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JMD 2006, Vol. 8, No. 3
Copyright © 2006 American Society for Investigative Pathology & Association for Molecular Pathology

Novel Functional Single Nucleotide Polymorphisms in the Latent Transforming Growth Factor-ß Binding Protein-1L Promoter

Effect on Latent Transforming Growth Factor-ß Binding Protein-1L Expression Level and Possible Prognostic Significance in Ovarian Cancer

Tomomi Higashi^*, Satoru Kyo, Masaki Inoue, Hideji Tanii^* and Kiyofumi Saijoh^*

From the Departments of Hygiene * and Obstetrics and Gynecology, Kanazawa University Graduate School of Medicine Science, Kanazawa, Japan

Latent transforming growth factor (TGF)-ß binding proteins (LTBPs) play important roles in the secretion and activation of TGF-ß. 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.

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