Epigenetic inactivation of HOXA11, a novel functional tumor suppressor for renal cell carcinoma, is associated with RCC TNM classification.
Epigenetic inactivation of HOXA11, a novel functional tumor suppressor for renal cell carcinoma, is associated with RCC TNM classification.
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HOXA11（一种新型肾细胞癌功能性肿瘤抑制因子）的表观遗传失活与 RCC TNM 分类相关
DOI：
10.18632/oncotarget.15668
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发表时间：
2017-03-28
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Wang L;Cui Y;Sheng J;Yang Y;Kuang G;Fan Y;Jin J;Zhang Q
HOXA 11是一种公认的肿瘤抑制因子，其表观遗传失活经常在许多实体瘤中观察到，但在RCC（肾细胞癌）中尚未描述。本研究旨在探讨HOXA 11在人肾细胞癌（RCC）中的表达、表观遗传学变化及其功能。HOXA 11在肾细胞癌细胞系和组织中沉默或下调。甲基化特异性PCR（MSP）和亚硫酸氢盐基因组测序（BGS）显示，HOXA 11启动子在5/6 RCC细胞系中高甲基化。去甲基化处理导致这些细胞系中启动子的去甲基化和HOXA 11表达的增加。原发性肾细胞癌中HOXA 11基因甲基化阳性率为70.5%（68/95），而癌旁正常肾组织中HOXA 11基因甲基化阳性率为13%（3/23）。HOXA 11基因甲基化与肾癌的TNM分期有关（p<0.05）。HOXA 11的异位表达可显著抑制肾癌细胞的增殖、集落形成、迁移和侵袭能力，并诱导肾癌细胞凋亡。此外，发现HOXA 11抑制Wnt信号传导。因此，我们的研究表明HOXA 11在RCC中作为肿瘤抑制因子发挥作用，而在RCC中它经常被启动子甲基化沉默。
Epigenetic inactivation of HOXA11, a putative tumor suppressor, is frequently observed in a number of solid tumors, but has not been described in RCC (renal cell carcinoma). In this study, we investigated the expression, epigenetic changes and the function of HOXA11 in human renal cell carcinoma (RCC). HOXA11 was silenced or down-regulated in RCC cell lines and tissues. Methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS) revealed that the HOXA11 promoter was hypermethylated in 5/6 RCC cell lines. Demethylation treatment resulted in demethylation of the promoter and increased HOXA11 expression in these cell lines. HOXA11 methylation was also detected in 68/95 (70.5%) primary RCC tumors, but only rare adjacent non-malignant renal tissues (13%, 3/23) showed hypermethylation of promoter. We also found that the methylation of HOXA11 was associated with higher TNM classification of RCC (p<0.05). Ectopic expression of HOXA11 led to significant inhibition of proliferation, colony formation, migration and invasion abilities and induced RCC cells apoptosis. Moreover, HOXA11 was found to inhibit Wnt signaling. Thus, our study demonstrated that HOXA11 function as a tumor suppressor in RCC, while it is frequently silenced by promoter methylation in RCC.