Ying Jianming, Li Hongyu, Yu Jun, Ng Ka Man, Poon Fan Fong, Wong Sze Chuen Cesar, Chan Anthony T C, Sung Joseph J Y, Tao Qian
Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Department of Clinical Oncology, Sir Y.K. Pao Center for Cancer, Hong Kong Cancer Institute, Hong Kong, China.
Clin Cancer Res. 2008 Jan 1;14(1):55-61. doi: 10.1158/1078-0432.CCR-07-1644.
Aberrant activation of the Wnt/beta-catenin signaling pathway is associated with multiple tumors including colorectal cancer (CRC). WNT5A is a member of the nontransforming Wnt protein family, whose role in tumorigenesis is still ambiguous. We investigated its epigenetic alteration in CRCs.
We examined its expression and methylation in normal colon, CRC cell lines, and tumors. We also evaluated its tumor-suppressive function and its modulation to Wnt signaling in CRC cells.
WNT5A is silenced in most CRC cell lines due to promoter methylation, but is expressed in most normal tissues including the colon, and is unmethylated in normal colon epithelial cells. WNT5A expression could be reactivated by pharmacologic or genetic demethylation, indicating that methylation directly mediates its silencing. WNT5A methylation was frequently detected in CRC tumors (14 of 29, 48%), but only occasionally in paired normal colon tissues (2 of 15, 13%; P = 0.025). Ectopic expression of WNT5A, but not its nonfunctional short-isoform with the WNT domain deleted, in silenced CRC cells resulted in substantial inhibition of tumor cell clonogenicity, which is associated with down-regulated intracellular beta-catenin protein level and concomitant decrease in beta-catenin activity.
WNT5A is frequently inactivated in CRC by tumor-specific methylation, and thus, is a potential biomarker. WNT5A could act as a tumor suppressor for CRC by antagonizing the Wnt/beta-catenin signaling.
Wnt/β-连环蛋白信号通路的异常激活与包括结直肠癌（CRC）在内的多种肿瘤相关。WNT5A是一种非转化型Wnt蛋白家族成员，其在肿瘤发生中的作用仍不明确。我们研究了其在结直肠癌中的表观遗传改变。
我们检测了其在正常结肠、结直肠癌细胞系和肿瘤中的表达及甲基化情况。我们还评估了其在结直肠癌细胞中的肿瘤抑制功能及其对Wnt信号的调节作用。
由于启动子甲基化，WNT5A在大多数结直肠癌细胞系中沉默，但在包括结肠在内的大多数正常组织中表达，且在正常结肠上皮细胞中未甲基化。WNT5A的表达可通过药物或基因去甲基化重新激活，表明甲基化直接介导其沉默。WNT5A甲基化在结直肠癌肿瘤中经常被检测到（29例中有14例，48%），但在配对的正常结肠组织中仅偶尔检测到（15例中有2例，13%；P = 0.025）。在沉默的结直肠癌细胞中异位表达WNT5A而非缺失WNT结构域的无功能短异构体，可导致肿瘤细胞克隆形成能力的显著抑制，这与细胞内β-连环蛋白蛋白水平下调及β-连环蛋白活性随之降低有关。
WNT5A在结直肠癌中常因肿瘤特异性甲基化而失活，因此是一种潜在的生物标志物。WNT5A可通过拮抗Wnt/β-连环蛋白信号通路而作为结直肠癌的肿瘤抑制因子。
