A Proteomic Study of Human Merkel Cell Carcinoma

Abstract

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin. The incidence has been quadrupled with a 5-year mortality rate of 46%, presently there is no cure for metastatic disease. Despite the contribution of Merkel cell polyomavirus, the molecular events of MCC carcinogenesis are poorly defined. To better understand MCC carcinogensis, we have performed the first quantitative proteomic comparison of formalin-fixed, paraffin-embedded (FFPE) MCC tissues using another neuroendocrine tumor (carcinoid tumor of the lung) as controls. Bioinformatic analysis of the proteomic data has revealed that MCCs carry distinct protein expression patterns. Further analysis of significantly over-expressed proteins suggested the involvement of MAPK, PI3K/Akt/mTOR, wnt, and apoptosis signaling pathways. Our previous study and that from others have shown mTOR activation in MCCs. Therefore, we have focused on two downstream molecules of the mTOR pathway, lactate dehydrogenase B (LDHB) and heterogeneous ribonucleoprotein F (hnRNPF). We confirm over-expression of LDHB and hnRNPF in two primary human MCC cell lines, 16 fresh tumors, and in the majority of 80 tissue microarray samples. Moreover, mTOR inhibition suppresses LDHB and hnRNPF expression in MCC cells. The results of the current study provide insight into MCC carcinogenesis and provide rationale for mTOR inhibition in pre-clinical studies.

Stable shRNA Silencing of Lactate Dehydrogenase A (LDHA) in Human MDA-MB-231 Breast Cancer Cells Fails to Alter Lactic Acid Production, Glycolytic Activity, ATP or Survival

“…Heightened expression of LDHB may contribute to tumor acidity, and growth (24) known to occur in parallel to activated RTK-PI3K-AKT-mTOR signaling (25) and is observed in various types of cancer including bladder (26) merkel cell carcinoma (27) lung cancer (28) glioma (29) or maxillary sinus squamous cell carcinoma, most reporting its association with poor survival rates (30). …”

Molecular characteristics and potential therapeutic targets in Merkel cell carcinoma

“…The oncogenic property of the large T antigen is via its capability to bind RB1 tumour suppressor gene 65. A quantitative proteomics study by Shao et al 84 showed dysregulation of MAPK, PI3K/AKT/mTOR, Wnt and apoptosis signalling pathways in MCC. LDHB and hnRNPFm, two downstream molecules of the mTOR pathway, are frequently overexpressed in MCC, and AKT phosphorylation determined by IHC occurs in 88% of MCC cases 84.…”

“…A quantitative proteomics study by Shao et al 84 showed dysregulation of MAPK, PI3K/AKT/mTOR, Wnt and apoptosis signalling pathways in MCC. LDHB and hnRNPFm, two downstream molecules of the mTOR pathway, are frequently overexpressed in MCC, and AKT phosphorylation determined by IHC occurs in 88% of MCC cases 84. Among MCCs with PIK3CA mutations, 2/2 (100%),77 1/7 (14%)66 and 1/3 (33.3%)69 tumours were reported to be MCPyV-positive.…”

The Promise of Proteomics in the Study of Oncogenic Viruses

“…An important study used LCM and proteomic analysis to demonstrate that the CD21 EBV receptor was only expressed on tonsil epithelial cells (71). A quantitative proteomic analysis of Merkel Cell carcinoma indicated that the MAPK, PI3K/Akt/mTOR, Wnt, and apoptosis signaling pathways were involved in the development of the tumor (72). As mass spectrometry techniques become more sensitive, studies such as these will be able to use proteomics to gain direct information about infection and disease states.…”