Characterization of a novel tumor-suppressor gene PLCδ1 at 3p22 in Esophageal squamous cell carcinoma
Characterization of a novel tumor-suppressor gene PLCδ1 at 3p22 in Esophageal squamous cell carcinoma
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DOI：
10.1158/0008-5472.can-07-2411
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Fu, Li;Qin, Yan-Ru;Guan, Xin-Yuan
3 p缺失是许多实体瘤（包括食管鳞状细胞癌（ESCC））中最常见的染色体改变之一，表明在3 p处存在一个或多个肿瘤抑制基因。最近，我们的杂合性丢失研究表明，3 p22在ESCC中频繁缺失，并且在3 p22区域内鉴定出候选肿瘤抑制基因（TSG），磷脂酶C-δ 1（PLC δ 1）。50例原发性食管鳞癌中有26例（52%）和9例食管鳞癌细胞系中有4例（44.4%）PLC delta 1表达缺失，与DNA拷贝数丢失和启动子甲基化密切相关（P < 0.05）。功能研究表明PLC delta 1能够抑制ESCC细胞的体外和体内致瘤能力，包括病灶形成、软琼脂集落形成和裸鼠成瘤。PLC delta 1的肿瘤抑制机制与其在细胞周期停滞在G（1）-S检查点的作用有关，其通过上调p21和下调磷酸化Akt（Ser（473））。此外，PLC delta 1蛋白表达下调与ESCC转移显著相关（P = 0.014），这与其增加细胞粘附和抑制细胞移动的功能有关。综上所述，我们的研究结果表明，PLC delta 1在ESCC的发展和进展中起着重要的抑制作用。
Deletion of 3p is one of the most frequent chromosomal alterations in many solid tumors, including esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor-suppressor genes at 3p. Recently, our loss of heterozygosity study revealed that 3p22 was frequently deleted in ESCC and a candidate tumor-suppressor gene (TSG), phospholipase C-delta 1 (PLC delta 1), was identified within the 3p22 region. In this study, absent expression of PLC delta 1 was detected in 26 of 50 (52%) primary ESCCs and 4 of 9 (44.4%) ESCC cell lines, which was significantly associated with DNA copy number loss and promoter hypermethylation (P < 0.05). Functional studies showed that PLC delta 1 was able to suppress both in vitro and in vivo tumorigenic ability of ESCC cells, including foci formation, colony formation in soft agar, and tumor formation in nude mice. The tumor-suppressive mechanism of PLC delta 1 was associated with its role in the cell cycle arrest at the G(1)-S checkpoint by up-regulation of p21 and down-regulation of phosphorylated Akt (Ser(473)). In addition, down-regulation of PLC delta 1 protein was significantly correlated with ESCC metastasis (P = 0.014), which was associated with its function in increasing cell adhesion and inhibiting cell mobility. Taken together, our results suggest that PLC delta 1 plays an important suppressive role in the development and progression of ESCC.