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Characterization of the gene structure, functional significance, and clinical application of RNF180, a novel gene in gastric cancer†
Version of Record online: 29 JUN 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 4, pages 947–959, 15 February 2012
How to Cite
Cheung, K.-F., Lam, C. N. Y., Wu, K., Ng, E. K. O., Chong, W. W. S., Cheng, A. S. L., To, K.-F., Fan, D., Sung, J. J. Y. and Yu, J. (2012), Characterization of the gene structure, functional significance, and clinical application of RNF180, a novel gene in gastric cancer. Cancer, 118: 947–959. doi: 10.1002/cncr.26189
We thank Mr. Patrick Leung and Dr. Joanna Tong for histopathology assistance.
- Issue online: 3 FEB 2012
- Version of Record online: 29 JUN 2011
- Manuscript Accepted: 23 MAR 2011
- Manuscript Revised: 7 MAR 2011
- Manuscript Received: 8 FEB 2011
- ring finger protein 180;
- epigenetic alteration;
- gastric cancer
By using genome-wide methylation screening, the authors identified ring finger protein 180 (RNF180) as preferentially methylated in cancer. This study was undertaken to clarify its structure and functional role in gastric cancer.
The transcription start site and core functional promoter region of RNF180 were revealed by 5′ rapid amplification of cDNA ends and luciferase activity assays. Promoter methylation was detected by combined bisulfite restriction analysis and bisulfite genomic sequencing. Cell growth was detected by colony formation assay, apoptosis by annexin V assay, and RNF180 target genes by cDNA microarray.
The authors revealed the transcription start site of RNF180 gene and identified the functional core promoter region (−202/+372) in the CpG island, which could be silenced by in vitro methylation assay. RNF180 was silenced in 6 of 7 gastric cancer cell lines and significantly down-regulated in primary gastric cancers compared with adjacent normal tissues (P = .001). Loss of gene expression was associated with promoter methylation. Re-expression of RNF180 suppressed cell growth (P < .001) and induced apoptosis (P < .05), which were mediated by up-regulating the antiproliferation regulators MTSS1 and CDKN2A and the proapoptotic mediator TIMP3. Promoter methylation of RNF180 was detected in 76% (150 of 198) of primary gastric cancers and 55% (11 of 20) of intestinal metaplasia, but in none of 23 normal gastric tissues. Methylated RNF180 DNA was detected in the plasma of 56% of gastric cancer patients, but not in healthy controls (P = .003). Patients with low or loss of RNF180 expression had significantly poorer overall survival.
RNF180 is a novel potential tumor suppressor in gastric carcinogenesis and has potential clinical utility as a biomarker for gastric cancer patients. Cancer 2012;. © 2011 American Cancer Society.