MicroRNA-371–373 cluster extracellular vesicle-based communication in testicular germ cell tumors

Authors and Affiliations:

Nuno Tiago Tavares^1,2, Catarina Lourenço^1,2,3, Vera Constâncio^1,2, Fernanda Fernandes-Pontes¹, Diana Fonseca¹, Rui Silva-Santos⁴, Isaac Braga⁵, Joaquina Maurício⁶, Rui Henrique^1,4,7, Michelle Liu⁸, Robert S. Weiss⁸, Aditya Bagrodia⁹, Carmen Jerónimo^1,7, João Lobo^1,4,7

1 - Cancer Biology and Epigenetics Group, Research Center of IPO Porto CI-IPOP/CI-IPOP@RISE-Associate Laboratory, Portuguese Oncology Institute of Porto IPO Porto, Porto Comprehensive Cancer Center Raquel Seruca Porto.CCC Raquel Seruca- 4200-072 Porto, Portugal.

2 - Doctoral Programme in Biomedical Sciences, ICBAS-School of Medicine and Biomedical Sciences- University of Porto, 4050-313 Porto, Portugal.

3 - i3S-Instituto de Investigação e Inovação em Saúde- Universidade do Porto- 4200-135 Porto- Portugal, Instituto Nacional de Engenharia Biomédica, Portugal, Portugal.

4 - Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto) 4200-072 Porto, Portugal.

5 – Urology Clinic, Department of Medical Oncology, Portuguese Oncology Institute of Porto IPO Porto- 4200-072 Porto, Portugal.

6 – Urology Clinic, Department of Urology, Portuguese Oncology Institute of Porto IPO Porto- 4200-072 Porto, Portugal.

7 - Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences - University of Porto (ICBAS-UP), 4050-313 Porto- Portugal.

8 - Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

9 - Department of Urology, University of California San Diego, San Diego – CA – USA.

Abstract:

Testicular germ cell tumors (TGCTs) represent the most common type of cancer in young adults. The cluster of microRNAs 371–373 is highly upregulated in TGCTs, and detection of miR-371a-3p specifically is currently being developed for clinical implementation as a sensitive and specific biomarker for TGCT, except for teratoma. Extracellular vesicles (EVs) are nano-sized particles used for cell communication, being increasingly regarded as potential sources of cancer biomarkers. Thus, the aim of this study was to characterize EVs from a wide range of TGCT samples, including cell lines, tissue explants and matched plasma samples from patients and healthy donors, and then use these samples to assess microRNA expression (miR-371–373 cluster and let-7e). TGCT-derived EVs were successfully isolated and characterized according to MISEV guidelines. TGCT cell lines showed different levels of EV-derived miR-371–373 cluster and let-7e. Upon differentiation of NT2 cells with ATRA, both cellular and EV-derived miR-371–373 cluster were downregulated, whereas let-7e was upregulated. TGCT patient samples presented high levels of EV-derived miR-371–373, except for the teratoma samples. We conclude that a significant portion of the circulating miR-371–373 cluster used as a TGCT biomarker in the clinic is secreted into EVs, and that this cluster and the let-7 family of microRNAs may be related with TGCT intercellular communication and differentiation.

Journal: Cell Communication and Signaling

Link: https://biosignaling.biomedcentral.com/articles/10.1186/s12964-025-02250-8