Piwil-2 represents a poor prognosticator in Merkel cell carcinomas that regulates oncoproteins, cell cycle arrest and SOX-2 expression.

Merkel cell carcinomas (MCCs) are rare, highly aggressive skin cancers with poor outcome due to early lymphatic tumor spread and frequent recurrences. MCCs mostly occur in the head and neck and are mainly caused by an infection with the Merkel cell polyomavirus (MCPyV). Increasing evidence suggests that Piwil-2 and small non-coding PIWI-interacting RNAs (piRNAs) play an important role in solid malignancies and we thought that this might also be the case for MCCs. Therefore, Piwil-2 expression was first evaluated in 27 MCC specimens and correlated with oncological outcome. We found an association with high Piwil-2 expression and advanced tumor stage, MCPyV positivity and poor outcome. Next, we utilized siRNAs for Piwil-2 knock-down in MCC cells. Downregulation of Piwil-2 caused a significant change of 202 different piRNAs and 419 proteins. Interestingly, proteins related to viral driven MCC pathways (TRRAP, BRD8, PRIM2, ORC4) were significantly downregulated. Moreover, there was a moderate cell cycle arrest of cells in the G0/G1-phase, as well as a significant upregulation of SOX-2, a key regulator of Merkel cells. Altogether, Piwil-2 poses a poor prognosticator in MCCs, which is linked to MCC oncogenesis and SOX-2. Further research is needed to better understand underlying mechanisms and to prove their clinical relevance.