浙江大學(xué)醫(yī)學(xué)院附屬邵逸夫醫(yī)院生物醫(yī)學(xué)研究中心,，浙江省生物療法重點(diǎn)實(shí)驗(yàn)室，中國(guó)南方國(guó)家重點(diǎn)腫瘤實(shí)驗(yàn)室,，香港中文大學(xué)癌癥研究所,，李嘉誠(chéng)健康科學(xué)研究中心的研究人員找到一個(gè)新的腫瘤抑制子，文章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在Oncogene在線版上發(fā)表,。
浙江大學(xué)醫(yī)學(xué)院何超教授等人發(fā)現(xiàn),，腫瘤抑制子基因座3p22上的PLCD1編碼一種介導(dǎo)調(diào)節(jié)能量代謝信號(hào)，鈣平衡和鈣離子胞內(nèi)移動(dòng)信號(hào)的酶,。通過(guò)鑒定發(fā)現(xiàn)PLCD1在胃癌發(fā)生機(jī)制中處于下游調(diào)節(jié)基因的地位,，并通過(guò)表觀遺傳學(xué)模式來(lái)調(diào)節(jié)信號(hào)。
在正常的組織細(xì)胞中,，PLCD1普遍表達(dá),，然而，在胃癌細(xì)胞中,，其表達(dá)量顯著下降,，或是PLCD1被沉默（有84%被沉默，16/19）,，該基因的沉默與其富含CpG的單拷貝非甲基化的基因座的甲基化狀態(tài)有關(guān),。
隨后，研究人員在臨床中發(fā)現(xiàn),，有62%（61/98）的胃癌患者原發(fā)性腫瘤細(xì)胞中CpG區(qū)域甲基化,。這表明，PLCD1的甲基化是腫瘤生長(zhǎng)期的一個(gè)表征,。PLCD1失活會(huì)導(dǎo)致癌癥的發(fā)生,。深入的研究證實(shí)，PLCD1是一個(gè)具有功能性的胃癌腫瘤抑制子,。 （生物谷Bioon.com）
生物谷推薦原始出處：
Oncogene 18 May 2009;doi: 10.1038/onc.2009.92
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
X -T Hu1, F -B Zhang1, Y -C Fan2, X -S Shu2, A H Y Wong2, W Zhou3, Q -L Shi1, H -M Tang1, L Fu4, X -Y Guan4, S Y Rha5, Q Tao2 and C He1,3
1Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China
2Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Department of Clinical Oncology, 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
3Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
4Department of Clinical Oncology, University of Hong Kong, Hong Kong
5Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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.
