Hypermethylation of the 16q23.1 tumor suppressor gene ADAMTS18 in clear cell renal cell carcinoma.
Hypermethylation of the 16q23.1 tumor suppressor gene ADAMTS18 in clear cell renal cell carcinoma.
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透明细胞肾细胞癌中 16q23.1 肿瘤抑制基因 ADAMTS18 的高甲基化
DOI：
10.3390/ijms16011051
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发表时间：
2015-01-05
影响因子：
5.6
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Xu B;Zhang L;Luo C;Qi Y;Cui Y;Ying JM;Zhang Q;Jin J
鉴定被高甲基化沉默的肿瘤抑制基因（TSGs），发现新的表观遗传生物标志物，用于早期癌症检测。位于16q23.1的ADAMTS18已被报道为多发原发肿瘤中的关键TSG；然而，这在透明细胞肾细胞癌（ccRCC）中尚未得到证实。我们探讨了ccRCC中该基因的表观遗传改变，并分析了可能的临床病理关联。采用半定量反转录PCR （RT-PCR）和甲基化特异性聚合酶链反应（MSP）检测了5株ccrcc来源细胞株在5-aza-2′-脱氧胞苷（5- azac）处理前后ADAMTS18基因的表达和甲基化。101例ccRCC原发肿瘤及20例癌旁正常组织行MSP检查。随后用亚硫酸氢盐基因组测序（BGS）和实时PCR检测部分细胞系和标本。此外，我们分析了ADAMTS18基因甲基化与ccRCC患者的临床病理特征（包括短期无病生存期（DFS））之间的关系。RT-PCR和MSP检测了cccc衍生细胞系中ADAMTS18的下调和高甲基化。5-AzaC治疗逆转了ADAMTS18基因的高甲基化并恢复了其表达。101例原发肿瘤中有44例（43.6%）和20例邻近正常组织中有3例（15.0%）存在高甲基化。但两组间差异有统计学意义（p = 0.02）。随后进行BGS分析和real-time PCR，以证实RT-PCR和MSP的结果。此外，ADAMTS18的甲基化状态与ccRCC患者的性别、年龄、部位、肿瘤直径、病理分期、核分级或短期DFS无显著相关性（p < 0.05）。在ccRCC衍生的细胞系和原发肿瘤中，ADAMTS18基因经常因高甲基化而下调，表明其作为TSG在ccRCC中起着关键作用。我们得出结论，ADAMTS18基因高甲基化可能参与了ccRCC的肿瘤发生，并可能作为该疾病的新生物标志物。
To identify tumor suppressor genes (TSGs) silenced by hypermethylation and discover new epigenetic biomarkers for early cancer detection. ADAMTS18, located at 16q23.1, has been reported to be a critical TSG in multiple primary tumors; however, this has not yet been verified in clear cell renal cell carcinoma (ccRCC). We explored epigenetic alterations in this gene in ccRCC and analyzed possible clinicopathological associations. We examined ADAMTS18 gene expression and methylation by semi-quantitative reverse transcription PCR (RT-PCR) and methylation-specific polymerase chain reaction (MSP) in 5 ccRCC-derived cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-AzaC). MSP was further performed for 101 ccRCC primary tumors and 20 adjacent normal tissues. Some cell lines and specimens were examined by subsequent bisulfite genomic sequencing (BGS) and real-time PCR. Further, we analyzed the relationship between the ADAMTS18 gene methylation and clinicopathological features, including short-term disease-free survival (DFS), in patients with ccRCC. ADAMTS18 down-regulation and hypermethylation were detected in the ccRCC-derived cell lines using RT-PCR and MSP. Treatment with 5-AzaC reversed the hypermethylation of the ADAMTS18 gene and restored its expression. Hypermethylation was further detected in 44 of 101 (43.6%) primary tumors and 3 of 20 (15.0%) adjacent normal tissues. However, a significant difference between both groups was observed (p = 0.02). BGS analysis and real-time PCR were subsequently performed to confirm the results of RT-PCR and MSP. Furthermore, the methylation status of ADAMTS18 was not significantly associated with gender, age, location, tumor diameter, pathological stage, nuclear grade or short-term DFS in patients with ccRCC (p > 0.05). The ADAMTS18 gene is often down-regulated by hypermethylation in ccRCC-derived cell lines and primary tumors, indicating its critical role as a TSG in ccRCC. We conclude that ADAMTS18 gene hypermethylation may be involved in the tumorigenesis of ccRCC and may serve as a novel biomarker for this disease.
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影响因子：
6
作者：
Murray, Paul G.;Fan, Yichao;Tao, Qian
通讯作者：
Tao, Qian
影响因子：
1.6
作者：
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影响因子：
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作者：
Zhang, Qlan;Ying, Jianming;Jin, Jie
通讯作者：
Jin, Jie
DOI：
10.1016/j.bbrc.2013.04.074
发表时间：
2013-06-14
影响因子：
3.1
作者：
He, Wei;Li, Xuesong;Chang, Guimin
通讯作者：
Chang, Guimin
影响因子：
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作者：
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