Galectin-4 in normal tissues and cancer

Galectin-4 belongs to a subfamily of galectins composed of two carbohydrate recognition domains within the same peptide chain. The two domains have all the conserved galectin signature amino acids, but their overall sequences are only approximately 40% identical. Both domains bind lactose with a similar affinity as other galectins, but their respective preferences for other disaccharides, and larger saccharides, are distinctly different. Thus galectin-4 has a property of a natural cross-linker, but in a modified sense since each domain prefers a different subset of ligands. Similarly to other galectins, galectin-4 is synthesized as a cytosolic protein, but can be externalized. During development and in adult normal tissues, galectin-4 is expressed only in the alimentary tract, from the tongue to the large intestine. It is often found in relatively insoluble complexes, as a component of either adherens junctions or lipid rafts in the microvillus membrane, and it has been proposed to stabilize these structures. Strong expression of galectin-4 can be induced, however, in cancers from other tissues including breast and liver. Within a collection of human epithelial cancer cell lines, galectin-4 is overexpressed and soluble in those forming highly differentiated polarized monolayers, but absent in less differentiated ones. In cultured cells, intracellular galectin-4 may promote resistance to nutrient starvation, whereas—as an extracellular protein—it can mediate cell adhesion. Because of its distinct induction in breast and other cancers, it may be a valuable diagnostic marker and target for the development of inhibitory carbohydrate-based drugs. Published in 2004. This revised version was published online in July 2006 with corrections to the Cover Date.     

GEPIS--quantitative gene expression profiling in normal and cancer tissues

MOTIVATION: Expression profiling in diverse tissues is fundamental to understanding gene function as well as therapeutic target identification. The vast collection of expressed sequence tags (ESTs) and the associated tissue source information provides an attractive opportunity for studying gene expression. RESULTS: To facilitate EST-based expression analysis, we developed GEPIS (gene expression profiling in silico), a tool that integrates EST and tissue source information to compute gene expression patterns in a large panel of normal and tumor samples. We found EST-based expression patterns to be consistent with published papers as well as our own experimental results. We also built a GEPIS Regional Atlas that depicts expression characteristics of all genes in a selected genomic region. This program can be adapted for large-scale screening for genes with desirable expression patterns, as illustrated by our large-scale mining for tissue- and tumor-specific genes. AVAILABILITY: The email server version of the GEPIS application is freely available at http://share.gene.com/share/gepis. An interactive version of GEPIS will soon be freely available at http://www.cgl.ucsf.edu/Research/genentech/gepis/. The source code, modules, data and gene lists can be downloaded at http://share.gene.com/share/gepis.     

Clonal selection parallels between normal and cancer tissues

Clonal selection and drift drive both normal tissue and cancer development. However, the biological mechanisms and environmental conditions underpinning these processes remain to be elucidated. Clonal selection models are centered in Darwinian evolutionary theory, where some clones with the fittest features are selected and populate the tissue or tumor. We suggest that different subclasses of stem cells, each of which is responsible for a distinct feature of the selection process, share common features between normal and cancer conditions. While active stem cells populate the tissue, dormant cells account for tissue replenishment/regeneration in both normal and cancerous tissues. We also discuss potential mechanisms that drive clonal drift, their interactions with clonal selection, and their similarities during normal and cancer tissue development.     

Microarray analysis of microRNA expression in liver cancer tissues and normal control

Background

Recently, many studies have focused on microRNAs (miRNAs) expression profiling in liver cancer, due to the ability of these small RNAs to potently influence cellular behavior. In this study, to further investigate the relationship between them, the miRNA expression profiling of the cancer liver tissues and normal liver tissues were compared.

Methods

The datasets of miRNAs microarray in liver cancer and normal control were downloaded from Gene Expression Omnibus. Then the SOAP analysis was performed to identify the differentially expressed miRNAs.

Results

A total of 221 differentially expressed miRNAs were found. Five of them (including hsa-miR-15b, hsa-miR-1975, hsa-miR-199a-3p, hsa-miR-199b-3p and hsa-miR-421) were determined by t-test and may be involved in the pathogenesis of liver cancer.

Conclusion

There differentially expressed miRNAs may be potential molecular markers for liver cancer screening.     

A similar cell-specific pattern of HOXA methylation in normal and in cancer tissues

HOX genes are developmental genes that determine anterior–posterior embryonic pattern and govern the process of differentiation. Inappropriate expression of HOX genes has been implicated in developmental abnormalities and hematopoietic malignancies. In addition, HOX genes silencing by DNA methylation has been reported in cancers and related to disease aggressiveness and outcome. On the other hand, accumulating evidence suggests that epigenetic changes at HOX genes are linked to normal development and differentiation. To better understand the relationship between HOXA methylation and cancer, we analyzed the methylation pattern of HOXA genes in human primary breast and colon carcinomas, normal tissues and normal white blood cells. Genome-wide methylation arrays of breast cancers and white blood cells demonstrated similar methylation patterns. Quantitative methylation analysis of seven representative HOXA genes revealed various levels of methylation in both normal tissues and cancers. Analysis of epithelial-enriched normal breast tissue and stroma indicated that the stroma was the major origin of HOXA methylation. Furthermore, in selected dense breast cancers, minimal increase in methylation of several HOXA genes did not correlate with the predominance of malignant epithelial cells in these tumors. Our results suggest that methylation of the HOXA cluster may be a normal developmental and cell type specific process rather than a cancer specific mechanism.     

Comparative proteome analysis of breast cancer and adjacent normal breast tissues in human

Two-dimensional polyacrylamide gel assisted laser desorption/ionization electrophoresis （2D-PAGE） and matrixtandem time-of-flight mass spectrometry （MALDI-TOF/TOF-MS）, incorporated with online database searching, were performed to investigate differential proteins of breast cancer and adjacent normal breast tissues. Considering that serum albumin is abundantly presented in normal control samples, 15 differential spots detected in 11 out of 12 （91.7%） breast cancer samples were identified by online SIENA-2DPAGE database searching and MALDI-TOF/TOF-MS analysis. The results indicate that pathological changes of breast cancer are concerned with augmentation of substance metabolism, promotion of proteolytic activity, decline of activity of some inhibitors of enzymes, and so on. Some important proteins involved in the pathological process of breast cancer with changed expression may be useful biomarkers, such as alpha-l-antitrypsin, EF- 1-beta, cathepsin D, TCTP, SMT3A, RPS12, and PSMA1, among which SMT3A, RPSl2, and PSMA1 were first reported for breast cancer in this study.     

Inhibition by rhodamine 123 of protein synthesis in mitochondria of normal and cancer tissues

The effect of the mitochondrial dye rhodamine 123 (Rho 123) on protein synthesis (PS) activity was investigated in mitochondria isolated from liver and from both chloroma and erythroleukemia tumors. Incorporation of labelled leucine into mitochondrial protein was used to measure the rate of PS. While PS specific activity was much higher in hematopoietic tumors mitochondria as compared to that of liver, the addition of increased concentration of Rho 123 in all tested organelles resulted in increased inhibition of PS to reach 75-82% with 10 micrograms/ml of the dye. Similar results were obtained with 10 micrograms/ml of chloramphenicol, the specific inhibitor of mitochondrial PS. Moreover, under the conditions of the study, the addition of Rho 123 to mitochondria did not trigger any ATPase activity, thus eliminating any competition for the energy source ATP between PS and ATPase. These results demonstrate that, in addition to its known inhibitory action on oxidative phosphorylation, the mitochondrial dye Rho 123 has a potent inhibitory effect on PS in both liver and hematopoietic tumors mitochondria.     

Carbohydrate-rich tissue components in lung cancer and in normal bronchial tissues: a histochemical study

Synopsis The carbohydrate-rich compounds in bronchopulmonary neoplasms and in non-neoplastic tissue have been characterized histochemically. Glycogen was present in few epidermoid and large-cell carcinomas. Epithelial mucosubstances were produced by adeno-, mucoepidermoid, and large-cell carcinomas. The mucosubstances produced by carcinoma cells had characteristics different from those occurring in normal tissue. The most striking characteristic was the presence of a sialidase-labile compound in certain neoplasms.Hyaluronic acid was present in the stroma of the carcinomas. In a third of the cases studied, chondroitin sulphates were also present. Higher sulphated compounds were observed as well. This stromal reaction was correlated with the occurrence of a round cell reaction, but not with mast cells. This was considered to indicate the production of stromal material and fibres, but it can also explain the high levels of carbohydrate-rich substances in serum and urine in cases where neoplastic tissue itself does not produce such substances. It also agrees with the theory of carbohydrate-rich compounds acting as a barrier preventing immunological reactions against neoplastic cells.     

Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells

We have previously reported that 1-benzyl-2-acetamido-2-deoxy-alpha-D-galactopyranoside (GalNAc alpha-O-bn), an inhibitor of glycosylation, perturbed apical biosynthetic trafficking in polarized HT-29 cells suggesting an involvement of a lectin-based mechanism. Here, we have identified galectin-4 as one of the major components of detergent-resistant membranes (DRMs) isolated from HT-29 5M12 cells. Galectin-4 was also found in post-Golgi carrier vesicles. The functional role of galectin-4 in polarized trafficking in HT-29 5M12 cells was studied by using a retrovirus-mediated RNA interference. In galectin-4-depleted HT-29 5M12 cells apical membrane markers accumulated intracellularly. In contrast, basolateral membrane markers were not affected. Moreover, galectin-4 depletion altered the DRM association characteristics of apical proteins. Sulfatides with long chain-hydroxylated fatty acids, which were also enriched in DRMs, were identified as high-affinity ligands for galectin-4. Together, our data propose that interaction between galectin-4 and sulfatides plays a functional role in the clustering of lipid rafts for apical delivery.     

Retinoid-induced apoptosis in normal and neoplastic tissues

Vitamin A and its derivatives (collectively referred to as retinoids) are required for many fundamental life processes, including vision, reproduction, metabolism, cellular differentiation, hematopoesis, bone development, and pattern formation during embryogenesis. There is also considerable evidence to suggest that natural and synthetic retinoids have therapeutical effects due to their antiproliferative and apoptosis-inducing effects in human diseases such as cancer. Therefore it is not surprising that a significant amount of research was dedicated to probe the molecular and cellular mechanisms of retinoid action during the past decade. One of the cellular mechanisms retinoids have been implicated in is the initiation and modulation of apoptosis in normal development and disease. This review provides a brief overview of the molecular basis of retinoid signaling, and focuses on the retinoid-regulation of apoptotic cell death and gene expression during normal development and in pathological conditions in vivo and in various tumor cell lines in vitro.     

Analysis of gene expression profiles of gastric normal and cancer tissues by SAGE

In an attempt to understand the molecular bases of gastric cancer progression, we have analyzed the differentially expressed genes in gastric cancer by SAGE. Four SAGE cDNA tag libraries were constructed from two sets of gastric cancer and normal tissues and 241,127 tags were obtained. By comparing the tags from cancer and normal tissues, 414 differentially expressed tags, representing 383 genes, were identified in cancer tissues (p 相似文献   

Molecular basis of the differences between normal and tumor tissues of gastric cancer

To be able to describe the differences between the normal and tumor tissues of gastric cancer at a molecular level would be essential in the study of the disease. We investigated the gene expression pattern in the two types of tissues from gastric cancer by performing expression profiling of 86 tissues on 17K complementary DNA microarrays. To select for the differentially expressed genes, class prediction algorithm was employed. For predictor selection, samples were first divided into a training (n=58), and a test set (n=28). A group of 894 genes was selected by a t-test in a training set, which was used for cross-validation in the training set and class (normal or tumor) prediction in the test set. Smaller groups of 894 genes were individually tested for their ability to correctly predict the normal or tumor samples based on gene expression pattern. The expression ratios of the 5 genes chosen from microarray data can be validated by real time RT-PCR over 6 tissue samples, resulting in a high level of correlation, individually or combined. When a representative predictor set of 92 genes was examined, pathways of 'focal adhesion' (with gene components of THBS2, PDGFD, MAPK1, COL1A2, COL6A3), 'ECM-receptor interaction' pathway (THBS2, COL1A2, COL6A3, FN1) and 'TGF-beta signaling' (THBS2, MAPK1, INHBA) represent some of the main differences between normal and tumor of gastric cancer at a molecular level.     

A human protein atlas for normal and cancer tissues based on antibody proteomics

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, approximately 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.     

Characterization of age signatures of DNA methylation in normal and cancer tissues from multiple studies

Background

DNA methylation (DNAm) levels can be used to predict the chronological age of tissues; however, the characteristics of DNAm age signatures in normal and cancer tissues are not well studied using multiple studies.

Results

We studied approximately 4000 normal and cancer samples with multiple tissue types from diverse studies, and using linear and nonlinear regression models identified reliable tissue type-invariant DNAm age signatures. A normal signature comprising 127 CpG loci was highly enriched on the X chromosome. Age-hypermethylated loci were enriched for guanine–and-cytosine-rich regions in CpG islands (CGIs), whereas age-hypomethylated loci were enriched for adenine–and-thymine-rich regions in non-CGIs. However, the cancer signature comprised only 26 age-hypomethylated loci, none on the X chromosome, and with no overlap with the normal signature. Genes related to the normal signature were enriched for aging-related gene ontology terms including metabolic processes, immune system processes, and cell proliferation. The related gene products of the normal signature had more than the average number of interacting partners in a protein interaction network and had a tendency not to interact directly with each other. The genomic sequences of the normal signature were well conserved and the age-associated DNAm levels could satisfactorily predict the chronological ages of tissues regardless of tissue type. Interestingly, the age-associated DNAm increases or decreases of the normal signature were aberrantly accelerated in cancer samples.

Conclusion

These tissue type-invariant DNAm age signatures in normal and cancer can be used to address important questions in developmental biology and cancer research.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-997) contains supplementary material, which is available to authorized users.