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Research Paper
Silencing of Lactotransferrin Expression by Methylation in Prostate Cancer Progression
Syed Shaheduzzaman, Anu Vishwanath, Bungo Furusato, Jennifer Cullen, Yongmei Chen, Lionel Bañez, Martin Nau, Lakshmi Ravindranath, Kee-Hong Kim, Ahmed Mohammed, Yidong Chen, Mathias Ehrich, Vasantha Srikantan, Isabell A. Sesterhenn, David G. McLeod, Maryanne Vahey, Gyorgy Petrovics, Albert Dobi and Shiv Srivastava
volume 6 | issue 7
July 2007Pages: 1088 - 1095
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Background: Cancer cells gain selection advantages by the coordinated silencing of protective and by the activation of cell proliferation/cell survival genes. Evaluations of epithelial cell transcriptome of benign and malignant prostate glands by laser capture microdissection (LCM) identified Lactotransferrin (LTF) as the most significantly downregulated gene in prostate cancer (CaP) cells (P<10-6). Frequent downregulation, significant association of LTF with PSA recurrence-free survival in CaP patients and the established anti-tumorigenic effects of LTF in experimental cancer models have provided impetus to evaluate LTF expression features and mechanisms in CaP specimens. Methods: LTF mRNA expression analysis was performed in LCM derived benign and malignant prostate epithelial cells by using Affymetrix GeneChip and QRT-PCR. LTF protein expression was assessed in tissue specimens by immunohistochemistry and in serum samples from CaP patients compared to healthy male control by using ELISA. Mechanism of LTF downregulation was analyzed in 5-azadeoxycytidine treated LNCaP and LAPC4 cells using MALDI-TOF MS. Proliferation and cell cycle analysis of CaP cells by FACS flow cytrometry was assessed in LNCaP cell cultures. Results: Quantitative analysis of LTF mRNA expression in tumor cells revealed marked downregulation of LTF with significant associations to decreased PSA recurrence-free survival of CaP patients (n=100, P ≤ 0.0322). Moreover, low levels of LTF protein expression was observed in tumor tissues as well as in sera from CaP patients (P ≤ 0.0001). LTF promoter downstream CpG island methylation was found in LNCaP and LAPC4 cells. Furthermore, replenishing of LTF by supplementing growth media with LTF protein resulted in the reduced cell growth. Cell cycle analysis revealed robust increases in apoptosis in response to LTF treatment. Conclusion: This study highlights the potential for LTF in chemoprevention and to become a biologically relevant prognostic marker of CaP, suggesting that silencing of the LTF gene may be causally linked to CaP progression.
Authors
Syed Shaheduzzaman
CPDR, Department of Surgery, USU, Rockville, MD
Anu Vishwanath
CPDR, Department of Surgery, USU, Rockville, MD
Bungo Furusato
Armed Forces Institute of Pathology, Washington, DC
Jennifer Cullen
CPDR, Department of Surgery, USU, Rockville, MD
Yongmei Chen
CPDR, Department of Surgery, USU, Rockville, MD
Lionel Bañez
CPDR, Department of Surgery, USU, Rockville, MD
Martin Nau
Division of Retrovirology, WRAIR, Rockville, MD
Lakshmi Ravindranath
CPDR, Department of Surgery, USU, Rockville, MD
Kee-Hong Kim
CPDR, Department of Surgery, USU, Rockville, MD
Ahmed Mohammed
CPDR, Department of Surgery, USU, Rockville, MD
Yidong Chen
Cancer Genetics Branch, NHGRI, NIH, Bethesda, MD
Mathias Ehrich
SEQUENOM, Inc.; San Diego, CA USA
Vasantha Srikantan
CPDR, Department of Surgery, USU, Rockville, MD
Isabell A. Sesterhenn
Armed Forces Institute of Pathology, Washington, DC
David G. McLeod
Walter Reed Army Medical Center, Washington, DC
Maryanne Vahey
Division of Retrovirology, WRAIR, Rockville, MD
Gyorgy Petrovics
CPDR, Department of Surgery, USU, Rockville, MD
Albert Dobi
CPDR/Department of Surgery/USUHS
Shiv Srivastava
Center for Prostate Disease Research, Department of Surgery, US Military Cancer Institute, Uniformed Services University; Rockville, MD USA
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.