Protocadherin PCDH10, involved in tumor progression, is a frequent and early target of promoter hypermethylation in cervical cancer.
Cervical cancer (CC) is the second most common cancer in women. Currently, no tractable molecular-based therapeutic targets exist for patients with invasive CC and no predictive markers of risk assessment for progression of precancerous lesions are identified. New molecular insights into CC pathogenesis are urgently needed. Towards this goal, we first determined the copy number alterations of chromosome 4 and then examined the role of PCDH10 mapped to 4q28 as a candidate tumor suppressor gene. We identified monosomy 4 in 47% of 81 invasive CC studied by SNP array and found that 91% of 130 invasive CC harboring methylation in the promoter region of the PCDH10 gene. We then showed that aberrant promoter hypermethylation of PCDH10 is associated with downregulation of gene expression and cell lines exposed to demethylating agent resulted in profound reactivated gene expression. We also showed that the promoter methylation in the PCDH10 gene occurs at an earliest identifiable stage of low-grade squamous intraepithelial lesion. Our studies demonstrate that inactivation of PCDH10 may be a critical event in CC progression and form a potentially useful therapeutic target for CC.
Narayan
Gopeshwar
G
Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
Scotto
Luigi
L
Neelakantan
Vijayalakshmi
V
Kottoor
Sherine H
SH
Wong
Ada Ho Yan
AH
Loke
Shee-Loong
SL
Mansukhani
Mahesh
M
Pothuri
Bhavana
B
Wright
Jason D
JD
Kaufmann
Andreas M
AM
Schneider
Achim
A
Arias-Pulido
Hugo
H
Tao
Qian
Q
Murty
Vundavalli V
VV
D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002894:Chromosomes, Human, Pair 4; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D009006:Monosomy; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000091363:Protocadherins; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism
D015820:Cadherins; C438603:PCDH10 protein, human; D000091363:Protocadherins
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