Extracellular Matrix (ECM) Activates β-catenin Signaling in Uterine Fibroids

Ko, Yi-An; Jamaluddin, M Fairuz B; Adebayo, Mariam Folashade; Bajwa, Preety; Scott, Rodney J.; Dharmarajan, Arun; Nahar, Pravin; Tanwar, Pradeep S.

doi:10.1530/rep-17-0339

Cited by 34 publications

(46 citation statements)

References 29 publications

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“…Cyclin D1 protein expression was also increased in MF and F when compared to M (Figure 5B), supporting the results from RNA-seq analysis. Since CCND1 was the only overlapping gene in all three comparisons, we investigated upstream pathways of CCND1, including the WNT signaling pathway, components of which have been shown to be upregulated in fibroid tissues [26][27][28]. Transcriptomic analysis found overrepresentation of the WNT pathway in F vs. MF only (FDR p-value = 0.003) (Figure S3), but the mitogen-activated protein kinase (MAPK) pathway, which is also upstream of CCND1, was upregulated in F and MF tissues when compared to M (FDR p-value < 0.01) (Figure S4).…”

Section: Overall Comparison Of Myometrial Samples From Non-fibroid Patients (M) Myometrial Samples From Fibroid Patients (Mf) and Fibroidmentioning

confidence: 99%

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-Diseased Myometrium

Paul

Burns

Carpenter

et al. 2021

IJMS

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Uterine fibroid tissues are often compared to their matched myometrium in an effort to understand their pathophysiology, but it is not clear whether the myometria of uterine fibroid patients represent truly non-disease control tissues. We analyzed the transcriptomes of myometrial samples from non-fibroid patients (M) and compared them with fibroid (F) and matched myometrial (MF) samples to determine whether there is a phenotypic difference between fibroid and non-fibroid myometria. Multidimensional scaling plots revealed that M samples clustered separately from both MF and F samples. A total of 1169 differentially expressed genes (DEGs) (false discovery rate < 0.05) were observed in the MF comparison with M. Overrepresented Gene Ontology terms showed a high concordance of upregulated gene sets in MF compared to M, particularly extracellular matrix and structure organization. Gene set enrichment analyses showed that the leading-edge genes from the TGFβ signaling and inflammatory response gene sets were significantly enriched in MF. Overall comparison of the three tissues by three-dimensional principal component analyses showed that M, MF, and F samples clustered separately from each other and that a total of 732 DEGs from F vs. M were not found in the F vs. MF, which are likely understudied in the pathogenesis of uterine fibroids and could be key genes for future investigation. These results suggest that the transcriptome of fibroid-associated myometrium is different from that of non-diseased myometrium and that fibroid studies should consider using both matched myometrium and non-diseased myometrium as controls.

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Section: Overall Comparison Of Myometrial Samples From Non-fibroid Patients (M) Myometrial Samples From Fibroid Patients (Mf) and Fibroidmentioning

confidence: 99%

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-Diseased Myometrium

Paul

Burns

Carpenter

et al. 2021

IJMS

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“…Catenin is directly activated in leiomyoma. 37,38 Other molecules related to Adherens junctions are cadherins, which are involved in homotypic adhesion between cells, and integrins, which mediate adhesion between cells and the ECM. Cadherins regulate integrin activation and matrix assembly; the integrinecadherin cross-talk contributes to the spatial organization of signaling components and forces within cells and coordinates cell movement ( Figure 4B).…”

Section: B-mentioning

confidence: 99%

From 2646 to 15: differentially regulated microRNAs between progenitors from normal myometrium and leiomyoma

Lazzarini

Caffarini

Carpini

et al. 2020

American Journal of Obstetrics and Gynecology

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BACKGROUND: Uterine leiomyomas (fibroids) are smooth muscle neoplasms of the myometrial layer of the uterus and are the most common benign tumors in women. Although their etiology is still unclear, progenitor cells seem to be implicated. OBJECTIVE: To identify the dysregulated pathways involved in leiomyoma onset by microRNA profiling of progenitor cells isolated from normal myometrium and leiomyoma tissue. MATERIALS AND METHODS: Pairs of normal myometrium and uterine fibroid specimens were collected from 12 myomectomy patients. Myometrial progenitor cells and leiomyoma progenitor cells were isolated and characterized for stemness. After total RNA extraction and profiling of their 2646 microRNAs, DIANA-miRPath analysis was applied to find any dysregulated pathways. RESULTS: Only 30 microRNAs showed a significant differential regulation between myometrial progenitor cells and leiomyoma progenitor cells. Removal of those that had values close to the cutoff or that were not consistent among triplicates left 15 microRNAs, of which 7 were downregulated and 8 were upregulated in leiomyoma progenitor cells compared to myometrial progenitor cells. According to DIANA-miRPath analysis, the 7 downregulated microRNAs (hsa-miR-146b-5p; hsa-miR-335-3p; hsa-miR-335-5p; hsa-miR-135b-5p; hsa-miR-10a-3p; hsa-miR-10a-5p; hsa-miR-200a-3p) are all related to 3 pathways, "ECM-receptor interaction" (33 targeted genes), "Adherens junction" (33 targeted genes), and "Hippo signaling" (69 targeted genes), whereas the 8 upregulated miRNAs (hsa-miR-146a-5p; hsa-miR-576-3p; hsa-miR-122-5p; hsa-miR-1246; hsa-miR-595; hsa-miR-658; hsa-miR-4284; hsa-miR-924) are related to 4 pathways, "PI3K-Akt signaling pathway" (71 targeted genes), "Pathways in Cancer" (80 targeted genes), "Cell Cycle" (37 targeted genes), and "Regulation of actin cytoskeleton" (41 targeted genes). CONCLUSION: The findings that only 15 of 2646 microRNAs are differentially regulated in normal myometrium and leiomyoma and that they are involved in 7 dysregulated pathways provides interesting insights into the development of uterine fibroids, and lends support to the hypothesis that leiomyoma onset is the result of alterations affecting progenitor cells.

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“…Previous studies have demonstrated that α-SMA is elevated in leiomyoma compared to myometrium [47]. In addition, several studies have reported that β-catenin expression was increased in UF compared to the adjacent myometrium tissue [48], which is associated with proliferation and ECM formation [49]. A recent study has shown that an increase in ECM stiffness triggers upregulation of β-catenin in UF cells [48].…”

Section: Discussionmentioning

confidence: 99%

Natural Antioxidant Resveratrol Suppresses Uterine Fibroid Cell Growth and Extracellular Matrix Formation In Vitro and In Vivo

et al. 2019

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Resveratrol (RSV) is a polyphenolic phytoalexin found in peanuts, grapes, and other plants. Uterine fibroids (UF) are benign growths that are enriched in extracellular matrix (ECM) proteins. In this study, we aimed to investigate the effects of RSV on UF using in vivo and in vitro approaches. In mouse xenograft models, tumors were implanted through the subcutaneous injection of Eker rat-derived uterine leiomyoma cells transfected with luciferase (ELT-3-LUC) in five-week-old female nude (Foxn1nu) mice. When the tumors reached a size of 50–100 mm3, the mice were randomly assigned to intraperitoneal treatment with RSV (10 mg·kg−1) or vehicle control (dimethyl sulfoxide). Tumor tissues were assayed using an immunohistochemistry analysis. We also used primary human leiomyoma cells as in vitro models. Cell viability was determined using the sodium bicarbonate and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression was assayed using Western blot analysis. The messenger ribonucleic acid (mRNA) expression was assayed using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Cell apoptosis was assayed using Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) and Hoechst 33342 staining. RSV significantly suppressed tumor growth in vivo and decreased the proportion of cells showing expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA). In addition, RSV decreased the protein expression of PCNA, fibronectin, and upregulated the ratio of Bax (Bcl-2-associated X) and Bcl-2 (B-cell lymphoma/leukemia 2) in vivo. Furthermore, RSV reduced leiomyoma cell viability, and decreased the mRNA levels of fibronectin and the protein expression of collagen type 1 (COL1A1) and α-SMA (ECM protein marker), as well as reducing the levels of β-catenin protein. RSV induced apoptosis and cell cycle arrest at sub-G1 phase. Our findings indicated the inhibitory effects of RSV on the ELT-3-LUC xenograft model and indicated that RSV reduced ECM-related protein expression in primary human leiomyoma cells, demonstrating its potential as an anti-fibrotic therapy for UF.

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Extracellular Matrix (ECM) Activates β-catenin Signaling in Uterine Fibroids

Cited by 34 publications

References 29 publications

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-Diseased Myometrium

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-Diseased Myometrium

From 2646 to 15: differentially regulated microRNAs between progenitors from normal myometrium and leiomyoma

Natural Antioxidant Resveratrol Suppresses Uterine Fibroid Cell Growth and Extracellular Matrix Formation In Vitro and In Vivo

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