Impact of Musashi-1 and Musashi-2 Double Knockdown on Notch Signaling and the Pathogenesis of Endometriosis

Strauß, Theresa; Greve, Burkhard; Gabriel, Michael; Achmad, Nurjannah; Schwan, Dhanusha; Espinoza-Sánchez, Nancy Adriana; Laganà, Antonio Simone; Kiesel, L.; Poutanen, Matti; Götte, Martin; Schäfer, Sebastian D.

doi:10.3390/ijms23052851

Cited by 16 publications

(11 citation statements)

References 42 publications

(86 reference statements)

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“…It is in agreement with (and extends beyond) the limited number of previous studies evaluating the role of Musashi-1 in endometrial cancer: Previous work showed that Musashi-1 is overexpressed in endometrial cancer [16] and high expression is prognostically unfavorable [18]. Msi-1 has also been demonstrated to be overexpressed in endometrial stem cells [35] and to be associated with stem cell pathways both in endometrial cancer [17] and endometriosis [67]. Finally, Musashi-1 has been identified as a potential therapeutic target in other malignancies, including breast cancer [15] and glioblastoma [68] and here, we report an in-depth evaluation of its targeting in endometrial cancer.…”

Section: Discussionsupporting

confidence: 90%

Knockdown of the stem cell marker Musashi-1 inhibits endometrial cancer growth and sensitizes cells to radiation

et al. 2022

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Background Endometrial carcinoma is the most common gynecological cancer in Europe. Musashi-1 is known to be a key regulator of endometrial cancer stem cells and a negative prognostic marker. In the present study, we aimed to understand growth and gene expression patterns in endometrial carcinoma after Musashi-1 knockdown in vitro and in vivo. Changes in therapeutic resistance were also assessed. Methods First, we performed analyses to understand Musashi-1 expression patterns using The Cancer Genome Atlas database. We then proceeded to assess effects of small interfering RNA-based Musashi-1 targeting in two endometrial carcinoma cell lines, Ishikawa and KLE. After quantifying baseline changes in cell metabolism, we used MTT tests to assess chemotherapy effects and colony formation assays to understand changes in radioresistance. For mechanistic study, we used quantitative polymerase chain reaction (qPCR) and western blotting of key Musashi-1 target genes and compared results to primary tissue database studies. Finally, xenograft experiments in a mouse model helped understand in vivo effects of Musashi-1 knockdown. Results Musashi-1 is aberrantly expressed in primary tumor tissues. In vitro, silencing of Musashi-1 resulted in a strong decline in cell proliferation and radioresistance, while chemoresistance remained unchanged. Loss of Musashi-1 led to downregulation of telomerase, DNA-dependent protein kinase, the Notch pathway and overexpression of cyclin-dependent kinase inhibitor p21, the latter of which we identified as a key mediator of Msi-1 knockdown-related anti-proliferative signaling. In vivo, the anti-proliferative effect was confirmed, with Msi-1 knockdown tumors being about 40% reduced in size. Conclusions Musashi-1 knockdown resulted in a strong decrease in endometrial cancer proliferation and a loss of radioresistance, suggesting therapeutic potential.

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Section: Discussionsupporting

confidence: 90%

Knockdown of the stem cell marker Musashi-1 inhibits endometrial cancer growth and sensitizes cells to radiation

et al. 2022

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“…Filipchiuk et al found increased expression of the BIRC5 gene in the peripheral blood of women with endometriosis, indicating a role in cell proliferation and anti‐apoptotic activity in the development of the disease 58 . Besides, Strauß et al demonstrated that stem cell marker and RNA‐binding protein Musashi‐1 have an impact on Notch signaling and the pathogenesis of endometriosis through the downregulation of proliferation, stemness characteristics and the upregulation of apoptosis 59 . These previous studies and our study consistently reveal critical roles for dysregulated proliferation and apoptosis in the pathogenesis of endometriosis.…”

Section: Discussionmentioning

confidence: 99%

GRIK1‐AS1 deficiency accelerates endometriosis progression by boosting DNMT1‐dependent SFRP1 promoter methylation in endometrial stromal cells

Liu

Wang

et al. 2023

The Journal of Gene Medicine

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BackgroundEndometriosis, a gynecological disease that affects up to 10% of women, is a major cause of pain and infertility. Deregulation of the epigenome is accountable for the onset and progression of endometriosis, although its exact mechanism is unknown. The purpose of the current study is to examine the role of the long non‐coding RNA (lncRNA) GRIK1‐AS1 in the epigenetic regulation of endometrial stromal cell proliferation and the development of endometriosis.MethodsEndometriosis datasets were screened to identify GRIKI‐AS1 as dramatically declining in endometriosis. Gain or loss of function endometrial stromal cell (ESC) models were established. The anti‐proliferation phenotype was investigated using in vitro and in vivo experiments. Epigenetic regulatory network analyses were conducted to suggest the intrinsic molecular mechanism.ResultsWith bioinformatic and clinical data, we observed that GRIK1‐AS1 and SFRP1 were expressed at low levels in endometriosis. Overexpressed GRIK1‐AS1 inhibited ESC proliferation, while SFRP1 knockdown rescued the antiproliferative ability of GRIK1‐AS1. Specifically, methylation‐dependent expression inhibition of SFRP1 was revealed in ESCs. Mechanistically, GRIK1‐AS1 hampers the occupancy of DNMT1 in SRFP1 promoter, leading to hypomethylation of SFRP1 and upregulated SFRP1 expression, thereby potentially suppressing Wnt signaling and its adverse proliferative effect. Therapeutically, lentivirus‐mediated upregulation of GRIK1‐AS1 inhibited endometriosis disease progression in vivo.ConclusionsOur study is a proof‐of‐concept demonstration for GRIKI‐AS1‐associated endometriosis pathogenesis and highlights a potential intervention target.

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“…According to retrograde menstruation theory, to develop endometriosis, live endometrial cells migrate through the fallopian tubes and are implanted on the surface of the pelvic cavity [6, 43], indicating that the ability of endometrial cell migration and invasion is also important for the establishment of ectopic lesions. The ability of migration and invasion, which is being studied in endometriosis by many studies, is also the biological behavior of endometriotic cells, which is similar to malignant cells [44, 45]. Therefore, in this study, in addition to the effect of BIBR1532 on cell proliferation, its effects on cell migration and invasion were also tested.…”

Section: Discussionmentioning

confidence: 99%

BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling

Zhao

Luo

Liu

et al. 2023

Gynecol Obstet Invest

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Objectives: The effect of telomerase inhibitor BIBR1532 on endometriotic cells was investigated to explore the inhibitory effect of targeting telomerase on endometriosis. Design: In vitro primary cell culture study. Participants/Materials: Primary endometrial cells derived from eutopic and ectopic endometrium in patients with endometriosis. Setting: The study was conducted in the university hospital. Methods: Paired eutopic and ectopic endometrial cells were collected from 6 patients from January 2018 to July 2021. A TRAP assay was performed to detect the telomerase activity of the cells. MTT, cell cycle, apoptosis, migration, and invasion assays were performed to study the inhibitory effect of BIBR1532. Enrichment analysis was performed to identify the key pathways involved in endometriosis progression and telomerase action. Then, Western blotting was used to investigate the expression of related proteins. Results: BIBR1532 treatment significantly inhibited the growth of eutopic and ectopic endometrial cells, with apoptosis and cell cycle signaling involved. Migration and invasion, important characteristics for the establishment of ectopic lesions, were also inhibited by BIBR1532. The MAPK signaling cascade, related to telomerase and endometriosis, was decreased in eutopic and ectopic endometrial stromal cells with the treatment of BIBR1532. Limitations: The severe side effects of telomerase inhibitors might be the main obstacle to clinical application, so it is necessary to find better drug delivery methods in vivo. Conclusions: The telomerase inhibitor BIBR1532 affects endometrial cell proliferation, migration, and invasion in endometriosis.

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Impact of Musashi-1 and Musashi-2 Double Knockdown on Notch Signaling and the Pathogenesis of Endometriosis

Cited by 16 publications

References 42 publications

Knockdown of the stem cell marker Musashi-1 inhibits endometrial cancer growth and sensitizes cells to radiation

Knockdown of the stem cell marker Musashi-1 inhibits endometrial cancer growth and sensitizes cells to radiation

GRIK1‐AS1 deficiency accelerates endometriosis progression by boosting DNMT1‐dependent SFRP1 promoter methylation in endometrial stromal cells

BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling

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