Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033377 (prolapse)
 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urocortin (UCN) is a 40-amino acid neuropeptide sharing 45% sequence homology with corticotropin-releasing factor (CRF). The human endometrium expresses both UCN and CRF, and CRF/UCN receptors type-1 (CRF-R1) and -2 (CRF-R2). CRF-R1 activation inhibits cell growth and proliferation of a tumor cell line derived from the human endometrium, and the UCN signaling pathway has been implicated in tumorigenesis of several tissues. Therefore, we investigated whether UCN mRNA and peptide are expressed by human endometrial adenocarcinoma, and whether their expression changes compared to controls. Samples of well (grade 1; n = 6 endometrioid adenocarcinoma, of whom n = 1 with squamous differentiation, and n = 1 clear-cell carcinoma) and poorly differentiated (grade 3; n = 3 endometrioid adenocarcinoma) endometrial adenocarcinoma were collected from nine women (age range 61-79 years) enrolled at the time of diagnosis. Healthy endometrium was collected from postmenopausal women (controls; n = 13; age range 64-78 years), who underwent hysterectomy for uterine prolapse. Immunohistochemistry was used to evaluate cellular UCN localization, with the intensity of immunostaining scored on a subjective scale. Quantitative real-time reverse transcriptase (RT)-PCR analysis was used to estimate mRNA expression changes and restriction analysis was used to confirm PCR products identity. UCN mRNA expression was significantly reduced (P < 0.0001) in endometrial adenocarcinoma than in healthy controls. Immunoreactive UCN was found in luminal and glandular epithelial cells in healthy, but not in neoplastic samples. UCN mRNA and peptide expressions are decreased in endometrial adenocarcinoma. These data and the evidence that endometrial cancer expresses UCN receptors and UCN is involved in tumorigenesis of several tissues together suggest a role for UCN in endometrial tumoral cell growth and proliferation.
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PMID:Urocortin expression is downregulated in human endometrial carcinoma. 1683 14

Interactions between the extracellular matrix (ECM) and cells are critical in embryonic development, tissue homeostasis, physiological remodeling, and tumorigenesis. Matricellular proteins, a group of ECM components, mediate cell-ECM interactions. One such molecule, Fibulin-5 is a 66-kDa glycoprotein secreted by various cell types, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. Fibulin-5 contributes to the formation of elastic fibers by binding to structural components including tropoelastin and fibrillin-1, and to cross-linking enzymes, aiding elastic fiber assembly. Mice deficient in the fibulin-5 gene (Fbln5) exhibit systemic elastic fiber defects with manifestations of loose skin, tortuous aorta, emphysematous lung and genital prolapse. Although Fbln5 expression is down-regulated after birth, following the completion of elastic fiber formation, expression is reactivated upon tissue injury, affecting diverse cellular functions independent of its elastogenic function. Fibulin-5 contains an evolutionally conserved arginine-glycine-aspartic acid (RGD) motif in the N-terminal region, which mediates binding to a subset of integrins, including alpha5beta1, alphavbeta3, and alphavbeta5. Fibulin-5 enhances substrate attachment of endothelial cells, while inhibiting migration and proliferation in a cell type- and context-dependent manner. The antagonistic function of fibulin-5 in angiogenesis has been demonstrated in vitro and in vivo; fibulin-5 may block angiogenesis by inducing the anti-angiogenic molecule thrompospondin-1, by antagonizing VEGF(165)-mediated signaling, and/or by antagonizing fibronectin-mediated signaling through directly binding and blocking the alpha5beta1 fibronectin receptor. The overall effect of fibulin-5 on tumor growth depends on the balance between the inhibitory property of fibulin-5 on angiogenesis and the direct effect of fibulin-5 on proliferation and migration of tumor cells. However, the effect of tumor-derived versus host microenvironment-derived fibulin-5 remains to be evaluated.
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PMID:Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. 1979 95

FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which are responsible for the Blepharophimosis Ptosis Epicanthus-inversus Syndrome (BPES), often associated with premature ovarian failure. Recent evidence has linked FOXL2 downregulation or somatic mutation (p.Cys134Trp) to cancer, although underlying molecular mechanisms remain unclear. Using a functional genomic approach, we find that FOXL2 modulates cell-cycle regulators in a way which tends to induce G1 arrest. Indeed, FOXL2 upregulation promotes cell accumulation in G1 phase and protects cells from oxidative damage, notably by promoting oxidized DNA repair and by increasing the amounts of anti-oxidant agent glutathione. In agreement with clinical observations, we find that FOXL2-mutated versions leading to BPES along with ovarian dysfunction mostly fail to transactivate cell-cycle and DNA repair targets, whereas mutations leading to isolated craniofacial defects (and normal ovarian function) activate them correctly. Interestingly, these assays revealed a mild promoter-specific hypomorphy of the tumor-associated mutation (p.Cys134Trp). Finally, the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell-cycle and DNA repair in a dose-dependent manner. Accordingly, we find that SIRT1 inhibition by nicotinamide limits proliferation, notably by increasing endogenous FOXL2 amount/activity. The body of evidence presented here supports the idea that FOXL2 plays a key role in granulosa cell homeostasis, the failure of which is central to ovarian ageing and tumorigenesis. As granulosa cell tumors respond poorly to conventional chemotherapy, our findings on the deacetylase inhibitor nicotinamide provide an interesting option for targeted therapy.
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PMID:Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. 2128 58

High-risk human papillomaviruses (HPV) are the causative agents of cervical cancer. However, not all infected women develop cervical cancer. Cervical tumorigenesis is characterized by a multifactorial etiology, with oxidative stress (OS) likely playing a major role. In addition to exogenous sources, metabolic processes also contribute to OS. In principle, variability in levels of cervical OS has the potential to influence the likelihood of conversion to cervical cancer. To ask whether such variability indeed existed, we assessed the levels of ROS and the oxidative DNA damage biomarker 8-oxodG in normal non-cancerous cervical tissues and cells obtained from women with uterovaginal pelvic organ prolapse following vaginal hysterectomy. We demonstrated five and ten-fold variability between tissues isolated from the transformation zone (TZ) and ectocervix (EC) of different women, respectively. Despite the greater variability (likely due to differences in tissue composition), the overall pattern of ROS levels in EC tissues mirrored those obtained in their corresponding TZ tissues. Our results also show that the levels of ROS in TZ tissues were always higher than or equal to those found in the respective EC tissues, providing a possible explanation for TZ tissue being the primary target for HPV infection and cervical carcinogenesis. Interestingly, primary keratinocytes isolated and cultured from these cervical specimens also displayed high variability in ROS levels, with some strongly mirroring the levels of ROS observed in their corresponding tissues, while others were less closely associated. Finally, we demonstrated that the levels of DNA damage mirrored the levels of ROS in the cultured primary cells. Understanding the factors and mechanisms that dispose certain individuals to develop cervical cancer has the potential to enable the development of approaches that make the conversion of HPV infection to cancer development even more rare.
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PMID:Oxidative stress markers in patient-derived non-cancerous cervical tissues and cells. 3314 15