The selected biomarker analysis in 5 types of uterine smooth muscle tumors.
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ABSTRACT:
SUBMITTER: Zhang Q
PROVIDER: S-EPMC6065267 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
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Project description:Intravenous leiomyomatosis is an unusual smooth muscle neoplasm with quasi-malignant intravascular growth but a histologically banal appearance. Herein, we report expression and molecular cytogenetic analyses of a series of 12 intravenous leiomyomatosis cases to better understand the pathogenesis of intravenous leiomyomatosis. All cases were analyzed for the expression of HMGA2, MDM2, and CDK4 proteins by immunohistochemistry based on our previous finding of der(14)t(12;14)(q14.3;q24) in intravenous leiomyomatosis. Seven of 12 (58%) intravenous leiomyomatosis cases expressed HMGA2, and none expressed MDM2 or CDK4. Colocalization of hybridization signals for probes from the HMGA2 locus (12q14.3) and from 14q24 by interphase fluorescence in situ hybridization (FISH) was detected in a mean of 89.2% of nuclei in HMGA2-positive cases by immunohistochemistry, but in only 12.4% of nuclei in negative cases, indicating an association of HMGA2 expression and this chromosomal rearrangement (P=8.24 × 10(-10)). Four HMGA2-positive cases had greater than two HMGA2 hybridization signals per cell. No cases showed loss of a hybridization signal by interphase FISH for the frequently deleted region of 7q22 in uterine leiomyomata. One intravenous leiomyomatosis case analyzed by array comparative genomic hybridization revealed complex copy number variations. Finally, expression profiling was performed on three intravenous leiomyomatosis cases. Interestingly, hierarchical cluster analysis of the expression profiles revealed segregation of the intravenous leiomyomatosis cases with leiomyosarcoma rather than with myometrium, uterine leiomyoma of the usual histological type, or plexiform leiomyoma. These findings suggest that intravenous leiomyomatosis cases share some molecular cytogenetic characteristics with uterine leiomyoma, and expression profiles similar to that of leiomyosarcoma cases, further supporting their intermediate, quasi-malignant behavior.
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Project description:Uterine contractions are important for various functions of the female reproductive cycle. Contractions are generated, in part, by electrical coupling of smooth muscle cells of the myometrium, the main muscle layer of the uterus. Aberrant myometrial electrical activity can lead to uterine dysfunction. To better understand and treat conditions associated with aberrant activity, it is crucial to understand the mechanisms that underlie normal activity. Here, we used microelectrode array (MEA) to simultaneously record and characterize myometrial electrical activities at high spatial and temporal resolution. Mouse myometrial longitudinal muscle tissue was isolated at different stages throughout the estrous cycle and placed on an 8×8 MEA. Electrical activity was recorded for 10 min at a sampling rate of 12.5 kHz. We used a spike-tracking algorithm to independently analyze each channel and developed a pipeline to quantify the amplitude, duration, frequency, and synchronicity of the electrical activities. Electrical activities in estrous were more synchronous, and had shorter duration, higher frequency, and lower amplitude than electrical activities in non-estrous. We conclude that MEA can be used to detect differential patterns of myometrial electrical activity in distinct estrous cycle stages. In the future, this methodology can be used to assess different physiological and pathological states and evaluate therapeutic agents that regulate uterine function.
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Project description:Comparison of Gene Expression in Uterine Smooth Muscle Tumors (including normal myometrium, benign uterine leiomyoma, malignant uterine and extra-uterine leiomyosarcoma. Total RNA was isolated with Trizol and converted to labeled cRNA by standard Affymetrix protocols. Before analysis, Avg Diff values were normalized to a sum of 3 million for each probe set on the chip and values less than 20 were adjusted to 20 to allow log scaling in subsequent analysis. Keywords: other
2004-01-01 | GSE764 | GEO
Project description:Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.
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Project description:The molecular mechanisms involved in uterine quiescence during gestation and those responsible for induction of labor are not completely known. Nitric oxide relaxes uterine smooth muscle in a manner disparate from that for other smooth muscles because global elevation of cGMP after activation of soluble guanylyl cyclase does not relax the muscle. S-Nitrosylation, the covalent addition of an nitric oxide (NO) group to a cysteine thiol is a likely mechanism to explain the ability of NO to relax myometrium. This work is the first to describe the myometrial S-nitrosylproteome in both pregnant and nonpregnant tissue states. Using the guinea pig model, we show that specific sets of proteins involved in contraction and relaxation are S-nitrosylated in laboring and nonlaboring muscle and that many of these proteins are uniquely S-nitrosylated in only one state of the tissue. In particular, we show that S-nitrosylation of the intermediate filament protein desmin is significantly increased (5.7-fold, p < 0.005) in pregnancy and that this increase cannot be attributed solely to the increase in protein expression (1.8-fold, p < 0.005) that accompanies pregnancy. Elucidation of the myometrial S-nitrosylproteome provides a list of mechanistically important proteins that can constitute the basis of hypotheses formed to explain the regulation of uterine contraction/relaxation.
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Project description:S-nitrosoproteome of human unterine smooth muscle in different states of pregnancy (Labor, non labor, and preterm labor). Samples were isolated by the biotin switch and streptavidin pulldown before being analyzed by MS/MS on an Orbitrap instrument. Database Searching and bioinformatics: Tandem mass spectra were extracted; charge state deconvolution and deisotoping were not performed. All MS/MS samples were analyzed using Sequest (Thermo Fisher Scientific, San Jose, CA, version v.27, rev. 11). Sequest was initiated to search the database containing ipi.HUMAN.v3.87, the Global Proteome Machine cRAP v.2012.01.01, and random decoy sequences (183158 entries) assuming the digestion enzyme trypsin. Sequest was searched with a fragment ion mass tolerance of 1.00 Da and a parent ion tolerance of 10 ppm. Oxidation of methionine, iodoacetamide derivative of cysteine, and n-ethylmaleimide on cysteine were specified in Sequest as variable modifications. Criteria for Protein Identification-PROTEOIQ (V2.6, www.nusep.com) was used to validate MS/MS based peptide and protein identifications. Peptides were parsed before analysis with a minimum Xcorr value of 1.5 and a minimum length of 6 amino acids. There were no matches to the concatenated decoy database and therefore a false discovery value is not applicable or "0". Peptide identifications were accepted if they could be established at greater than 95.0% probability as specified by the Peptide Prophet algorithm. Protein identifications were accepted if they could be established at greater than 95.0% probability and contained at least two identified peptides with 5 spectra per peptide. Protein probabilities were assigned by the Protein Prophet algorithm. Proteins that contained similar peptides and could not be differentiated based on MS/MS analysis alone were grouped to satisfy the principles of parsimony.
2014-03-02 | PXD000226 | Pride
Project description:The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III β-tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III β-tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III β-tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III β-tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III β-tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III β-tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III β-tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III β-tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.
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Project description:Mechanical strain associated with the expanding uterus correlates with increased preterm birth rates. Mechanical signals result in a cascading network of protein phosphorylation events. These signals direct cellular activities and may lead to changes in contractile phenotype and calcium signaling. In this study, the complete phospho-proteome of uterine smooth muscle cells subjected to mechanical strain for 5 min was compared to un-strained controls. Statistically significant, differential phosphorylation events were annotated by Ingenuity Pathway Analysis to elucidate mechanically induced phosphorylation networks. Mechanical strain leads to the direct activation of ERK1/2, HSPB1, and MYL9, in addition to phosphorylation of PAK2, vimentin, DOCK1, PPP1R12A, and PTPN11 at previously unannotated sites. These results suggest a novel network reaction to mechanical strain and reveal proteins that participate in the activation of contractile mechanisms leading to preterm labor.
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Project description:Comparison of Gene Expression in Uterine Smooth Muscle Tumors (including normal myometrium, benign uterine leiomyoma, malignant uterine and extra-uterine leiomyosarcoma). Total RNA was isolated with Trizol and converted to labeled cRNA by standard Affymetrix protocols. Before analysis, Avg Diff values were normalized to a sum of 3 million for each probe set on the chip and values less than 20 were adjusted to 20 to allow log scaling in subsequent analysis.
2007-09-25 | E-GEOD-764 | biostudies-arrayexpress
Project description:Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) represent a heterogeneous group of tumors that cannot be histologically diagnosed as unequivocally benign or malignant. For this reason, many authors are working to obtain a better definition of diagnostic and prognostic criteria. In this work, we analyzed the genomic and epigenomic profile of uterine smooth muscle tumors (USMTs) in order to find similarities and differences between STUMPs, leiomyosarcomas (LMSs) and leiomyomas (LMs), and possibly identify prognostic factors in this group of tumors. Array-CGH data on 23 USMTs demonstrated the presence of a more similar genomic profile between STUMPs and LMSs. Some genes, such as PRKDC and PUM2, with a potential prognostic value, were never previously associated with STUMP. The methylation data appears to be very promising, especially with regards to the divergent profile found in the sample that relapsed, characterized by an overall CGI hypomethylation. Finally, the Gene Ontology analysis highlighted some cancer genes that could play a pivotal role in the unexpected aggressive behavior that can be found in some of these tumors. These genes could prove to be prognostic markers in the future.
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