Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.
- MeSH
- dospělí MeSH
- genomika metody MeSH
- Kaplanův-Meierův odhad MeSH
- karcinogeneze genetika MeSH
- leiomyosarkom genetika mortalita patologie terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- myometrium patologie MeSH
- nádory dělohy genetika mortalita patologie terapie MeSH
- onkogeny genetika MeSH
- proliferace buněk genetika MeSH
- receptory vazoaktivního intestinálního peptidu typu II genetika MeSH
- regulace genové exprese u nádorů genetika MeSH
- sekvenční analýza RNA metody MeSH
- sekvenování celého genomu metody MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- signální transdukce genetika MeSH
- tumor supresorové geny MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that belongs to a family of structurally related peptide hormones including pituitary adenylate cyclase-activating peptide (PACAP). These hormones are widely distributed in the nervous system, where they act as neurotransmitters. Their biological effects are mediated by specific receptors, VPAC1 and VPAC2, which have comparable affinity for VIP and PACAP, and PAC1, which binds VIP with 1,000-fold lower affinity than PACAP. Both peptides are involved in autonomic regulation of the cardiovascular system, where they exert positive inotropic and chronotropic effects, and cause coronary vasodilatation. Additionally, PACAP inhibits proliferation of cardiac fibroblasts. Several cardiovascular diseases, such as myocardial fibrosis, heart failure, cardiomyopathy and pulmonary hypertension, have been found to be associated with changes in myocardial VIP concentration or with alteration of affinity, density and physiological responsiveness of VIP/PACAP receptors. Application of the peptides or their agonists has beneficial effect in hypertension, heart failure and myocardial fibrosis. Taken together, VIP and PACAP have beneficial effects in various pathological conditions.
- MeSH
- hypofyzární adenylátcyklázu aktivující peptid metabolismus MeSH
- hypofyzární polypeptid aktivující adenylátcyklasu - receptory typu I metabolismus MeSH
- hypofyzární polypeptid aktivující adenylátcyklasu - receptory MeSH
- receptory vazoaktivního intestinálního peptidu typu I * metabolismus MeSH
- receptory vazoaktivního intestinálního peptidu typu II metabolismus MeSH
- vazoaktivní intestinální peptid * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that belongs to a family of structurally related peptide hormones including pituitary adenylate cyclase-activating peptide (PACAP). These hormones are widely distributed in the nervous system, where they act as neurotransmitters. Their biological effects are mediated by specific receptors, VPAC1 and VPAC2, which have comparable affinity for VIP and PACAP, and PAC1, which binds VIP with 1,000-fold lower affinity than PACAP. Both peptides are involved in autonomic regulation of the cardiovascular system, where they exert positive inotropic and chronotropic effects, and cause coronary vasodilatation. Additionally, PACAP inhibits proliferation of cardiac fibroblasts. Several cardiovascular diseases, such as myocardial fibrosis, heart failure, cardiomyopathy and pulmonary hypertension, have been found to be associated with changes in myocardial VIP concentration or with alteration of affinity, density and physiological responsiveness of VIP/PACAP receptors. Application of the peptides or their agonists has beneficial effect in hypertension, heart failure and myocardial fibrosis. Taken together, VIP and PACAP have beneficial effects in various pathological conditions. (c) 2005 Prous Science. All rights reserved.
- MeSH
- autonomní nervový systém metabolismus MeSH
- cévy inervace metabolismus MeSH
- ganglia parasympatická metabolismus MeSH
- hypofyzární adenylátcyklázu aktivující peptid metabolismus MeSH
- hypofyzární polypeptid aktivující adenylátcyklasu - receptory typu I metabolismus MeSH
- kardiotonika terapeutické užití MeSH
- kardiovaskulární nemoci etiologie metabolismus prevence a kontrola MeSH
- kardiovaskulární systém inervace metabolismus MeSH
- lidé MeSH
- myokard metabolismus MeSH
- plicní hypertenze etiologie metabolismus prevence a kontrola MeSH
- receptory vazoaktivního intestinálního peptidu typu I metabolismus MeSH
- receptory vazoaktivního intestinálního peptidu typu II metabolismus MeSH
- signální transdukce MeSH
- srdeční selhání etiologie metabolismus prevence a kontrola MeSH
- vazoaktivní intestinální peptid metabolismus terapeutické užití MeSH
- vazodilatace účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
