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The in vivo effects of knockdown of long non-coding RNA XIST on fibroid growth and gene expression.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Nov 15; Vol. 38 (21), pp. e70140. - Publication Year :
- 2024
-
Abstract
- The role of long non-coding RNAs in fibroid pathogenesis remains largely unexplored. In a previous study, we found elevated XIST (X-inactive specific transcript) levels in fibroids, which sponged miR-29c and miR-200c, leading to the overexpression of their target genes. This study aimed to assess the therapeutic potential of XIST downregulation in fibroid treatment. Ovariectomized SCID (severe combined immunodeficiency) mice were implanted with fibroid tumors transduced with XIST siRNA or a control via lentivirus. After 1 month, animals were sacrificed and the xenografts were removed for further analysis. XIST knockdown reduced tumor weight by 15% and increased miR-29c and miR-200c expression by 3.9-fold and 2.2-fold, respectively. The mRNA expression of miR-29c targets (COL3A1, TGF-β3, CDK2, SPARC) and miR-200c targets (CDK2, FN1, TDO2), as well as PRL, E2F1, and EZH2, was significantly decreased. Protein abundance of collagen, COL3A1, FN1, CDK2, SPARC, and EZH2 was also reduced. IHC analysis of xenograft sections using the markers of Ki67 for cell proliferation and cleaved caspase 3 for apoptosis showed decreased cell proliferation and no changes in apoptosis in the XIST knockdown xenografts. This analysis also revealed decreased collagen and E2F1 staining nuclei in the XIST knockdown xenografts. These results indicate that downregulation of XIST in fibroids has beneficial therapeutic effects, by reducing tumor growth and the expression of genes involved in cell proliferation, inflammation, and extracellular matrix regulation.<br /> (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Subjects :
- Animals
Female
Mice
Humans
Mice, SCID
Cell Proliferation
Gene Knockdown Techniques
Uterine Neoplasms genetics
Uterine Neoplasms metabolism
Uterine Neoplasms pathology
Cell Line, Tumor
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
Leiomyoma genetics
Leiomyoma metabolism
Leiomyoma pathology
MicroRNAs genetics
MicroRNAs metabolism
Gene Expression Regulation, Neoplastic
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 38
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 39475327
- Full Text :
- https://doi.org/10.1096/fj.202401982R