with the acquisition of proliferative lesions. Herein we demonstrate that autocrine production of hGH in human mammary carcinoma cells dramatically enhances anchorage-independent growth in a Janus kinase 2–dependent manner. Forced expression of the hGH gene in immortalized human mammary epithelial cells increased proliferation, decreased apoptosis, altered the cellular morphology and resulted in oncogenic transformation. Autocrine hGH was therefore sufficient to support anchorage-independent growth of immortalized human mammary epithelial cells and tumor formation in vivo. Moreover, autocrine hGH disrupted normal mammary acinar architecture with luminal filling and deregulated proliferation in three-dimensional epithelial cell culture. Autocrine hGH utilized homeobox A1 to govern the transcriptional program required for autocrine hGH–stimulated oncogenic transformation of human mammary epithelial cells, including transcriptional up-regulation of c-Myc, cyclin D1, and Bcl-2. Forced expression of a single orthotopically expressed wild-type gene is therefore sufficient for oncogenic transformation of the immortalized human mammary epithelial cell.
Cell Cycle Checkpoints, DNA Damage/Repair, and Lung Cancer Risk
Authors: Wu Xifeng , Roth Jack A. , Zhao Hua , Luo Sherry , Zheng Yun-Ling , Chiang Silvia , Spitz Margaret R. 
Published: June 2022

Abstract
Given that defects in cell cycle control and DNA repair capacity may contribute to tumorigenesis, we hypothesized that patients with lung cancer would be more likely than healthy controls to exhibit deficiencies in cell cycle checkpoints and/or DNA repair capacity as gauged by cellular response to in vitro carcinogen exposure. In an ongoing case-control study of 155 patients with newly diagnosed lung cancer and 153 healthy controls, we used the comet assay to investigate the roles of cell cycle checkpoints and DNA damage/repair capability in lung tumorigenesis. The median γ-radiation-induced and benzo(a)pyrene diol epoxide–induced Olive tail moments, the comet assay parameter for measuring DNA damage, were significantly higher in the case group (5.31 and 4.22, respectively) than in the control group (4.42 and 2.83, respectively; P &lt; 0.001). Higher tail moments of γ-radiation and benzo(a)pyrene diol epoxide–induced comets were significantly associated with 2.32- and 4.49-fold elevated risks, respectively, of lung cancer. The median γ-radiation-induced increases of cells in the S and G2 phases were significantly lower in cases (22.2% and 12.2%, respectively) than in controls (31.1% and 14.9%, respectively; P &lt; 0.001). Shorter durations of the S and G2 phases resulted in 4.54- and 1.85-fold increased risks, respectively, of lung cancer. Also observed were joint effects between γ-radiation-induced increases of S and G2 phase frequencies and mutagen-induced comets. In addition, we found that in controls, the S phase decreased as tail moment increased. This study is significant because it provides the first molecular epidemiologic evidence linking defects in cell cycle checkpoints and DNA damage/repair capacity to elevated lung cancer risk.
Characterization of γ-Aminobutyric Acid Type A Receptor–Associated Protein, a Novel Tumor Suppressor, Showing Reduced Expression in Breast Cancer
Authors: Klebig Christiane , Seitz Susanne , Arnold Wolfgang , Deutschmann Nicole , Pacyna-Gengelbach Manuela , Scherneck Siegfried , Petersen Iver 
Published: June 2022

Abstract
Frequent allelic loss of the chromosomal region 17p13 in breast cancer has suggested that more tumor suppressor genes, besides p53, are located in this region. By doing suppression subtractive hybridization to detect differentially expressed genes between the breast cancer cell line CAL51 and a nontumorigenic microcell hybrid CAL/17-1, we identified the gene for the γ-aminobutyric acid type A (GABAA) receptor associated protein (GABARAP), located on 17p13.1. GABARAP displayed high expression levels in the microcell hybrid CAL/17-1 but only weak expression in CAL51 and other breast cancer cell lines tested. Furthermore, we observed large vesicles in CAL/17-1 by immunofluorescence staining, whereas no signal could be detected in the tumor cell line. GABARAP mRNA expression and protein expression were significantly down-regulated in invasive ductal and invasive lobular carcinomas compared with normal breast tissue measured by semiquantitative reverse transcription–PCR and immunohistochemistry, respectively. We assessed that neither mutations in the coding region of the gene nor hypermethylation of CpG islands in the promoter region are responsible for loss of gene expression in CAL51; however, 5-aza-2′-deoxycytidine treatment was effective in gene up-regulation, suggesting a methylation-dependent upstream effect. Stable transfection of GABARAP into CAL51 resulted in an increase of gene expression and remarkably influenced the ability of colony formation in soft agar and the growth rate in vitro and, moreover, suppressed the tumorigenicity of the cells in nude mice. In summary, our data suggest that GABARAP acts via a vesicle transport mechanism as a tumor suppressor in breast cancer.
Bone Morphogenic Proteins Are Overexpressed in Malignant Melanoma and Promote Cell Invasion and Migration
Authors: Rothhammer Tanja , Poser Ina , Soncin Fabrice , Bataille Frauke , Moser Markus , Bosserhoff Anja-Katrin 
Published: June 2022

Abstract
Malignant melanoma cells are known to have altered expression of growth factors compared with normal human melanocytes. These changes probably favor tumor growth and progression and influence the tumor environment. The induction of transforming growth factor β1 (TGF-β1), TGF-β2, and TGF-β3 expression in malignant melanoma has been reported before, whereas the expression of related bone morphogenic protein (BMP) molecules has not been analyzed in melanomas until now. Here, we show that BMP4 and BMP7 are up-regulated in nine melanoma cell lines, whereas BMP2 is overexpressed in only two of the analyzed cell lines. Immunohistochemistry of primary and metastatic melanoma also shows increased BMP4 and BMP7 expression compared with nevi. Promoter studies reveal that expression is controlled at the transcriptional level. The transcription factor Ets-1 was identified as a positive regulator for BMP4 expression. In order to determine the functional relevance of BMP expression in malignant melanoma, chordin-expressing cell clones and antisense BMP4 cell clones were generated. The clones in which BMP4 activity and expression are reduced show no changes in proliferation or in attachment-independent growth when compared with controls. However, a strong reduction of migratory and invasive properties was observed in these cells, suggesting that BMP4 promotes melanoma cell invasion and migration and therefore has an important role in the progression of malignant melanoma.
A Functional Common Polymorphism in a Sp1 Recognition Site of the Epidermal Growth Factor Receptor Gene Promoter
Authors: Liu Wanqing , Innocenti Federico , Wu Michael H. , Desai Apurva A. , Dolan M. Eileen , Cook Edwin H. , Ratain Mark J. 
Published: June 2022

Abstract
The epidermal growth factor receptor (EGFR) plays a prominent role in cell growth and development. Its regulation in humans is complex and incompletely understood. In this study, 12 new polymorphisms were discovered in the 5′-regulatory region of EGFR gene and 2 common single nucleotide polymorphisms (−216G/T and −191C/A) were found in the essential promoter area, one of which is located in a Sp1 recognition site (−216). Transient transfection in human cancer and primary cell lines showed significantly different promoter activity between the two most common haplotypes (−216G-191C and −216T-191C). The replacement of G by T at position −216 increases the promoter activity by 30%. A transient transfection assay in the Sp1-deficient cell line (Schneider cell line 2) showed a strong dependence of EGFR promoter activity on Sp1 and confirmed the effect of the aforementioned polymorphisms. Electrophoretic mobility shift assay also showed a significantly higher binding efficiency of nuclear protein or pure Sp1 protein to the T allele compared with the G allele. We then investigated the allelic imbalance of EGFR transcription in fibroblast cell lines with heterozygous genotype at −216G/T but C/C homozygous genotype at −191C/A. The expression of mRNA carrying T-C haplotype was significantly stronger compared with that of G-C haplotype (P &lt; 0.02). Thus, we successfully showed that a common polymorphism in the EGFR promoter was associated with altered promoter activity and gene expression both in vitro and in vivo. Our findings have implications for cancer etiology and therapy and may also be relevant to the inherited susceptibility of other common diseases.
Calcium Sensing Receptor in Human Colon Carcinoma: Interaction with Ca2+ and 1,25-Dihydroxyvitamin D3
Authors: Chakrabarty Subhas , Wang Hongmei , Canaff Lucie , Hendy Geoffrey N. , Appelman Henry , Varani James 
Published: June 2022

Abstract
Recent studies show that the human parathyroid calcium sensing receptor (CaSR) is expressed in human colon epithelium and functions to regulate epithelial proliferation and differentiation. In this study, we show that the cells of the colon crypt acquire CaSR expression as they differentiate and migrate towards the apex of the crypt. CaSR expression was weak in colon carcinomas with a more-differentiated histologic pattern, whereas CaSR expression was undetectable in less-differentiated tumors. We found that Ca2+ and/or 1,25(OH)2D3 stimulated CaSR promoter activity and CaSR protein expression in the human colon carcinoma CBS cells, which possessed a functional CaSR. Both agents concomitantly induced a series of changes in the CBS cells that influence proliferation and differentiation, but cellular responses to the two agents were not identical. Ca2+ strongly induced E-cadherin expression and inhibited the expression of the nuclear transcription factor, TCF4. 1,25(OH)2D3 was weaker in its effect on E-cadherin and was not able to inhibit TCF4 expression. 1,25(OH)2D3 was as strong or stronger than Ca2+ in its induction of the cyclin-dependent kinase inhibitors, P21 and p27. It is concluded that CaSR may function in the colon to regulate epithelial differentiation and that loss of CaSR expression may be associated with abnormal differentiation and/or malignant progression. Extracellular Ca2+ and 1,25(OH)2D3 are potential candidates involved in regulating CaSR expression in the colon and the chemopreventive actions of Ca2+ and 1,25(OH)2D3 in colon cancer may be mediated, in part, through the CaSR.
Polymorphisms in DNA Base Excision Repair Genes ADPRT and XRCC1 and Risk of Lung Cancer
Authors: Zhang Xuemei , Miao Xiaoping , Liang Gang , Hao Bingtao , Wang Yonggang , Tan Wen , Li Yi , Guo Yongli , He Fuchu , Wei Qingyi , Lin Dongxin 
Published: June 2022

Abstract
Adenosine diphosphate ribosyl transferase (ADPRT) and X-ray repair cross-complementing 1 (XRCC1) are two major DNA base excision repair (BER) proteins and act interactively in stimulating and executing BER processes. Polymorphisms of ADPRT Val762Ala and XRCC1 Arg399Gln have been associated with altered protein function and BER activity. This case-control study examined the contribution of these two polymorphisms, alone and in combination, or in interaction with smoking, to the risk of developing lung cancer. We estimated the risk of lung cancer associated with these polymorphisms in 1,000 cases and 1,000 cancer-free controls using logistic regression models. Subjects having the ADPRT Ala/Ala genotype had an odds ratio (OR) of 1.68 [95% confidence interval (95% CI), 1.27-2.23] compared with those having the Val/Val genotype. A greater than multiplicative joint effect between the ADPRT polymorphism and smoking was observed. The ORs (95% CI) of the Ala/Ala genotype for nonsmokers and smokers who smoked ≤16, 16 to 28, or &gt;28 pack-years were 1.13 (0.79-1.62), 1.35 (0.68-2.70), 2.46 (1.35-4.51) or 17.09 (8.15-35.83), respectively (P trend test &lt; 0.001). Gene-gene interaction of ADPRT and XRCC1 polymorphisms increased risk of lung cancer in a supermultiplicative manner (OR for the presence of both ADPRT 762Ala/Ala and XRCC1 399Gln/Gln genotypes, 5.91; 95% CI, 2.09-16.72), although the XRCC1 polymorphism itself was not associated with the risk. In conclusion, the ADPRT Val762Ala polymorphism plays an important role in smoking-related lung cancer and the XRCC1 Arg399Gln polymorphism may serve as a risk modifier.
Premature Senescence Is a Primary Fail-safe Mechanism of ERBB2-Driven Tumorigenesis in Breast Carcinoma Cells
Authors: Trost Tatjana M. , Lausch Ekkehart U. , Fees Stephan A. , Schmitt Steffen , Enklaar Thorsten , Reutzel Dirk , Brixel Lili R. , Schmidtke Peter , Maringer Marko , Schiffer Ilka B. , Heimerdinger Carolin K. , Hengstler Jan G. , Fritz Gerhard , Bockamp Ernst O. , Prawitt Dirk , Zabel Bernhard U. , Spangenberg Christian 
Published: June 2022

Abstract
The receptor tyrosine kinase ERBB2 plays a central role in the development of breast cancer and other epithelial malignancies. Elevated ERBB2 activity is believed to transform cells by transmitting mitogenic and antiapoptotic signals. Here we show that tightly regulated overexpression of oncogenic ERBB2 in human breast carcinoma cells does not stimulate proliferation but provokes premature senescence, accompanied by up-regulation of the cyclin-dependent kinase inhibitor P21WAF1/CIP1. A similar effect was caused by retrovirus-mediated overexpression of oncogenic ERBB2 in low-passage murine embryonic fibroblasts. In contrast to previous observations based on constitutively overexpressing cell lines, P21 induced by tetracycline-regulated ERBB2 localizes to the nucleus in arrested cells. P21 up-regulation seems to be independent of the P53 tumor suppressor protein, and senescence-associated phenotypic alterations are reversed by specific inhibition of P38 mitogen-activated protein kinases. Functional inactivation of P21 by antisense oligonucleotides is sufficient to prevent cell cycle arrest as well as the senescent phenotype, thereby identifying the P21 protein as the key mediator of hypermitogenic cell cycle arrest and premature senescence in breast carcinoma cells. Our results may thus indicate that premature senescence represents an inherent anticarcinogenic program during ERBB2-driven mammary tumorigenesis. We propose a multistep model for the process of malignant transformation by ERBB2 wherein secondary lesions either target P21 or downstream effectors of senescence to bypass this primary fail-safe mechanism.
Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species
Authors: Laurent Alexis , Nicco Carole , Chéreau Christiane , Goulvestre Claire , Alexandre Jérôme , Alves Arnaud , Lévy Eva , Goldwasser Francois , Panis Yves , Soubrane Olivier , Weill Bernard , Batteux Frédéric 
Published: June 2022

Abstract
Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H2O2), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H2O2 is controlled by catalase. N-acetylcysteine, which decreases H2O2 levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H2O2 concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H2O2 levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P &lt; 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.