Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer.
BACKGROUND
Perineural invasion (PNI) is the dominant pathway for local invasion in prostate cancer. To date, only few studies have investigated the molecular differences between prostate tumors with PNI and those without it.


METHODS
To evaluate the involvement of both microRNAs and protein-coding genes in PNI, we determined their genome-wide expression with a custom microRNA microarray and Affymetrix GeneChips in 50 prostate adenocarcinomas with PNI and 7 without it. In situ hybridization (ISH) and immunohistochemistry was used to validate candidate genes.


RESULTS
Unsupervised classification of the 57 adenocarcinomas revealed two clusters of tumors with distinct global microRNA expression. One cluster contained all non-PNI tumors and a subgroup of PNI tumors. Significance analysis of microarray data yielded a list of microRNAs associated with PNI. At a false discovery rate (FDR)<10%, 19 microRNAs were higher expressed in PNI tumors than in non-PNI tumors. The most differently expressed microRNA was miR-224. ISH showed that this microRNA is expressed by perineural cancer cells. The analysis of protein-coding genes identified 34 transcripts that were differently expressed by PNI status (FDR<10%). These transcripts were down-regulated in PNI tumors. Many of those encoded metallothioneins and proteins with mitochondrial localization and involvement in cell metabolism. Consistent with the microarray data, perineural cancer cells tended to have lower metallothionein expression by immunohistochemistry than nonperineural cancer cells.


CONCLUSIONS
Although preliminary, our findings suggest that alterations in microRNA expression, mitochondrial function, and cell metabolism occur at the transition from a noninvasive prostate tumor to a tumor with PNI.
Prueitt
Robyn L
RL
Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892-4258, USA.
Yi
Ming
M
Hudson
Robert S
RS
Wallace
Tiffany A
TA
Howe
Tiffany M
TM
Yfantis
Harris G
HG
Lee
Dong H
DH
Stephens
Robert M
RM
Liu
Chang-Gong
CG
Calin
George A
GA
Croce
Carlo M
CM
Ambs
Stefan
S
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics; D035683:MicroRNAs / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010525:Peripheral Nerves / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011991:Receptors, Virus / Q000235:genetics
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011991:Receptors, Virus; D008668:Metallothionein