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Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503
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Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503
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Journal Article
Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503
2025
Overview
Endometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGFβ-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the upregulation of several miRNAs caused by PTEN deficiency and/or TGFβ stimulation. The miR-424(322)
~
503 cluster drew our attention due to its involvement in regulating apoptosis and proliferation. However, miR-424(322)
~
503 cluster has a paradoxical role in cancer, exhibiting either oncogenic and tumor suppressive functions depending on cell type or context. To ascertain the function of miR-424(322)
~
503 in endometrial carcinogenesis caused by PTEN deficiency, we generated a double Pten/miR-424(322)
~
503 knock-out mice. We demonstrate that loss of miR-424(322)
~
503 impairs proliferation of both wild type or
Pten
deficient endometrial organoids by interfering with growth factor and PI3K/AKT signaling. Furthermore, the absence of miR-424(322)
~
503 restores TGFβ-induced apoptosis, which is otherwise compromised by PTEN deficiency. In vivo,
Pten
/miR-424(322)
~
503 knock-out mice exhibit reduced endometrial cancer progression compared to
Pten
deficient mice through a cell-autonomous mechanism.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
1-Phosphatidylinositol 3-kinase
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/ 96/95
/ Animals
/ Biomedical and Life Sciences
/ Endometrial Neoplasms - genetics
/ Endometrial Neoplasms - metabolism
/ Endometrial Neoplasms - pathology
/ Female
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Mice
/ miRNA
/ Mutation
/ PTEN Phosphohydrolase - genetics
/ PTEN Phosphohydrolase - metabolism
/ Transforming Growth Factor beta - metabolism
/ Tumors
