Downregulation of the Integrin α&lt;sub&gt;&lt;i&gt;v&lt;/i&gt;&lt;/sub&gt; Signaling Pathway in Uterine Leiomyomas

Tsai, Feng-Chou; Liu, Weimin; Pai, Man Hui; Hsieh, Mao Chih; Lin, Jui Yu; Chou, Cheng‐Yang

doi:10.1159/000320784

Cited by 8 publications

(8 citation statements)

References 57 publications

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“…This enzyme catalyzes the posttranslational formation of 4‐hydroxyproline in ‐Xaa‐Pro‐Gly‐ sequences in collagens and excessive collagen production is a hallmark of fibrotic conditions including uterine fibroids. Three integrins (ITGA3, ITGA7, and ITGB1) are downregulated in myoma that is consistent with independent earlier findings on integrin alpha signaling in this disease . Similarly, as noted before , we observe a clear reduction in the levels of Retinal dehydrogenase 1, (ALDH1A1) the enzyme producing the low molecular weight molecule retinoic acid that regulates the transcription of a number of developmental genes, possibly also in leiomyoma.…”

Section: Resultssupporting

confidence: 92%

Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention

Lemeer

Gholami

et al. 2014

Proteomics

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Uterine leiomyomas are benign tumors affecting a large proportion of the female population. Despite the very high prevalence, the molecular basis for understanding the onset and development of the disease are still poorly understood. In this study, we profiled the proteomes and kinomes of leiomyoma as well as myometrium samples from patients to a depth of >7000 proteins including 200 kinases. Statistical analysis identified a number of molecular signatures distinguishing healthy from diseased tissue. Among these, nine kinases (ADCK4, CDK5, CSNK2B, DDR1, EPHB1, MAP2K2, PRKCB, PRKG1, and RPS6KA5) representing a number of cellular signaling pathways showed particularly strong discrimination potential. Preliminary statistical analysis by receiver operator characteristics plots revealed very good performance for individual kinases (area under the curve, AUC of 0.70-0.94) as well as binary combinations thereof (AUC 0.70-1.00) that might be used to assess the activity of signaling pathways in myomas. Of note, the receptor tyrosine kinase DDR1 holds future potential as a drug target owing to its strong links to collagen signaling and the excessive formation of extracellular matrix typical for leiomyomas in humans.

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Section: Resultssupporting

confidence: 92%

Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention

Lemeer

Gholami

et al. 2014

Proteomics

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“…No significant difference was observed in the expression of these pro-survival factors between UL and MM. Similar pAkt expression in UL and normal myometrial tissue has been reported by other researchers222324. Further, pAkt expression was low or absent in a large number of leiomyoma samples (73%) in our study, a finding supported by another study25.…”

Section: Discussionsupporting

confidence: 93%

PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas

Makker¹,

Goel²,

Mahdi³

et al. 2016

Indian J Med Res

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Background & objectives:Despite their high occurrence and associated significant level of morbidity manifesting as spectrum of clinical symptoms, the pathogenesis of uterine leiomyomas (ULs) remains unclear. We investigated expression profile of tumour suppressor genes PTEN (phosphatase and tensin homolog deleted on chromosome ten) and LKB1 (liver kinase B1), and key signaling components of P13K (phosphatidylinositol 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in leiomyomas and adjacent normal myometrium in women of reproductive age, to explore the possibility of targeting this pathway for future therapeutic implications.Methods:Real time PCR (qPCR) was used to quantify relative gene expression levels of PTEN, Akt1, Akt2, mTOR, LKB1 and VEGFA (vascular endothelial growth factor A) in leiomyoma as compared to adjacent normal myometrium. Immunohistochemistry was subsequently performed to analyze expression of PTEN, phospho-Akt, phospho-mTOR, phospho-S6, LKB1 and VEGFA in leiomyoma and adjacent normal myometrium.Results:Significant upregulation of PTEN (2.52 fold; P=0.03) and LKB1 (3.93 fold; P=0.01), and downregulation of VEGFA (2.95 fold; P=0.01) genes were observed in leiomyoma as compared to normal myometrium. Transcript levels of Akt1, Akt2 and mTOR did not vary significantly between leiomyoma and myometrium. An increased immunoexpression of PTEN (P=0.015) and LKB1 (P<0.001) and decreased expression of VEGFA (P=0.01) was observed in leiomyoma as compared to myometrium. Immunostaining for activated (phosphorylated) Akt, mTOR and S6 was absent or low in majority of leiomyoma and myometrium.Interpretation & conclusions:Upregulation of PTEN and LKB1 in concert with negative or low levels of activated Akt, mTOR and S6 indicates that PI3K/Akt/mTOR pathway may not play a significant role in pathogenesis of leiomyoma.

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“…Evidence for the interaction between serotonin (5-hydroxytryptamine, 5-HT) and thyroid hormones originates mostly from the experimentally induced hypothyroid state in animals [3]. Decreased 5-HT [7, 8] and increased 5-hydroxyinoleacetic acid [9] concentrations were observed in neonatal and adult hypothyroid rats, suggesting an increased 5-HT turnover [7, 10], while T 3 administration to hypothyroid animals normalized 5-HT turnover to normal values [10]. …”

Section: Introductionmentioning

confidence: 99%

Platelet Serotonin Concentration and Monoamine Oxidase Activity in Hypothyroid Patients

Stipčević

Kusačić-Kuna²,

Deželjin

et al. 2009

Horm Res Paediatr

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Background/Aim: The relationship between the hypothalamic-pituitary-thyroid (HPT) axis and the serotonergic (5-hydroxytryptamine, 5-HT) system is not clear. The aim of the study was to determine platelet biochemical markers (5-HT concentration and monoamine oxidase B, MAO-B, activity) in hypothyroid patients. Methods: The study included 25 medication-free female hypothyroid patients in postoperative follow-up after total thyroidectomy due to papillary thyroid carcinoma, who had not been treated with synthetic thyroxine (T₄) for 4 weeks, and 44 age-matched euthyroid healthy women. The platelet 5-HT concentration, platelet MAO-B activity, total T₄ and thyroid-stimulating hormone (TSH) levels were determined using spectrofluorimetric methods, radioimmunoassay and fluoroimmunoassay, respectively. Results: Hypothyroid patients had significantly higher TSH, significantly lower T₄ levels and platelet 5-HT concentrations, and unchanged platelet MAO-B activity than healthy subjects. A positive correlation was found between the 5-HT concentration and platelet MAO-B activity, and between the platelet MAO-B activity and T₄ in control subjects. Conclusions: Reduced platelet 5-HT concentrations in hypothyroid patients suggests a complex interaction between the 5-HT system and HPT axis activity, which could be related to the frequent occurrence of depressive symptoms in hypothyroid patients. The determination of platelet 5-HT concentrations should be considered a diagnostic tool for the evaluation of depressive symptoms in hypothyroid patients during the hormone withdrawal procedure.

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Downregulation of the Integrin α<sub><i>v</i></sub> Signaling Pathway in Uterine Leiomyomas

Cited by 8 publications

References 57 publications

Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention

Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention

PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas

Platelet Serotonin Concentration and Monoamine Oxidase Activity in Hypothyroid Patients

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