Hoxc6 is overexpressed in gastrointestinal carcinoids and interacts with JunD to regulate tumor growth.
OBJECTIVE
The molecular alterations that underlie carcinoid tumor pathogenesis remain poorly defined. The homeobox gene HOXC6 was highly up-regulated in human gastrointestinal carcinoid tumors, and we sought to define its pathogenic role.


METHODS
The functional and physical properties of Hoxc6 were investigated by establishing carcinoid cells that stably overexpressed Hoxc6 or were deficient in Hoxc6. Cellular proliferation assays, luciferase reporter assays, Western blotting, immunoprecipitation, DNA affinity precipitation, and DNA microarray studies were performed.


RESULTS
Expression of Hoxc6 in cultured human BON1 carcinoid cells enhanced their proliferation, and knock-down of Hoxc6 inhibited their growth. Hoxc6 activated the oncogenic activator protein-1 signaling pathway through a physical interaction with JunD. Mutations in the homeodomain of Hoxc6 blocked this interaction and inhibited proliferation of carcinoid cells. Of note, Hoxc6 induced the expression of genes that characteristically are up-regulated in carcinoid tumors, including neurotensin and connective tissue growth factor.


CONCLUSIONS
A novel molecular pathway has been identified that links Hoxc6 with oncogenic signaling through the activator protein-1 pathway in carcinoid tumorigenesis.
Fujiki
Kotoyo
K
Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Duerr
Eva-Maria
EM
Kikuchi
Hirotoshi
H
Ng
Aylwin
A
Xavier
Ramnik J
RJ
Mizukami
Yusuke
Y
Imamura
Takaaki
T
Kulke
Matthew H
MH
Chung
Daniel C
DC
D000368:Aged; D002276:Carcinoid Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
C094289:HOXC6 protein, human; D018398:Homeodomain Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1