Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation.
BACKGROUND
The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network.


METHODS
Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as "cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry.


RESULTS
EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively.


CONCLUSIONS
Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation.
Schulz
Wolfgang A
WA
Department of Urology, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany. wolfgang.schulz@uni-duesseldorf.de
Ingenwerth
Marc
M
Djuidje
Carolle E
CE
Hader
Christiane
C
Rahnenführer
Jörg
J
Engers
Rainer
R
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000368:Aged; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D003599:Cytoskeleton / Q000378:metabolism*; D019175:DNA Methylation; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008875:Middle Aged; D009479:Neuropeptides / Q000096:biosynthesis; D009857:Oncogenes; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D000071230:Transcriptional Regulator ERG
D000199:Actins; D003598:Cytoskeletal Proteins; C072312:ERG protein, human; D008565:Membrane Proteins; D009479:Neuropeptides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C120557:erythrocyte membrane protein band 4.1-like 1; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi