Proneural and proneuroendocrine transcription factor expression in cutaneous mechanoreceptor (Merkel) cells and Merkel cell carcinoma.
Merkel cells form part of the peripheral neuroendocrine system of the skin and act as mechanoreceptors in touch response. Merkel cell carcinoma (MCC) is a rare, aggressive disease with similarities to small cell lung cancer (SCLC), which is also of neuroendocrine origin. We previously identified a novel DNA binding protein complex specific for MCC suspension cell lines, termed Merkel nuclear factor (MNF) by its binding to the POU-IV family DNA binding consensus sequence. Here we report that MNF contains the POU-IV family member Brn-3c and that Brn-3c is expressed in normal Merkel cells. Additionally, Brn-3c protein reactivity is restricted to a subset of MCC biopsies and is not seen in biopsies revealing adherent, variant cell lines lacking neuroendocrine markers. Recently, proper development of murine Merkel cells was shown to require the proneural basic helix-loop-helix transcription factor, atonal family member, MATH1. We demonstrate a correlation between Brn-3c and HATH1 reactivity in MCC biopsies and cell lines with retention of neuroendocrine phenotype. In SCLC, the related basic helix-loop-helix transcription factor HASH1 is responsible for neuroendocrine phenotype, but HASH1 transcripts were not detected in MCC cell lines. We propose that HATH1 and Brn-3c may form a transcriptional hierarchy responsible for determining neuroendocrine phenotype in Merkel cells and that lack of Brn-3c and/or HATH1 in MCC may indicate a more aggressive disease requiring closer patient follow-up.
Leonard
J Helen
JH
Queensland Radium Institute Research Unit, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia. helenL@qimr.edu.au
Cook
Anthony L
AL
Van Gele
Mireille
M
Boyle
Glen M
GM
Inglis
Kelly J
KJ
Speleman
Frank
F
Sturm
Richard A
RA
D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D015266:Carcinoma, Merkel Cell / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D018862:Merkel Cells / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050819:Transcription Factor Brn-3A; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D050819:Transcription Factor Brn-3A; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C065500:ASCL1 protein, human; C494188:POU4F1 protein, human; C078493:HES1 protein, human