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PubMed2003

Examination of reproductive endpoints in goldfish (Carassius auratus) exposed in situ to municipal sewage treatment plant effluent discharges in Michigan, USA.

Effects of representative mid-Michigan (USA) wastewater treatment plant (WWTP) effluents on the reproductive physiology of common goldfish (Carassius auratus) were assessed in situ by measuring plasma concentrations of vitellogenin (VTG), 17 beta-estradiol (E2), and testosterone (T), and evaluating gonad histology. Caged adult male and female goldfish were exposed for six weeks to WWTP effluents. One riverine site and one lacustrine site were included as references for comparison to WWTP sites. There was differential growth and gonadal development among locations, which confounded the interpretation of biomarker responses. A linear contrast model was developed by analysis of covariance, and adjusted values were developed for concentrations of VTG, E2, and T in the plasma of both male and female fish. In general, VTG concentrations were significantly less in male than in female goldfish. Most concentrations of VTG in male goldfish were less than the method detection limit. There were no significant differences in plasma VTG of either male or female goldfish among locations or between sites at WWTPs and reference sites. Concentrations of E2 in the plasma of female goldfish were similar among WWTP sites, all of which were less than in females at a pond reference location. Concentrations of E2 in the plasma of male goldfish were similar at all WWTP locations, except for one, where they were greater. No consistent trends in hormone concentrations or gonadal histology could be attributed to putative endocrine disrupter exposure in WWTP effluents. The results indicate that the risk for estrogen agonist exposure below these mid-Michigan WWTPs is small.

Animals↗

PubMed2001

Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers.

BACKGROUND: Human exposure to chemicals is normally monitored by measurement of environmental pollutants in external media. We investigated whether biomarkers in adolescents can show exposure to, and health effects of, common environmental pollutants. METHODS: We recruited 200 17-year-old adolescents (120 girls) from a rural control area and from two suburbs polluted by a lead smelter and two waste incinerators. We measured biomarkers of exposure and of effect in blood and urine samples, and obtained questionnaire data. School doctors measured testicular volume and staged sexual maturation. FINDINGS: Internal exposure was mostly within current standards. Concentrations of lead and cadmium in blood, PCBs (polychlorinated biphenyls) and dioxin-like compounds in serum samples, and metabolites of VOCs (volatile organic compounds) in urine were higher in one or both suburbs than in the control area. Children who lived near the waste incinerators matured sexually at an older age than others, and testicular volume was smaller in boys from the suburbs than in controls. Biomarkers of glomerular or tubular renal dysfunction in individuals were positively correlated with blood lead. Biomarkers of DNA damage were positively correlated with urinary metabolites of PAHs (polycyclic aromatic hydrocarbons) and VOCs. Interpretation Biomarkers can be used to detect environmental exposure to pollutants and measure their biological effects before overt disease develops. Our findings suggest that current environmental standards are insufficient to avoid measurable biological effects.

Adolescent↗

PubMed2006

The amplified peptidome: the new treasure chest of candidate biomarkers.

Mass spectrometric analysis of the low-molecular weight (LMW) range of the serum/plasma proteome is revealing the existence of large numbers of previously unknown peptides and protein fragments predicted to be derived from low-abundance proteins. This raises the question of why such low abundance molecules would be retained at detectable levels in the circulation, instead of being rapidly cleared and excreted. Theoretical models of biomarker production and association with serum carrier proteins have been developed to elucidate the mechanisms governing biomarker half-life in the bloodstream. These models predict that the vast majority of LMW biomarkers exist in association with circulating high molecular mass carrier proteins. Moreover, the total serum/plasma concentration of the biomarker is largely determined by the clearance rate of the carrier protein, not the free-phase biomarker clearance itself. These predictions have been verified experimentally using molecular mass fractionation of human serum before mass spectrometry sequence analysis. These principles have profound implications for biomarker discovery and measurement.

Biomarkers↗

PubMed2003

Cervical cancer chemoprevention, vaccines, and surrogate endpoint biomarkers.

At the Second International Conference on Cervical Cancer, held April 11-14, 2002, experts in cervical cancer prevention, detection, and treatment reviewed the need for more research in chemoprevention, including prophylactic and therapeutic vaccines, immunomodulators, peptides, and surrogate endpoint biomarkers. Investigators and clinicians noted the need for more rigorous Phase I randomized clinical trials, more attention to the risk factors that can affect study results in this patient population, and validation of optical technologies that will provide valuable quantitative information in real time regarding disease regression and progression. They discussed the role of the human papillomavirus (HPV) in cervical cancer development and the importance of developing strategies to suppress HPV persistence and progression. Results in Phase I randomized clinical trials have been disappointing because few have demonstrated statistically significant regression attributable to the agent tested. Researchers recommended using a transgenic mouse model to test and validate new compounds, initiating vaccine and immunomodulator trials, and developing immunologic surrogate endpoint biomarkers.

Biomarkers, Tumor↗

PubMed2005

Translational medicine: can it really facilitate the transition of research "from bench to bedside"?

Translational medicine is intended to facilitate the transition of basic science results to clinical practice, thereby sharing major aspects of clinical pharmacology. Biomarkers need to be developed to achieve this, and their predictive values need to be assessed. Despite all the attempts to increase output from costly pharmaceutical research investments, all stakeholders complain of the decreasing efficiency of drug development processes, and expensive late attritions seem to be seen at increasing rates. How can translational medicine improve this apparent mismatch between effort and tangible result for daily medical practice? What is missing, and where do we stand?

Animals↗

PubMed1999

Biomarkers of exposure, sensitivity and disease.

PURPOSE: This review is to evaluate the use of biomarkers as an indication of past exposure to radiation or other environmental insults, individual sensitivity and risk for the development of late occurring disease. OVERVIEW: Biomarkers can be subdivided depending on their applications. Markers of exposure and dose can be used to reconstruct and predict past accidental or occupational exposures when limited or no physical measurements were available. Markers of risk or susceptibility can help identify sensitivity individuals that are at increased risk for development of spontaneous disease and may help predict the increased risk in sensitive individuals associated with environmental or therapeutic radiation exposures. Markers of disease represent the initial cellular or molecular changes that occur during disease development. Each of these types of biomarkers serves a unique purpose. OUTLINE: This paper concentrates on biomarkers of dose and exposure and provides a brief review of biomarkers of sensitivity and disease. The review of biomarkers of dose and exposure will demonstrate the usefulness of biomarkers in evaluation of physical factors associated with radiation exposure, such as LET, doserate and dose distribution. It will also evaluate the use of biomarkers to establish relationships that exist between exposure parameters such as energy deposition, environmental concentration of radioactive materials, alpha traversals and dose. In addition, the importance of biological factors on the magnitude of the biomarker response will be reviewed. Some of the factors evaluated will be the influence of species, tissue, cell types and genetic background. The review will demonstrate that markers of sensitivity and disease often have little usefulness in dose-reconstruction and, by the same token, many markers of dose or exposure may not be applicable for prediction of sensitivity or risk.

Animals↗

PubMed1997

Detection of gelatinase B expression reveals osteoclastic bone resorption as a feature of early calvarial bone development.

Gelatinase B is a matrix metalloproteinase (MMP-9) produced by osteoclasts involved in bone resorption. Bone modeling, of which resorption is an integral part, is particularly evident in the intramembranous bones of the craniofacial region. To determine the role of osteoclasts in developing intramembranous bones we localized osteoclasts in calvariae from mice aged between embryonic day 16 and postnatal day 6, using gelatinase B and tartrate-resistant acid phosphatase activity (TRAP) as osteoclast markers. Through a combined approach of in situ hybridization and enzyme histochemistry, phenotypic differences between osteoclasts associated with calvarial bone were noted. Some cells expressed gelatinase B mRNA but were TRAP negative, whereas others demonstrated an overlap in enzyme profile exhibiting both TRAP activity and expressing gelatinase B mRNA. During more advanced development, most osteoclasts exhibited TRAP activity but did not express gelatinase B mRNA. The distribution of these cells differed, TRAP positive cells being detected in a widespread pattern at all ages, while gelatinase B transcripts were increasingly concentrated in areas of new and rapid bone growth, notably around the sutures. We propose the use of gelatinase B as an osteoclastic marker in the developing mouse. We conclude that gelatinase B may have a key role during early bone formation, the regulation of bone modeling, and perhaps in the maintenance of suture width.

Acid Phosphatase↗

PubMed1999

Intrinsic and extrinsic biomarkers for the assessment of risks from environmental UV radiation.

In the last decades the knowledge of the effects of UV radiation on human health, especially in skin cancerogenesis, but also in immunsuppression, photoaging, eye damages, has enlarged strongly. The increasing solar UV radiation and changes in life style strengthen the necessity to identify and quantitate intrinsic biomarkers which are indicative for the individual UV susceptibility and the accumulated individual UV burden. For the risk assessment of potentially deleterious UV effects extrinsic biomarkers have to be developed and tested as personal biological UV dosimeters. One example for such a well characterized biological UV dosimeter is the DLR-biofilm which consists of spores of the bacterium Bacillus subtilis as UV sensitive target.

Adolescent↗

PubMed2004

Development of the lymphatic vascular system: a mystery unravels.

The blood vascular and the lymphatic system play complementary roles in tissue perfusion and fluid reabsorption. Despite its critical role in mediating tissue fluid homeostasis, intestinal lipid absorption, and the immune response, the lymphatic system has not received as much attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of lymphatic development and function. A series of recent landmark studies now significantly has advanced our understanding of the lymphatic system. Based upon the discovery and characterization of lymphatic-specific growth factors, receptors, and transcriptional regulators, the mystery of lymphatic vascular system development begins to be unraveled. The successful isolation and cultivation of blood vascular and lymphatic endothelial cells has enabled comparative molecular and cellular analyses of these two genetically and developmentally closely related cell lineages. Moreover, studies of several genetic mouse models have set the framework for a new molecular model of embryonic lymphatic vascular development and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Although these rapid advances already have led to development of the first lymphatic-targeted molecular therapies, there still remain many unanswered questions regarding almost every aspect of lymphatic vascular biology, making the lymphatic system a highly exciting and rewarding field of study.

Animals↗

PubMed2001

A critical assessment of some biomarker approaches linked with dietary intake.

In this review many examples are given of the complexities involved in using some biomarkers in relation to assessing the effects of dietary exposure, when there is frequently a need to determine changes following long-term low level exposure to dietary components. These range from understanding why the biomarker might be valuable and how best it can be measured, to the pitfalls which can occur in the interpretation of data. Analytical technique is considered in relation to folate and selenium, and flavonoid and carotenoid species are used to illustrate how the metabolism of a compound may alter the validity or adequacy of a marker. Vitamin A is discussed in relation to the difficulties which can arise when there are several biomarkers that may be available to assess exposure to one nutrient. Vitamin B12 is discussed in relation to the dietary choices made by individuals. Possible interactions and the role of measuring total antioxidant capacity is considered in some detail. In contrast to most nutrients, there is a marked lack of biomarkers of either exposure or effect for most non-nutrients. The role of biological effect monitoring is considered for dietary contaminants, fumonisins and polyhalogenated aromatic hydrocarbons. Aflatoxins are discussed to exemplify food contaminants for which the biomarker approach has been extensively studied. Finally some compounds which are deliberately added to foods and some which appear as processing contaminants are each considered briefly in relation to the requirement for a biomarker of exposure to be developed.

Aflatoxins↗

PubMed1997

Analysis of human urine for pyridine-N-oxide metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific lung carcinogen.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in rodents and is believed to be a causative factor for lung cancer in smokers. NNK also may be involved in oral cancer etiology in users of smokeless tobacco products. Pyridine-N-oxidation of NNK and its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), produces NNK-N-oxide and NNAL-N-oxide, respectively, which are detoxification products of NNK metabolism and are excreted in the urine of rodents and primates. Our goal is to develop a panel of urinary biomarkers to assess the metabolic activation and detoxification of NNK in humans. In this study, we developed methodology to analyze human urine for NNK-N-oxide and NNAL-N-oxide. The key step in the method was conversion of the N-oxides to NNK and NNAL by treatment with Proteus mirabilis. The resulting samples were then analyzed essentially by methods that we have described previously. 4-(Methylnitrosamino)-4-(3-pyridyl-N-oxide)-1-butanol (iso-NNAL-N-oxide) was used as internal standard. Levels of NNAL-N-oxide in smokers' urine ranged from 0.06 to 1.4 pmol/mg creatinine, mean +/- SD 0.53 +/- 0.36 pmol/mg creatinine. Its presence was confirmed by high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. NNK-N-oxide was not detected in smokers' urine. Levels of NNAL-N-oxide in the urine of smokeless tobacco users ranged from 0.02 to 1.2 pmol/mg creatinine, mean +/- SD 0.41 +/- 0.35 pmol/mg creatinine. The amounts of NNAL-N-oxide in urine were less than 20% of those of [4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc) and were approximately 50% as great as those of free NNAL. These results demonstrate that pyridine-N-oxidation is a relatively minor detoxification pathway of NNK and NNAL in humans. The method was applied to analysis of urine from 11 smokers who consumed a diet containing watercress. In an earlier study (S.S. Hecht et al., Cancer Epidemiol., Biomarkers & Prev., 4: 877-884, 1995), we showed that consumption of watercress, a source of phenethyl isothiocyanate (PEITC), caused an increase in urinary excretion of NNAL plus NNAL-Gluc. This was attributed to inhibition of alpha-hydroxylation of NNK by PEITC, as seen in rodents in which PEITC also inhibits the pulmonary carcinogenicity of NNK. However, PEITC also could have inhibited pyridine-N-oxidation of NNK and NNAL. The urine of these smokers was analyzed for NNAL-N-oxide. The results demonstrated that watercress consumption had no effect on levels of NNAL-N-oxide in urine, supporting the conclusion that PEITC does inhibit the metabolic activation of NNK in humans.

Anticarcinogenic Agents↗

PubMed1999

The role of epidemiology in determining when evidence is sufficient to support nutrition recommendations. Summary statement.

This statement summarizes the key points of discussion among a group of nutritional epidemiologists who met in Washington, DC, for 2 d in October of 1997 to reflect on the role of nutritional epidemiology in the development of dietary recommendations for the public. Although imprecision in the measurement of diet places limits on nutritional epidemiology, no other field of nutritional science can provide direct information on relations between nutrition and health in free-living human populations. Among the nutritional sciences, therefore, epidemiology was regarded as being critically important. Nutritional epidemiology can be improved in the future by the development of more precise measures of long-term dietary exposures, both by improved methods of self-reporting of diet and by the development of more useful biomarkers of long-term nutritional status. There is a need as well to reconsider the applicability of causal criteria as applied to nutritional epidemiology, because many of the important associations between dietary behaviors and chronic diseases cannot necessarily be expected to be either strong or to manifest linear dose-response relations. In the future, scientific evidence from the rapidly growing field of nutritional epidemiology will likely play an increasingly important role in developing nutrition policy and advice for the public.

Causality↗

PubMed2002

Dietary conjugated linoleic acid (CLA) intake assessment and possible biomarkers of CLA intake in young women.

OBJECTIVE: The habitual intake of the conjugated linoleic acid (CLA) isomer C18:2 c9t11 (rumenic acid, RA) was assessed and compared with plasma biomarkers. DESIGN: The newly developed food-frequency questionnaire (FFQ) comprised 46 food items and was validated by means of a 7-day estimated record (7-d ER). Additionally, the dietary intake results of the FFQ, 7-d ER, the last day (1-d ER) and the last two days (2-d ER) before blood sampling of the 7-d ER were compared to the content of C18:2 c9t11 in plasma phospholipids (PL) and triglycerides (TG) as possible biomarkers. SETTING: Metabolic unit of a university institute. SUBJECTS: Fifty-seven students completed both dietary instruments. From all participants fasting blood samples were taken. RESULTS: Mean daily intake of rumenic acid was 246 mg day(-1) and 323 mg day(-1) as measured by the FFQ and the 7-d-ER, respectively. The degree of correspondence between both assessment methods was acceptable; this is indicated by a total kappa value of kappa = 0.31 (P < 0.01) and a Pearson correlation coefficient of r = 0.46 (P < 0.01). Rumenic acid content in plasma triglycerides was twice as high as found in phospholipids. The correlation between the intake results gained with the 7-d ER and the plasma PL contents of C18:2 c9t11 was statistically significant; this was also true for the C18:2 c9tl 1 values in plasma TG compared with the intake results of one or two days before blood sampling. CONCLUSIONS: Regarding RA intake, the FFQ data revealed an acceptable degree of correspondence with the 7-d ER data but failed to show significant correlations to the potential biomarkers. However, with respect to the results of the 7-d ER, the RA content in plasma PL and TG are possible biomarkers of short-term and medium-term intake, respectively.

Adult↗

PubMed1998

Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling.

Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure--activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with a time-course medium-term liver foci assay, molecular biology and cell proliferation studies. Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures.

Algorithms↗

PubMed1994

Biochemical markers for assessing skeletal growth.

Many of the biochemical markers for assessing skeletal turnover are based on the unique metabolism of fibrillar collagens. Intracellular modifications lead to the formation of hydroxyproline and hydroxylysine glycosides, both of which have been used as markers of collagen degradation. However, hydroxyproline is metabolised extensively in the liver and both components may be derived from several different tissue sources. The pyridinium crosslinks of collagen have been shown to provide more specific and sensitive markers of collagen degradation, since these compounds are only present in the mature, insoluble fibrils. In addition, pyridinium crosslinks are unaffected by diet and are not metabolised in the body. Following development of HPLC methods for the quantification of urinary crosslinks, these techniques have been validated as indices of bone resorption in studies of a wide range of metabolic bone diseases. Subsequently, the proportion of free crosslinks in urine was shown to be relatively consistent in different individuals, allowing development of a simple, direct immunoassay. The excretion of crosslinks in children was related to growth velocity and, in studies of malnourished children, the values before treatment were related to the child's growth response. For measuring bone formation, the serum concentrations of the C-terminal propeptide of procollagen type I (PICP) appear to reflect the activity of the osteoblasts, but additional information on physiological variations is necessary. The major non-collagenous components of bone in serum, osteocalcin or bone Gla protein, has long been used as a marker of bone formation, but there are a number of factors that complicate interpretation of the results. These include variations in the immunochemical reactivity, the possible presence of degradation fragments in serum and the dependence of vitamin K status for adequate enzymatic carboxylation. Nevertheless, assays for intact osteocalcin have been shown to be related to growth velocity in children. There are few suitable serum or urinary indices for cartilage metabolism and development of more specific markers, particularly for growth plate cartilage, are required to distinguish between linear growth and bone remodelling. Assessments of skeletal metabolism should, wherever possible, include a combination of different markers so that the balance between formative and resorptive events can be adequately evaluated.

Adolescent↗

PubMed1995

Tissue differentiation and correlated changes in enzymatic activities during primary antler development in fallow deer (Dama dama).

BACKGROUND: Deer antlers are useful models for studying bone growth and biomineralization in mammals. To achieve a better understanding of the mechanisms underlying the formation of primary cranial appendages in deer, the present study relates the histogenesis of primary antlers to changes in enzymatic (phosphatase) activities in the different tissue zones of this organ. METHODS: The growing tips of the primary antlers (4.3 to 5 cm in length) were removed from five fallow bucks, aged about 10 months. Part of the material was processed for light microscopy. The other part was cryofixed, and the different histologically defined regions were analyzed for the activities of alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) as well as for the concentrations of inorganic and organic phosphate. RESULTS AND CONCLUSIONS: Histologically, the primary antler could in distoproximal direction be divided into eight different zones (dermis; perichondrium; zones of cartilage formation, hypertrophy, mineralization, and degeneration; primary spongiosa; secondary spongiosa). The histological results demonstrate that the elongation of the primary antler proceeded through a modified form of endochondral ossification, resembling that seen during formation of pedicles and secondary antlers. The concentrations of the extractable activities of ALP and TRAP progressively increased from the perichondrium to the zone of cartilage mineralization. Thus, highest activity of TRAP during primary antler formation occurred at an earlier stage of tissue differentiation than in somatic endochondral ossification, where the enzyme is a biochemical marker of osteoclastic activity during bone remodeling. The present results might reflect the presence of osteoclastic precursor cells in the zone of cartilage mineralization as an adaptation to the rapidity of antler growth. Our findings of the contents of extractable ALP, inorganic and organic phosphate in the different tissue zones of the developing primary antler are in good agreement with previous studies analyzing epiphyseal growth plates and point to the fact that ALP causes a rise in inorganic phosphate and the removal of inhibitors for mineralization, like pyrophosphate.

Acid Phosphatase↗

PubMed2005

Development of the enteric nervous system, smooth muscle and interstitial cells of Cajal in the human gastrointestinal tract.

The generation of functional neuromuscular activity within the pre-natal gastrointestinal tract requires the coordinated development of enteric neurons and glial cells, concentric layers of smooth muscle and interstitial cells of Cajal (ICC). We investigated the genesis of these different cell types in human embryonic and fetal gut material ranging from weeks 4-14. Neural crest cells (NCC), labelled with antibodies against the neurotrophin receptor p75NTR, entered the foregut at week 4, and migrated rostrocaudally to reach the terminal hindgut by week 7. Initially, these cells were loosely distributed throughout the gut mesenchyme but later coalesced to form ganglia along a rostrocaudal gradient of maturation; the myenteric plexus developed primarily in the foregut, then in the midgut, and finally in the hindgut. The submucosal plexus formed approximately 2-3 weeks after the myenteric plexus, arising from cells that migrated centripetally through the circular muscle layer from the myenteric region. Smooth muscle differentiation, as evidenced by the expression of alpha-smooth muscle actin, followed NCC colonization of the gut within a few weeks. Gut smooth muscle also matured in a rostrocaudal direction, with a large band of alpha-smooth muscle actin being present in the oesophagus at week 8 and in the hindgut by week 11. Circular muscle developed prior to longitudinal muscle in the intestine and colon. ICC emerged from the developing gut mesenchyme at week 9 to surround and closely appose the myenteric ganglia by week 11. By week 14, the intestine was invested with neural cells, longitudinal, circular and muscularis mucosae muscle layers, and an ICC network, giving the fetal gut a mature appearance.

Actins↗

PubMed2006

Identification of PEG10 as a progression related biomarker for hepatocellular carcinoma.

Widespread DNA copy number alterations are well recognized in hepatocellular carcinoma (HCC), although the affected genes expression remained largely undefined. In this study, we performed genome-wide analysis on HCC to examine the relationship between gene copy number and corresponding transcriptional changes. To ensure analysis on a homogenous population of tumor cells, integrative analysis of array-based CGH and expression profilings was performed on 20 HCC cell lines using a 19,200-element cDNA microarray platform. Further validation studies were carried out on a large series of primary HCC tumors and paired adjacent non-malignant liver to ascertain finding. Correlative analyses highlighted 31 candidate genes that manifested both copy gains and gene up-regulations (R2>0.5; p<0.05). Of interest was over-expressed paternally expressed 10 (PEG10) resided within the chromosome region 7q21 that has been implicated in the progression of HCC. Quantitative PCR and qRT-PCR studies verified concurrent genomic gains and over-expression of PEG10 in HCC cell lines and primary tumors (34/40 cases; 85%). In addition, qRT-PCR demonstrated a significant progressive trend of increasing PEG10 expressions from the putative pre-malignant adjacent livers to early resectable HCC tumors, and to late inoperable HCCs (p=0.007). In summary, the present study demonstrated the usefulness of integrated genomic and expression profilings in identifying candidate genes within regions of genomic alteration. Our results also suggested that PEG10 may be a potential biomarker in the progressive development of HCC, and that genomic gain represents one of the major mechanisms in the induction of PEG10 over-expressions.

Apoptosis Regulatory Proteins↗