Publications

@article{Cardenas2024-ev,

title = {NANOG controls testicular germ cell tumour stemness through  regulation of MIR9-2},

author = {Ryan P Cardenas and Ahmad Zyoud and Alan McIntyre and Ramiro Alberio and Nigel P Mongan and Cinzia Allegrucci},

doi = {10.1186/s13287-024-03724-1},

year  = {2024},

date = {2024-05-01},

urldate = {2024-05-01},

journal = {Stem Cell Res. Ther.},

volume = {15},

number = {1},

pages = {128},

publisher = {Springer Science and Business Media LLC},

abstract = {BACKGROUND: Testicular germ cell tumours (TGCTs) represent a 

 clinical challenge; they are most prevalent in young individuals 

 and are triggered by molecular mechanisms that are not fully 

 understood. The origin of TGCTs can be traced back to primordial 

 germ cells that fail to mature during embryonic development. 

 These cells express high levels of pluripotency factors, 

 including the transcription factor NANOG which is highly 

 expressed in TGCTs. Gain or amplification of the NANOG locus is 

 common in advanced tumours, suggesting a key role for this 

 master regulator of pluripotency in TGCT stemness and 

 malignancy. METHODS: In this study, we analysed the expression 

 of microRNAs (miRNAs) that are regulated by NANOG in TGCTs via 

 integrated bioinformatic analyses of data from The Cancer Genome 

 Atlas and NANOG chromatin immunoprecipitation in human embryonic 

 stem cells. Through gain-of-function experiments, MIR9-2 was 

 further investigated as a novel tumour suppressor regulated by 

 NANOG. After transfection with MIR9-2 mimics, TGCT cells were 

 analysed for cell proliferation, invasion, sensitivity to 

 cisplatin, and gene expression signatures by RNA sequencing. 

 RESULTS: For the first time, we identified 86 miRNAs regulated 

 by NANOG in TGCTs. Among these, 37 miRNAs were differentially 

 expressed in NANOG-high tumours, and they clustered TGCTs 

 according to their subtypes. Binding of NANOG within 2 kb 

 upstream of the MIR9-2 locus was associated with a negative 

 regulation. Low expression of MIR9-2 was associated with tumour 

 progression and MIR9-2-5p was found to play a role in the 

 control of tumour stemness. A gain of function of MIR9-2-5p was 

 associated with reduced proliferation, invasion, and sensitivity 

 to cisplatin in both embryonal carcinoma and seminoma tumours. 

 MIR9-2-5p expression in TGCT cells significantly reduced the 

 expression of genes regulating pluripotency and cell division, 

 consistent with its functional effect on reducing cancer 

 stemness. CONCLUSIONS: This study provides new molecular 

 insights into the role of NANOG as a key determinant of 

 pluripotency in TGCTs through the regulation of MIR9-2-5p, a 

 novel epigenetic modulator of cancer stemness. Our data also 

 highlight the potential negative feedback mediated by MIR9-2-5p 

 on NANOG expression, which could be exploited as a therapeutic 

 strategy for the treatment of TGCTs.},

keywords = {Differentiation, MIR-9, NANOG, Pluripotency, stemness, Testicular germ cell tumours},

pubstate = {published},

tppubtype = {article}

}