The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties.,Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors.,Notably, several viral oncoproteins are capable of binding and inhibiting PPs.,Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells.,Therefore, we analyzed the interaction of MCPyV-LT with the PPs.,Co-IP experiments indicate that MCPyV-LT binds potently only to RB1.,Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown.,Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression.,Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent.,Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.
Merkel cell carcinoma (MCC) is an aggressive and lethal type of neuroendocrine skin cancer.,Mutated Merkel cell polyomavirus (MCV) is commonly found in MCC, and leads to upregulation of the survivin oncogene.,However, ∼20% of MCC tumors do not have detectable MCV, suggesting alternative etiologies for this tumor type.,In this study, our aim was to evaluate microRNA (miRNA) expression profiles and their associations with MCV status and clinical outcomes in MCC.,We showed that miRNA expression profiles were distinct between MCV-positive (MCV+) and MCV-negative (MCV−) MCCs and further validated that miR-203, miR-30a-3p, miR-769-5p, miR-34a, miR-30a-5p, and miR-375 were significantly different.,We also identified a subset of miRNAs associated with tumor metastasis and MCC-specific survival.,Functionally, overexpression of miR-203 was found to inhibit cell growth, induce cell cycle arrest, and regulate survivin expression in MCV− MCC cells, but not in MCV+ MCC cells.,Our findings reveal a mechanism of survivin expression regulation in MCC cells, and provide insights into the role of miRNAs in MCC tumorigenesis.