Protocadherin PCDH10, involved in tumor progression, is a frequent and early target of promoter hypermethylation in cervical cancer

Abstract

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 down-regulation 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 (LSIL). Our studies demonstrate that inactivation of PCDH10 may be a critical event in CC progression and form a potentially useful therapeutic target for CC.

A Novel Wnt Regulatory Axis in Endometrioid Endometrial Cancer

“…Although the downregulation of PCDH10 has been reported in a wide range of cancers (6,(9)(10)(11)(12)(13)(14)(15)(16), as far as we know, this is the first study to demonstrate its association with EEC. Our results clearly showed that PCDH10 promoter is hypermethylated through both genomic bisulfite sequencing analysis of locally collected EC samples and analyzing TCGA data from worldwide EEC samples.…”

“…Inactivation of PCDH10 because of promoter CpG hypermethylation has been detected in gastric, hepatocellular, colorectal, breast, cervical, lung, nasopharyngeal, esophageal, pancreatic, and bladder cancer (6,(9)(10)(11)(12)(13)(14)(15)(16). Functional studies revealed that re-expression of PCDH10 inhibits cell growth, reduces clonogenicity, restrains cell invasion, and induces cell apoptosis, substantiating its tumor suppressor roles (10,13,14,16). Moreover, methylation of PCDH10 manifests its significance through its association with clinical parameters.…”

“…PCDH10 is reported to be silenced in multiple human cancers (6,(9)(10)(11)(12)(13)(14)(15)(16). To investigate its potential involvement in EEC, we first examined its mRNA expression in five EEC cells lines, AN3CA, HEC-1-A, HEC-1-B, RL95-2, and KLE as well as microdissected EEC tumor samples using normal endometrial (NE) tissue as controls.…”

Aberrant gene-specific DNA methylation signature analysis in cervical cancer

“…55,56 One of the limitations of this study is the moderate clinical sample size with limited samples in the premalignant group. In India, unlike in Western countries, routine screening is not popular, and therefore, few women are diagnosed at the stage of premalignant stage.…”

Epigenetic silencing of protocadherin 10 in colorectal cancer

“…PCDH10 downregulation is involved into several types of cancer, including gastric, hepatocellular, colorectal, breast, cervical, lung, nasopharyngeal, esophageal, pancreatic and bladder cancer (30)(31)(32)(33)(34)(35). Functional studies have also identified PCDH10 as a potential novel tumor suppressor gene in multiple types of cancer (18,32,33).…”