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Cancers (Basel). 2018 Nov 14;10(11). pii: E443. doi: 10.3390/cancers10110443.

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

Kumar S1,2, Xie H3,4,5, Scicluna P6,7,8, Lee L9,10, Björnhagen V11, Höög A12,13,14, Larsson C15,16,17, Lui WO18,19.

Author information

1
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. satendra.kumar@ki.se.
2
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. satendra.kumar@ki.se.
3
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. xiehong@tmu.edu.cn.
4
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. xiehong@tmu.edu.cn.
5
Tianjin Life Science Research Center and Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. xiehong@tmu.edu.cn.
6
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. patrick.scicluna@ki.se.
7
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. patrick.scicluna@ki.se.
8
Department of Cell and Molecular Biology, Karolinska Institutet, SE-17165 Stockholm, Sweden. patrick.scicluna@ki.se.
9
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. Linkiatlee@gmail.com.
10
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. Linkiatlee@gmail.com.
11
Department of Reconstructive Plastic Surgery, Karolinska University Hospital, SE-17176 Stockholm, Sweden. viveca.bjornhagen-safwenberg@sll.se.
12
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. anders.hoog@ki.se.
13
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. anders.hoog@ki.se.
14
Department of Clinical Pathology and Cytology, Karolinska University Hospital, SE-17176 Stockholm, Sweden. anders.hoog@ki.se.
15
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. catharina.larsson@ki.se.
16
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. catharina.larsson@ki.se.
17
Department of Clinical Pathology and Cytology, Karolinska University Hospital, SE-17176 Stockholm, Sweden. catharina.larsson@ki.se.
18
Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden. weng-onn.lui@ki.se.
19
Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden. weng-onn.lui@ki.se.

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.

KEYWORDS:

LDHB; Merkel cell carcinoma; Merkel cell polyomavirus; cell growth; miR-375

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