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Abstract:
Background
Alterations of chromosome 8 and hypomethylation of LINE-1 retrotransposons are
common alterations in advanced prostate carcinoma. In a former study including
many metastatic cases, they strongly correlated with each other. To elucidate a
possible interaction between the two alterations, we investigated their
relationship in less advanced prostate cancers.
Results
In 50 primary tumor tissues, no correlation was observed between chromosome 8
alterations determined by comparative genomic hybridization and LINE-1
hypomethylation measured by Southern blot hybridization. The discrepancy
towards the former study, which had been dominated by advanced stage cases,
suggests that both alterations converge and interact during prostate cancer
progression. Therefore, interaction analysis was performed on microarray-based
expression profiles of cancers harboring both alterations, only one, or none.
Application of a novel bioinformatic method identified Gene Ontology (GO)
groups related to innate immunity, cytoskeletal organization and cell adhesion
as common targets of both alterations. Many genes targeted by their interaction
were involved in type I and II interferon signaling and several were
functionally related to hereditary prostate cancer genes. In addition, the
interaction appeared to influence a switch in the expression pattern of EPB41L
genes encoding 4.1 cytoskeleton proteins. Real-time RT-PCR revealed GADD45A,
MX1, EPB41L3/DAL1, and FBLN1 as generally downregulated in prostate cancer,
whereas HOXB13 and EPB41L4B were upregulated. TLR3 was downregulated in a
subset of the cases and associated with recurrence. Downregulation of EPB41L3,
but not of GADD45A, was associated with promoter hypermethylation, which was
detected in 79% of carcinoma samples.
Conclusion
Alterations of chromosome 8 and DNA hypomethylation in prostate cancer probably
do not cause each other, but converge during progression. The present analysis
implicates their interaction in innate immune response suppression and
cytoskeletal changes during prostate cancer progression. The study thus
highlights novel mechanisms in prostate cancer progression and identifies novel
candidate genes for diagnostic and therapeutic purposes. In particular, TLR3
expression might be useful for prostate cancer prognosis and EPB41L3
hypermethylation for its detection.
