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Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer

Oncogene volume 28, pages 2466–2475 (2009)Cite this article

Abstract

Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2′-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.

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Acknowledgements

This study was supported by a grant from the Chinese University of Hong Kong, a grant from National Natural Science Foundation of China (Grant no. 30770920/C03030202) and a grant from Natural Science Foundation of Zhejiang Province (Grant no. Y206090).

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Authors and Affiliations

  1. Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China

    X -T Hu, F -B Zhang, Q -L Shi, H -M Tang & C He

  2. Department of Clinical Oncology, Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong

    Y -C Fan, X -S Shu, A H Y Wong & Q Tao

  3. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China

    W Zhou & C He

  4. Department of Clinical Oncology, University of Hong Kong, Hong Kong

    L Fu & X -Y Guan

  5. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    S Y Rha

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  1. X -T Hu
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Correspondence to Q Tao or C He.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Hu, XT., Zhang, FB., Fan, YC. et al. Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene 28, 2466–2475 (2009). https://doi.org/10.1038/onc.2009.92

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