Aberrant methylation of SPARC in human lung cancers.
SPARC (secreted protein acidic and rich in cysteine) is an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth. We investigated loss of expression of SPARC gene and promoter methylation in lung cancers and correlated the data with clinicopathological features. We observed loss of SPARC expression in 12 of 20 (60%) lung cancer cell lines. Treatment of expression-negative cell lines with a demethylating agent restored expression in all cases. Methylation frequencies of SPARC gene were 55% in 20 lung cancer cell lines. Primary tumours had methylation at a rate of 69% (119 of 173), while nonmalignant lung tissues (n=60) had very low rates (3%). In lung adenocarcinomas, SPARC methylation correlated with a negative prognosis (P=0.0021; relative risk 4.65, 95% confidence interval 1.75-12.35, multivariate Cox's proportional-hazard model). Immunostaining revealed protein expression in bronchial epithelium (weak intensity) and in juxtatumoral stromal tissues (strong intensity) accompanied by frequent loss in cancer cells that correlated with the presence of methylation (P<0.001). Our findings are of biological interest and potentially of clinical importance in human lung cancers.
Suzuki
M
M
Hamon Center for Therapeutic Oncology Research, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. smakoto@chiba-cc.jp
Hao
C
C
Takahashi
T
T
Shigematsu
H
H
Shivapurkar
N
N
Sathyanarayana
U G
UG
Iizasa
T
T
Fujisawa
T
T
Hiroshima
K
K
Gazdar
A F
AF
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015676:Osteonectin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014158:Transcription, Genetic
D017931:DNA Primers; D004273:DNA, Neoplasm; D015676:Osteonectin; D012333:RNA, Messenger