Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.
OBJECTIVE
NKX3.1, a member of the family of homeobox genes, exhibits prostate tissue specific expression and appears to play a role in mouse prostate development. Rapid induction of NKX3.1 gene expression in response to androgens has also been described. On the basis of the established role of androgens in prostatic growth and differentiation and studies showing an association of aberrant homeobox gene expression with the neoplastic process, we hypothesize that alterations of NKX3.1 gene expression play a role in prostate tumorigenesis.


METHODS
NKX3.1 expression was analyzed in matched, microdissected normal and tumor tissues from 52 primary prostate cancer specimens from radical prostatectomy by semiquantitative RT-PCR and in situ hybridization and correlated with the clinicopathologic features. NKX3.1 expression was quantified as differential expression between matched tumor and normal tissues and was grouped as overexpression in tumor tissue, reduced expression in tumor tissue and no change between tumor and normal tissues. Androgen regulation of NKX3.1 expression was also studied in LNCaP cells. Androgen receptor (AR) expression in prostate tumor and normal tissue was correlated with NKX3.1 expression.


RESULTS
Comparison of NKX3.1 expression between normal and tumor tissues revealed overexpression in 31% tumor specimens (16 of 52), decreased expression in 21% tumor specimens (11 of 52) and no change in 48% specimens (25 of 52). When these expression patterns were stratified by organ confined and non-organ-confined tumor, a higher percentage of patients exhibited NKX3.1 overexpression in non-organ confined tumor (40%) versus organ confined tumor (22%). Elevated NKX3.1 expression significantly correlated with tumor volume and serum prostate specific antigen (PSA) level in the NKX3.1 overexpression group (p<0.05). Metastatic prostate cancer cell lines did not exhibit mutations in the protein coding sequence of NKX3.1. Additionally, the NKX3.1 expression correlated with AR expression (p<0.01) in vivo in human prostate tissues. Comparison of PSA and NKX3.1 expression in response to androgen revealed a rapid androgen mediated induction of NKX3.1 expression in LNCaP cells. In situ hybridization analysis of representative specimens confirmed RT-PCR observations.


CONCLUSIONS
These results suggest an association of NKX3.1 with a more aggressive phenotype of carcinoma of the prostate. Correlation of AR expression with NKX3.1 in human prostate tissues underscores the androgen regulation of NKX3.1 in the physiologic context of human prostate tissues.
Xu
L L
LL
Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20852, USA.
Srikantan
V
V
Sesterhenn
I A
IA
Augustus
M
M
Dean
R
R
Moul
J W
JW
Carter
K C
KC
Srivastava
S
S
D000728:Androgens / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005801:Genes, Homeobox / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA; D045165:Testosterone Congeners / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000728:Androgens; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D045165:Testosterone Congeners; D014157:Transcription Factors; D015741:Metribolone