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oai:recercat.cat:10459.1/4690052025-11-17T19:20:08Zcom_2072_3622col_2072_479130

2025-11-17T19:20:08Z urn:hdl:10459.1/469005 Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503 Vidal Sabanés, Maria Bonifaci, Núria Navaridas, Raúl Egea Navarro, Joaquim Encinas Martín, Mario Rodriguez-Barrueco, Ruth Silva, Jose M. Matias-Guiu, Xavier Llobet Navas, David Dolcet Roca, Xavier 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. 2025-11-17T19:20:08Z 2025-11-17T19:20:08Z 2025-10 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/10459.1/469005 Reproducció del document publicat a: https://doi.org/10.1038/s41419-025-08022-z Cell Death & Disease, 2025, vol. 16, núm. 1, 705 cc-by, (c) Maria Vidal Sabanés et al., 2025 Attribution 4.0 International info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/ Springer Nature