Tumor and reproductive traits are linked by RNA metabolism genes in the mouse ovary: a transcriptome-phenotype association analysis

BackgroundThe link between reproductive life history and incidence of ovarian tumors is well known. Periods of reduced ovulations may confer protection against ovarian cancer. Using phenotypic data available for mouse, a possible association between the ovarian transcriptome, reproductive records and spontaneous ovarian tumor rates was investigated in four mouse inbred strains. NIA15k-DNA microarrays were employed to obtain expression profiles of BalbC, C57BL6, FVB and SWR adult ovaries.ResultsLinear regression analysis with multiple-test control (adjusted p ≤ 0.05) resulted in ovarian tumor frequency (OTF) and number of litters (NL) as the top-correlated among five tested phenotypes. Moreover, nearly one-hundred genes were coincident between these two traits and were decomposed in 76 OTF(–) NL(+) and 20 OTF(+) NL(–) genes, where the plus/minus signs indicate the direction of correlation. Enriched functional categories were RNA-binding/mRNA-processing and protein folding in the OTF(–) NL(+) and the OTF(+) NL(–) subsets, respectively. In contrast, no associations were detected between OTF and litter size (LS), the latter a measure of ovulation events in a single estrous cycle.ConclusionLiterature text-mining pointed to post-transcriptional control of ovarian processes including oocyte maturation, folliculogenesis and angiogenesis as possible causal relationships of observed tumor and reproductive phenotypes. We speculate that repetitive cycling instead of repetitive ovulations represent the actual link between ovarian tumorigenesis and reproductive records.

[1]  J. D. Neill,et al.  The Physiology of reproduction , 1988 .

[2]  Lee M. Silver,et al.  Mouse Genetics: Concepts and Applications , 1995 .

[3]  M. Brown,et al.  A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  W. Prime,et al.  Heterogeneous nuclear ribonucleoprotein A2/B1 up-regulation in bronchial lavage specimens: a clinical marker of early lung cancer detection. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  M. Ko,et al.  Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  S. Dudoit,et al.  Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. , 2002, Nucleic acids research.

[7]  R. Meidan,et al.  Endothelin-1 receptors and biosynthesis in the corpus luteum: molecular and physiological implications. , 2002, Domestic animal endocrinology.

[8]  D. Na,et al.  Molecular Cloning and Characterization of CAPER, a Novel Coactivator of Activating Protein-1 and Estrogen Receptors* , 2002, The Journal of Biological Chemistry.

[9]  J. Fleming,et al.  Changes in the mouse ovarian surface epithelium with age and ovulation number , 2002, Molecular and Cellular Endocrinology.

[10]  C. Perrett,et al.  Angiogenesis in epithelian ovarian cancer , 2002, Molecular pathology : MP.

[11]  V. Siskind,et al.  Ovulation and risk of epithelial ovarian cancer , 2003, International journal of cancer.

[12]  V. Siskind,et al.  FREQUENCY OF OVULATION INCREASES OVARIAN CANCER RISK , 2003 .

[13]  Haruhiko Koseki,et al.  Prediction of the coding sequences of mouse homologues of KIAA gene: III. the complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries. , 2003, DNA research : an international journal for rapid publication of reports on genes and genomes.

[14]  K. Burns,et al.  Expression profiling analyses of gonadotropin responses and tumor development in the absence of inhibins. , 2003, Endocrinology.

[15]  Qing-Yuan Sun,et al.  Involvement of Mitogen-Activated Protein Kinase Cascade During Oocyte Maturation and Fertilization in Mammals1 , 2004, Biology of reproduction.

[16]  S. Do,et al.  OGT functions as a catalytic chaperone under heat stress response: a unique defense role of OGT in hyperthermia. , 2004, Biochemical and biophysical research communications.

[17]  Haruhiko Koseki,et al.  Prediction of the coding sequences of mouse homologues of FLJ genes: the complete nucleotide sequences of 110 mouse FLJ-homologous cDnas identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries. , 2004, DNA research : an international journal for rapid publication of reports on genes and genomes.

[18]  S. Nilsson,et al.  Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies , 2004, Acta obstetricia et gynecologica Scandinavica.

[19]  B. Vanderhyden,et al.  Models of ovarian cancer—Are we there yet? , 2005, Molecular and Cellular Endocrinology.

[20]  Xiang-Dong Fu,et al.  Mass Spectrometric and Kinetic Analysis of ASF/SF2 Phosphorylation by SRPK1 and Clk/Sty* , 2005, Journal of Biological Chemistry.

[21]  B. O’Malley,et al.  Steroid hormone receptor coactivation and alternative RNA splicing by U2AF65-related proteins CAPERalpha and CAPERbeta. , 2005, Molecular cell.

[22]  Lu Zhang,et al.  Large scale real-time PCR validation on gene expression measurements from two commercial long-oligonucleotide microarrays , 2006, BMC Genomics.

[23]  T. Klonisch,et al.  Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction. , 2005, Reproduction.

[24]  P. Keightley,et al.  Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways. , 2005, Physiological genomics.

[25]  Arpad Kelemen,et al.  Associating phenotypes with molecular events: recent statistical advances and challenges underpinning microarray experiments , 2005, Functional & Integrative Genomics.

[26]  U. Urzúa,et al.  Microarray Comparative Genomic Hybridization Profile of a Murine Model for Epithelial Ovarian Cancer Reveals Genomic Imbalances Resembling Human Ovarian Carcinomas , 2005, Tumor Biology.

[27]  B. O’Malley,et al.  Steroid Hormone Receptor Coactivation and Alternative RNA Splicing by U2AF65-Related Proteins CAPERα and CAPERβ , 2005 .

[28]  Carol Friedman,et al.  A Natural Language Processing (NLP) Tool to Assist in the Curation Of the Laboratory Mouse Tumor Biology Database , 2006, AMIA.

[29]  B. van den Hazel,et al.  Transcriptome analysis of FSH and FSH variant stimulation in granulosa cells from IVM patients reveals novel regulated genes. , 2006, Molecular human reproduction.

[30]  Qing-Yuan Sun,et al.  Meiotic spindle, spindle checkpoint and embryonic aneuploidy. , 2006, Frontiers in bioscience : a journal and virtual library.

[31]  J. Powell,et al.  Transcriptomic analysis of an in vitro murine model of ovarian carcinoma: Functional similarity to the human disease and identification of prospective tumoral markers and targets , 2006, Journal of cellular physiology.

[32]  S. Matsuzaki,et al.  Differential expression of genes in eutopic and ectopic endometrium from patients with ovarian endometriosis. , 2006, Fertility and sterility.

[33]  J. Richter,et al.  CPEB controls oocyte growth and follicle development in the mouse , 2006, Development.

[34]  P. Rangarajan,et al.  Identification and characterization of a virus-inducible non-coding RNA in mouse brain. , 2006, The Journal of general virology.

[35]  D. Castrillon,et al.  Genomewide Discovery and Classification of Candidate Ovarian Fertility Genes in the Mouse , 2007, Genetics.

[36]  E. Conway de Macario,et al.  Molecular chaperones: multiple functions, pathologies, and potential applications. , 2007, Frontiers in bioscience : a journal and virtual library.

[37]  P. Leung,et al.  Gonadotropins and ovarian cancer. , 2007, Endocrine reviews.

[38]  Pradeep P. Kayampilly,et al.  Follicle-stimulating hormone increases tuberin phosphorylation and mammalian target of rapamycin signaling through an extracellular signal-regulated kinase-dependent pathway in rat granulosa cells. , 2007, Endocrinology.

[39]  S. Saha,et al.  Procollagen Synthesis is Increased in Hypothyroid Rat Ovary by a Parallel and Compensatory Pathway , 2007, Cellular Physiology and Biochemistry.

[40]  Philip Thomas,et al.  A review of genome mutation and Alzheimer's disease. , 2006, Mutagenesis.

[41]  Rongheng Lin,et al.  Gene set enrichment analysis for non-monotone association and multiple experimental categories , 2008, BMC Bioinformatics.

[42]  Chen-Yang Shen,et al.  Increased expression of SRp40 affecting CD44 splicing is associated with the clinical outcome of lymph node metastasis in human breast cancer. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[43]  Janan T. Eppig,et al.  Mouse Tumor Biology Database (MTB): status update and future directions , 2006, Nucleic Acids Res..

[44]  Macario Aj,et al.  Molecular chaperones: multiple functions, pathologies, and potential applications. , 2007 .

[45]  M. Simon,et al.  Hypoxia-inducible factors: central regulators of the tumor phenotype. , 2007, Current opinion in genetics & development.

[46]  M. Ladomery,et al.  Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors , 2008, Journal of Cell Science.

[47]  David I. Smith,et al.  Long, abundantly expressed non-coding transcripts are altered in cancer. , 2008, Human molecular genetics.

[48]  B. Capel,et al.  Development of germ cells in the mouse. , 2008, Current topics in developmental biology.

[49]  E. Boscolo,et al.  Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma , 2008, Nature Medicine.

[50]  H. Fan,et al.  Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation , 2008, Development.

[51]  M. Martín-Bermudo,et al.  A role for the chaperone Hsp70 in the regulation of border cell migration in the Drosophila ovary , 2008, Mechanisms of Development.

[52]  M. Evans,et al.  Optimization of minuscule samples for use with cDNA microarrays. , 2008, Journal of biochemical and biophysical methods.

[53]  Simak Ali,et al.  The DEAD box RNA helicases p68 (Ddx5) and p72 (Ddx17): novel transcriptional co-regulators. , 2008, Biochemical Society transactions.

[54]  João Ricardo Sato,et al.  Comparing Pearson, Spearman and Hoeffding's d Measure for Gene Expression Association Analysis , 2009, J. Bioinform. Comput. Biol..

[55]  G. Ning,et al.  Lanosterol metabolic product(s) is involved in primordial folliculogenesis and establishment of primordial folliclepool in mouse fetal ovary , 2009, Molecular reproduction and development.

[56]  D. Stocco,et al.  Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. , 2009, Molecular human reproduction.

[57]  S. Gaines,et al.  The Mouse , 2011 .

[58]  Carol J. Bult,et al.  Mouse Phenome Database (MPD) , 2011, Nucleic Acids Res..