Novel functional single nucleotide polymorphisms in the latent transforming growth factor-beta binding protein-1L promoter: effect on latent transforming growth factor-beta binding protein-1L expression level and possible prognostic significance in ovarian cancer.
Latent transforming growth factor (TGF)-beta binding proteins (LTBPs) play important roles in the secretion and activation of TGF-beta. We previously reported that LTBP-1L is overexpressed in some patients with ovarian cancer. To clarify the molecular mechanism of LTBP-1L regulation, we analyzed DNA sequences in the promoter region of LTBP-1L and identified two novel single nucleotide polymorphisms, -202G/C and +20A/C. While the alleles with -202C and +20C were initially reported, our data demonstrated that -202G and +20A are common in both ovarian cancer patients and healthy patients in the Japanese population. Luciferase reporter assays revealed that the G-A haplotype induced transcriptional activation in a Sp1-dependent manner. Electrophoretic mobility shift assays showed that increased binding affinity of Sp1 to the promoter with -202G and +20A. Interestingly, ovarian cancer patients (n = 42) with G-A/G-A homozygous genotype had increased expression of LTBP-1 and apparently poorer survival than those with other genotypes (P = 0.02). These findings suggest that the single nucleotide polymorphisms -202G/C and +20A/C on the LTBP-1L promoter may affect the clinical outcome of ovarian cancer patients, probably via up-regulating protein expression. Further studies using a larger number of samples will definitively determine the correlation between LTBP-1 haplotype and clinical behavior of ovarian cancer.
Higashi
Tomomi
T
Department of Hygiene, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Ishikawa 920-8640, Japan. saijohk@med.kanazawa-u.ac.jp
Kyo
Satoru
S
Inoue
Masaki
M
Tanii
Hideji
H
Saijoh
Kiyofumi
K
D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D053779:Latent TGF-beta Binding Proteins; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
D047908:Intracellular Signaling Peptides and Proteins; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D016212:Transforming Growth Factor beta