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Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation.

ABSTRACT: BACKGROUND: Mycoplasmas are the smallest microorganisms capable of self-replication. Our previous studies show that some mycoplasmas are able to induce malignant transformation of host mammalian cells. This malignant transformation is a multistage process with the early infection, reversible and irreversible stages, and similar to human tumor development in nature. The purpose of this study is to explore mechanisms for this malignant transformation. METHODS: To better understand mechanisms for this unique process, we examined gene expression profiles of C3H cells at different stages of the mycoplasma-induced transformation using cDNA microarray technology. A total of 1185 genes involved in oncogenesis, apoptosis, cell growth, cell-cycle regulation, DNA repair, etc. were examined. Differences in the expression of these genes were compared and analyzed using the computer software AtlasImage. RESULTS: Among 1185 genes screened, 135 had aberrant expression at the early infection stage, 252 at the reversible stage and 184 at the irreversible stage. At the early infection stage, genes with increased expression (92 genes) were twice more than those with decreased expression (42 genes). The global gene expression at the reversible stage appeared to be more volatile than that at any other stages but still resembled the profile at the early infection stage. The expression profile at the irreversible stage shows a unique pattern of a wide range of expression levels and an increased number of expressing genes, especially the cancer-related genes. Oncogenes and tumor suppressors are a group of molecules that showed significant changes in expression during the transformation. The majority of these changes occurred in the reversible and irreversible stages. A prolonged infection by mycoplasmas lead to the expression of more cancer related genes at the irreversible stage. CONCLUSION: The results indicate that the expression profiles correspond with the phenotypic features of the cells in the mycoplasma induced transformation process. The early mycoplasma infection stage shares a common phenomenon with many other acute infections, genes with increased expression significantly outnumbering those with decreased expression. The reversible stage is a transition stage between benignancy and malignancy at the molecular level. Aberrant expression of oncogenes and tumor repressors plays a key role in mycoplasma-induced malignant transformation.

SUBMITTER: Zhang S

PROVIDER: S-EPMC1559712 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation.

Zhang Shimin S Tsai Shien S Lo Shyh-Ching SC

BMC cancer 20060504

<h4>Background</h4>Mycoplasmas are the smallest microorganisms capable of self-replication. Our previous studies show that some mycoplasmas are able to induce malignant transformation of host mammalian cells. This malignant transformation is a multistage process with the early infection, reversible and irreversible stages, and similar to human tumor development in nature. The purpose of this study is to explore mechanisms for this malignant transformation.<h4>Methods</h4>To better understand mec ...[more]

PMID: 16674811

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Project description:BackgroundArsenic is a carcinogen that targets the urogenital system, including the prostate. Although the mechanisms for arsenic-induced carcinogenesis are undefined, arsenic drives overaccumulation of stem cells and cancer stem cells (CSCs) in vivo and in vitro, indicating that these cells are a key target population. Disruption of stem cell population dynamics may be critical to acquisition of cancer phenotype. We tested the hypothesis that prostate stem cells have a survival selection advantage during arsenic exposure that favors their accumulation and facilitates their malignant transformation.MethodsInnate and acquired resistance to acute (24-72 hours of exposure) and chronic (6 weeks of exposure) arsenite-induced cytolethality and apoptosis were assessed in a human prostate stem cell line (WPE-stem) and the mature parental cell line (RWPE-1). Real-time reverse transcription-polymerase chain reaction and/or Western blot analysis was used to measure the expression of apoptosis-, stress-, and arsenic-related genes. Arsenic-, cadmium-, and N-methyl-N-nitrosourea-induced isogenic malignant transformants of RWPE-1 cells were compared for acquisition of CSC-like qualities by holoclone and sphere formation assays, growth in soft agar, and expression of CSC biomarkers. All statistical tests were two-sided.ResultsWPE-stem cells showed innate resistance to arsenic-induced cytolethality (arsenite concentration lethal to 50% of the cells [LC(50)] = 32.4 microM, 95% confidence interval [CI] = 31.5 to 33.3 muM) and apoptosis compared with parental RWPE-1 cells (LC(50) = 10.4 muM, 95% CI = 7.4 to 13.4 microM). Compared with RWPE-1 cells, WPE-stem cells showed noticeably higher expression of antiapoptotic (ie, BCL2, MT), stress-related (ie, NFE2L2, SOD1, PRODH), and arsenic adaptation (ie, ABCC1, GSTP1) factors and noticeably lower expression of proapoptotic factors (ie, BAX, caspases 3, 7, 8, and 9). WPE-stem cells also showed hyper-adaptability to chronic arsenite exposure (5 microM, 6 weeks) compared with RWPE-1 cells (LC(50) = 94.7 vs 32.1 microM, difference = 62.6 muM, 95% CI = 53.3 to 71.9 muM) at levels that in previous work induced a malignant phenotype in RWPE-1 after 30 weeks of exposure. Quantification of CSC-like cells in isogenic RWPE-1 transformants showed that marked overproduction was unique to a malignant phenotype acquired in response to arsenic exposure but not in response to cadmium or N-methyl-N-nitrosourea exposure.ConclusionsAn apparent stem cell survival advantage with regard to arsenic causes selection during malignant transformation that manifests itself as an overabundance of CSC-like cells specifically after arsenic-driven acquisition of malignant phenotype. The increased resistance to apoptosis and arsenite hyper-adaptability of WPE-stem cells suggests that arsenite transformation of RWPE-1 cells involves an increase in the number of CSC-like cells.

Project description:Hypertension induced by high-salt diet in Dahl salt-sensitive rats leads to compensatory cardiac hypertrophy by approximately 11 wk, cardiac dysfunction at approximately 17 wk, and death from cardiac dysfunction at approximately 21 wk. It is unclear what molecular hallmarks distinguish the compensatory hypertrophy from the decompensated cardiac dysfunction phase. Here we compared the gene expression in rat cardiac tissue from the compensatory hypertrophic phase (11 wk, n = 6) with the cardiac dysfunction phase (17 wk, n = 6) and with age-matched normotensive controls. Messenger RNA levels of 93 genes, selected based on predicted association with cardiac dysfunction, were measured by quantitative real-time PCR. In the hypertrophic phase, the expression of three genes, atrial natriuretic peptide (ANP; P = 0.0089), brain natriuretic peptide (P = 0.0012), and endothelin-1 precursor (P = 0.028), significantly increased, whereas there was decreased expression of 24 other genes including SOD2 (P = 0.0148), sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (P = 0.0002), and ryanodine receptor 2 (P = 0.0319). In the subsequent heart cardiac dysfunction phase, the expression of an additional 20 genes including inducible nitric oxide synthase (NOS; P = 0.0135), angiotensin I-converting enzyme (P = 0.0082), and IL-1beta (P < 0.0001) increased, whereas the expression of seven genes decreased compared with those of age-matched controls. Furthermore, the expression of 22 genes, including prepro-endothelin-1, ANP, angiotensin I-converting enzyme, beta(1)-adrenergic receptor, SOD2, and endothelial NOS, significantly changed in the cardiac dysfunction phase compared with the compensatory hypertrophic phase. Finally, principal component analysis successfully segregated animals with decompensatory cardiac dysfunction from controls, as well as from animals at the compensated hypertrophy phase, suggesting that we have identified molecular markers for each stage of the disease.

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Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation.

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Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation.

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