Testicular germ cell tumours (TGCTs) are the most common malignancy in young men. Originating from foetal testicular germ cells that fail to differentiate correctly, TGCTs appear after puberty as germ cell neoplasia in situ cells that transform through unknown mechanisms into distinct seminoma and non-seminoma tumour types. A balance between activin and BMP signalling may influence TGCT emergence and progression, and we investigated this using human cell line models of seminoma (TCam-2) and non-seminoma (NT2/D1). Activin A- and BMP4-regulated transcripts measured at 6 h post-treatment by RNA-sequencing revealed fewer altered transcripts in TCam-2 cells but a greater responsiveness to activin A, while BMP4 altered more transcripts in NT2/D1 cells. Activin significantly elevated transcripts linked to pluripotency, cancer, TGF-β, Notch, p53, and Hippo signalling in both lines, whereas BMP4 altered TGF-β, pluripotency, Hippo and Wnt signalling components. Dose-dependent antagonism of BMP4 signalling by activin A in TCam-2 cells demonstrated signalling crosstalk between these two TGF-β superfamily arms. Levels of the nuclear transport protein, IPO5, implicated in BMP4 and WNT signalling, are highly regulated in the foetal mouse germline. IPO5 knockdown in TCam-2 cells using siRNA blunted BMP4-induced transcript changes, indicating that IPO5 levels could determine TGF-β signalling pathway outcomes in TGCTs.
Cells. 2023 Mar 24*** epublish ***
Karthika Radhakrishnan, Michael Luu, Josie Iaria, Jessie M Sutherland, Eileen A McLaughlin, Hong-Jian Zhu, Kate L Loveland
Centre for Reproductive Health, Hudson Institute of Medical Research, 27-31 Kanooka Grove, Clayton, VIC 3168, Australia., Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Australia., Priority Research Centre for Reproductive Science, Schools of Biomedical Science & Pharmacy and Environmental & Life Sciences, University of Newcastle, Callaghan, NSW 2305, Australia.