Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer

Jun Yu; Yuen Y. Cheng; Qian Tao; Kin F. Cheung; Cleo N.Y. Lam; Hua Geng; Lin Wei Tian; Ying P. Wong; Joanna H.M. Tong; Jian Ming Ying; Hongchuan Jin; Ka F. To; Francis K.L. Chan; Joseph J.Y. Sung

doi:10.1053/j.gastro.2008.10.050

Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer

Jun Yu^*, Yuen Y. Cheng, Qian Tao, Kin F. Cheung, Cleo N.Y. Lam, Hua Geng, Lin Wei Tian, Ying P. Wong, Joanna H.M. Tong, Jian Ming Ying, Hongchuan Jin, Ka F. To, Francis K.L. Chan, Joseph J.Y. Sung

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

Abstract

Background & Aims: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methods: Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. Results: PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. Conclusions: PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

Original language	English (US)
Journal	Gastroenterology
Volume	136
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2008.10.050
State	Published - Jan 1 2009

ASJC Scopus subject areas

Hepatology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1053/j.gastro.2008.10.050

Cite this

Yu, J., Cheng, Y. Y., Tao, Q., Cheung, K. F., Lam, C. N. Y., Geng, H., Tian, L. W., Wong, Y. P., Tong, J. H. M., Ying, J. M., Jin, H., To, K. F., Chan, F. K. L., & Sung, J. J. Y. (2009). Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer. Gastroenterology, 136(2). https://doi.org/10.1053/j.gastro.2008.10.050

@article{7b1a738e74f2459ca5a5b8a6da2e0f8e,

title = "Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer",

abstract = "Background & Aims: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methods: Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. Results: PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. Conclusions: PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.",

author = "Jun Yu and Cheng, {Yuen Y.} and Qian Tao and Cheung, {Kin F.} and Lam, {Cleo N.Y.} and Hua Geng and Tian, {Lin Wei} and Wong, {Ying P.} and Tong, {Joanna H.M.} and Ying, {Jian Ming} and Hongchuan Jin and To, {Ka F.} and Chan, {Francis K.L.} and Sung, {Joseph J.Y.}",

year = "2009",

month = jan,

day = "1",

doi = "10.1053/j.gastro.2008.10.050",

language = "English (US)",

volume = "136",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "2",

}

TY - JOUR

T1 - Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer

AU - Yu, Jun

AU - Cheng, Yuen Y.

AU - Tao, Qian

AU - Cheung, Kin F.

AU - Lam, Cleo N.Y.

AU - Geng, Hua

AU - Tian, Lin Wei

AU - Wong, Ying P.

AU - Tong, Joanna H.M.

AU - Ying, Jian Ming

AU - Jin, Hongchuan

AU - To, Ka F.

AU - Chan, Francis K.L.

AU - Sung, Joseph J.Y.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - Background & Aims: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methods: Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. Results: PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. Conclusions: PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

AB - Background & Aims: By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methods: Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. Results: PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. Conclusions: PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

UR - http://www.scopus.com/inward/record.url?scp=58649120820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58649120820&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2008.10.050

DO - 10.1053/j.gastro.2008.10.050

M3 - Article

C2 - 19084528

AN - SCOPUS:58649120820

SN - 0016-5085

VL - 136

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this