Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma
Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma
复制标题
DOI：
10.1002/ijc.21450
复制
发表时间：
2006-02-15
影响因子：
6.4
通讯作者：
Murakami, Y
中科院分区：
文献类型：
--
作者：
Yamada, D;Kikuchi, S;Murakami, Y
肾透明细胞癌（RCCC）是一种预后不良的恶性肿瘤，其发生率高，易发生远端器官转移。虽然转移性RCCC细胞经常表现出异常的细胞骨架组织，但其潜在机制尚未阐明。DAL-1/4.1B是一种肌动蛋白结合蛋白，参与细胞凋亡相关过程，但经常观察到其失活。在肺癌、乳腺癌和脑膜瘤中，表明4.1B是一种潜在的肿瘤抑制因子。我们研究了4.1B在RCCC中的可能参与，并将其作为临床指标进行评估。4.1B蛋白在人肾近曲小管中表达，推测其为RCCC的起源细胞。另一方面，在19个肾细胞癌（RCC）细胞中的10个（53%）和19个细胞中的12个（63%）中观察到其表达的丢失或显著降低。通过逆转录-PCR检测手术切除的RCCC。亚硫酸氢盐测序或亚硫酸氢盐SSCP分析显示，4.1B启动子在9/19（47%）RCC细胞和25/55（45%）手术切除的RCCC中甲基化，并与4.1B表达呈负相关（p < 0.0001）。异常甲基化似乎是一个相对早期的事件，因为超过40%的pT 1a肿瘤表现出高甲基化。此外，4.1B甲基化与核分级（p = 0.017）和无复发生存率（p = 0.0036）相关，并提供了一个独立的预后因素（p = 0.038，相对风险10.5）。这些结果表明，4.1B启动子甲基化是RCCC中最常见的表观遗传学改变之一，并可预测手术切除的RCCC的转移复发。(c)2005 Wiley-Liss，Inc.
Renal clear cell carcinoma (RCCC) is a malignant tumor with poor prognosis caused by the high incidence of metastasis to distal organs. Although metastatic RCCC cells frequently show aberrant cytoskeletal organization, the underlying mechanism has not been elucidated. DAL-1/4.1B is an actin-binding protein implicated in the cytoskeleton-associated processes, while its inactivation is frequently observed. in lung and breast cancers and meningiomas, suggesting that 4.1B is a potential tumor suppressor. We studied a possible involvement of 4.1B in RCCCs and evaluated it as a clinical indicator. 4.1B protein was detected in the proximal convuluted tubules of human kidney, the presumed cell of origin of RCCC. On the other hand, loss or marked reduction of its expression was observed in 10 of 19 (53%) renal cell carcinoma (RCC) cells and 12 of 19 (63%). surgically resected RCCC by reverse transcription-PCR. Bisulfite sequencing or bisulfite SSCP analyses revealed that the 4.1B promoter was methylated in 9 of 19 (47%) RCC cells and 25 of 55 (45%) surgically resected RCCC, and inversely correlated with 4.1B expression (p < 0.0001). Aberrant methylation appeared to be a relatively early event because more than 40% of the tumors with pT1a showed hypermethylation. Furthermore, 4.1B methylation correlated with a nuclear grade (p = 0.017) and a recurrence-free survival (p = 0.0036) and provided an independent prognostic factor (p = 0.038, relative risk 10.5). These results indicate that the promoter methylation of the 4.1B is one of the most frequent epigenetic alterations in RCCC and could predict the metastatic recurrence of the surgically resected RCCC. (c) 2005 Wiley-Liss, Inc.