Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells

Fenu, Grazia; Griñán-Lisón, Carmen; Etzi, Federica; González-Titos, Aitor; Pisano, Andrea; Toledo, Belén; Farace, Cristiano; Sabalic, Angela; Carrillo, Esmeralda; Marchal, Juan Antonio; Madeddu, Roberto

doi:10.3390/ijms26072830

Open AccessArticle

Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells

by

Grazia Fenu

^1,†

,

Carmen Griñán-Lisón

^{2,3,4,5,*,†}

,

Federica Etzi

¹

,

Aitor González-Titos

^4,5,6,7,

Andrea Pisano

^1,*

,

Belén Toledo

^4,5,

Cristiano Farace

¹

,

Angela Sabalic

¹

,

Esmeralda Carrillo

^4,5,6

,

Juan Antonio Marchal

^4,5,6,‡

and

Roberto Madeddu

^1,8,9,‡

¹

Department of Biomedical Science, University of Sassari, 07100 Sassari, Italy

²

Department of Biochemistry and Molecular Biology 2, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain

³

Centre for Genomics and Oncological Research, GENYO, Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain

⁴

Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100 Granada, Spain

⁵

Excellence Research Unit “Modeling Nature” (MNat), University of Granada, 18100 Granada, Spain

⁶

Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain

⁷

Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, 18016 Granada, Spain

⁸

National Institute of Biostructures and Biosystems, 00136 Rome, Italy

⁹

International Society for Research on Cadmium and Trace Element Toxicity, 07100 Sassari, Italy

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

These authors also contributed equally to this work as last authors.

Int. J. Mol. Sci. 2025, 26(7), 2830; https://doi.org/10.3390/ijms26072830

Submission received: 25 January 2025 / Revised: 3 March 2025 / Accepted: 16 March 2025 / Published: 21 March 2025

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases: 2nd Edition)

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Its poor prognosis is closely related to late-stage diagnosis, which results from both nonspecific symptoms and the absence of biomarkers for early diagnosis. MicroRNAs (miRNAs) exert a regulatory role in numerous biological processes and their aberrant expression has been found in a broad spectrum of diseases, including cancer. Cancer stem cells (CSCs) represent a driving force for PDAC initiation, progression, and metastatic spread. Our previous research highlighted the interesting behavior of miR-216a-5p and miR-125a-5p related to PDAC progression and the CSC phenotype. The present study aimed to evaluate the effect of miR-216a-5p and miR-125a-5p on the acquisition or suppression of pancreatic CSC traits. BxPC-3, AsPC-1 cell lines, and their CSC-like models were transfected with miR-216a-5p and miR-125a-5p mimics and inhibitors. Following transfection, we evaluated their impact on the expression of CSC surface markers (CD44/CD24/CxCR4), ALDH1 activity, pluripotency- and EMT-related gene expression, and clonogenic potential. Our results show that miR-216a-5p enhances the expression of CD44/CD24/CxCR4 while negatively affecting the activity of ALDH1 and the expression of EMT genes. MiR-216a-5p positively influenced the clonogenic property. MiR-125a-5p promoted the expression of CD44/CD24/CxCR4 while inhibiting ALDH1 activity. It enhanced the expression of Snail, Oct-4, and Sox-2, while the clonogenic potential appeared to be affected. Comprehensively, our results provide further knowledge on the role of miRNAs in pancreatic CSCs. Moreover, they corroborate our previous findings about miR-216a-5p’s potential dual role and miR-125a-5p’s promotive function in PDAC.

Keywords: PDAC; CSC; miRNA; functional study; miR-216a-5p; miR-125a-5p; miRNA regulation

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MDPI and ACS Style

Fenu, G.; Griñán-Lisón, C.; Etzi, F.; González-Titos, A.; Pisano, A.; Toledo, B.; Farace, C.; Sabalic, A.; Carrillo, E.; Marchal, J.A.; et al. Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells. Int. J. Mol. Sci. 2025, 26, 2830. https://doi.org/10.3390/ijms26072830

AMA Style

Fenu G, Griñán-Lisón C, Etzi F, González-Titos A, Pisano A, Toledo B, Farace C, Sabalic A, Carrillo E, Marchal JA, et al. Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells. International Journal of Molecular Sciences. 2025; 26(7):2830. https://doi.org/10.3390/ijms26072830

Chicago/Turabian Style

Fenu, Grazia, Carmen Griñán-Lisón, Federica Etzi, Aitor González-Titos, Andrea Pisano, Belén Toledo, Cristiano Farace, Angela Sabalic, Esmeralda Carrillo, Juan Antonio Marchal, and et al. 2025. "Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells" International Journal of Molecular Sciences 26, no. 7: 2830. https://doi.org/10.3390/ijms26072830

APA Style

Fenu, G., Griñán-Lisón, C., Etzi, F., González-Titos, A., Pisano, A., Toledo, B., Farace, C., Sabalic, A., Carrillo, E., Marchal, J. A., & Madeddu, R. (2025). Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells. International Journal of Molecular Sciences, 26(7), 2830. https://doi.org/10.3390/ijms26072830

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Functional Characterization of miR-216a-5p and miR-125a-5p on Pancreatic Cancer Stem Cells

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