MiR-375 Regulation of LDHB Plays Distinct Roles in Polyomavirus-Positive and -Negative Merkel Cell Carcinoma.

Satendra Kumar,Viveca Björnhagen,Catharina Larsson,Patrick Scicluna,Hong Xie,Anders Höög,Linkiat Lee,Weng-Onn Lui

doi:10.3390/cancers10110443

Satendra Kumar, Viveca Björnhagen + Show 6 more

Open Access

https://doi.org/10.3390/cancers10110443

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Abstract

MicroRNA-375 (miR-375) is deregulated in multiple tumor types and regulates important targets involved in tumorigenesis and metastasis. This miRNA is highly expressed in Merkel cell carcinoma (MCC) compared to normal skin and other non-MCC skin cancers, and its expression is high in Merkel cell polyomavirus (MCPyV)-positive (MCPyV+) and low in MCPyV-negative (MCPyV−) MCC tumors. In this study, we characterized the function and target of miR-375 in MCPyV+ and MCPyV− MCC cell lines. Ectopic expression of miR-375 in MCPyV− MCC cells resulted in decreased cell proliferation and migration, as well as increased cell apoptosis and cell cycle arrest. However, in MCPyV+ MCC cells, inhibition of miR-375 expression reduced cell growth and induced apoptosis. Additionally, the expression of lactate dehydrogenase B (LDHB), a known target of miR-375, was inversely correlated with miR-375. Silencing of LDHB reduced cell growth in MCPyV− cell lines, while its silencing in MCPyV+ cell lines rescued the cell growth effect mediated by miR-375 inhibition. Together, our results suggest dual roles of miR-375 and LDHB in MCPyV and non-MCPyV-associated MCCs. We propose that LDHB could be a therapeutic target in MCC and different strategies should be applied in virus- and non-virus-associated MCCs.

Highlights

Merkel cell carcinoma (MCC) is a highly aggressive form of neuroendocrine cancer of the skin
MicroRNA-375 expression was found to be significantly higher in the Merkel cell polyomavirus (MCPyV)+ than the MCPyV− MCC tumors
This miRNA is highly specific to MCC compared to non-MCC tumors and cell lines [19,20]; its expression is higher in serum samples of MCC patients than tumor-free patients or healthy individuals, suggesting its potential use as a surrogate marker for tumor burden in MCC [19]

Summary

Introduction

Merkel cell carcinoma (MCC) is a highly aggressive form of neuroendocrine cancer of the skin. Cancers 2018, 10, 443 reported different clinical and molecular features between MCPyV+ and MCPyV− MCCs [13,14,15,16,17,18]. MicroRNA-375 (miR-375) expression was found to be significantly higher in the MCPyV+ than the MCPyV− MCC tumors. This miRNA is highly specific to MCC compared to non-MCC tumors and cell lines [19,20]; its expression is higher in serum samples of MCC patients than tumor-free patients or healthy individuals, suggesting its potential use as a surrogate marker for tumor burden in MCC [19]

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