Microarray analysis of aberrant gene expression in actinic keratosis: effect of the Toll-like receptor-7 agonist imiquimod.
BACKGROUND
The molecular events leading to actinic keratosis (AK) are not well understood.


OBJECTIVE
To identify and compare gene expression changes in AK lesions and in sun-exposed nonlesional skin and to determine the effect of imiquimod 5% cream on these changes.


METHODS
A double-blind, vehicle-controlled, randomized study was conducted to evaluate the molecular changes in AK treated with imiquimod. Seventeen male subjects with >/= 5 AK lesions on the scalp applied vehicle or imiquimod three times a week for 4 weeks. Gene expression analysis using Affymetrix oligonucleotide arrays was performed on shave biopsies of lesions taken before and after treatment. Confocal microscopy was performed on the study area as an adjunctive diagnostic procedure.


RESULTS
We identified gene expression changes which occur in sun-exposed, nonlesional skin as well as in AK lesions. These changes include, but are not limited to, the overexpression of oncogenic and proliferative genes and diminished expression of tumour suppressor genes. The gene expression changes observed in AK lesions and in sun-exposed, nonlesional skin were consistent with the confocal microscopy observations, which showed abnormalities in the sun-exposed, nonlesional skin, similar in nature but less pronounced than abnormalities seen in AK. Imiquimod partially or totally reversed the aberrant expression of some of the genes observed in AK, consistent with clearing of lesions and normalization of confocal cellular images.


CONCLUSIONS
The data show that profound gene expression changes occur in sun-exposed, nonlesional skin which progress further in AK lesions. The data also suggest that imiquimod may play a role in normalizing gene expression and cellular morphology in sun-damaged skin.
Torres
A
A
Dermatology Office, Loma Linda University Medical Center, Loma Linda, CA, USA.
Storey
L
L
Anders
M
M
Miller
R L
RL
Bulbulian
B J
BJ
Jin
J
J
Raghavan
S
S
Lee
J
J
Slade
H B
HB
Birmachu
W
W
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000287:Administration, Topical; D000368:Aged; D000369:Aged, 80 and over; D000634:Aminoquinolines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005500:Follow-Up Studies; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D000077271:Imiquimod; D007642:Keratosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010787:Photosensitivity Disorders / Q000188:drug therapy / Q000235:genetics*; D012536:Scalp Dermatoses / Q000188:drug therapy / Q000235:genetics*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D051199:Toll-Like Receptor 7; D000077271:Imiquimod