Loss of secreted frizzled-related protein-1 expression in renal cell carcinoma reveals a critical tumor suppressor function.
Loss of secreted frizzled-related protein-1 expression in renal cell carcinoma reveals a critical tumor suppressor function.
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肾细胞癌中分泌性卷曲相关蛋白 1 表达的丧失揭示了关键的肿瘤抑制功能。
DOI：
10.1158/1078-0432.ccr-07-1077
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Bottaro,DonaldP
中科院分区：
文献类型：
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作者：
Rubin,JeffreyS;Bottaro,DonaldP
在本期临床癌症研究中，Gumz 等人。关于透明细胞肾细胞癌（RCC；参考文献 1）中分泌型卷曲相关蛋白 1 (sFRP-1) 丢失的报告。 sFRP-1 是结合 Wnt 的蛋白质家族的成员，可以在胚胎发育和成人稳态过程中抑制 Wnt 信号转导 (2, 3)。不适当的 Wnt 信号传导是多种恶性肿瘤中一种公认的肿瘤发生机制，在这些情况下，sFRP 已被视为潜在的肿瘤抑制因子。与这一假设一致，sFRP 的染色体位点与各种肿瘤类型的杂合性丧失相关 (4, 5)。此外，多项研究已证明癌症中由于启动子高甲基化而导致 SFRP 表达丧失 (3)。最近的文献，包括 Gumz 等人 (1) 的文章，表明 SFRP 表达（尤其是 SFRP1）的沉默在 RCC 中非常常见 (6, 7)。重要的是，Gumz 等人。研究表明，SFRP1 表达的恢复不仅降低了 Wnt 靶基因的表达，而且还显着抑制了无胸腺裸鼠培养物、软琼脂和异种移植物中的肿瘤细胞生长 (1)。这些发现强烈表明，sFRP-1 的缺失在 RCC 中具有关键作用，并且其表达的恢复可能具有治疗益处。此外，SFRP 基因高甲基化分析可能对 RCC 的检测和管理具有诊断和预后价值 (6)，目前仅在美国每年就有超过 13,000 人因此丧生 (8)。 Wnt 在胚胎发生过程中具有许多不同的功能，包括在肾脏发育中发挥关键作用 (9)，并且它们有助于成人的干细胞更新 (2)。经典 Wnt/h-连环蛋白通路的组成型激活在许多癌症中很常见，它被认为是肿瘤发生的早期事件，特别是在结直肠癌中 (2)。刺激该通路可抑制胞质 h-连环蛋白的降解，促进其在细胞核中的积累，并与 T 细胞因子/淋巴增强因子 (TCF/LEF) 家族的成员结合，发挥转录激活剂的作用（图 1）。尽管癌症中该通路的激活通常归因于下游效应子（例如，h-连环蛋白）或抑制子[例如，腺瘤性息肉病大肠杆菌 (APC) 蛋白或 Axin] 的失调，但自分泌机制也已被描述 (10)。最大刺激可能涉及两种机制的组合 (11)。其他 Wnt 信号级联已得到充分表征，包括与转移性黑色素瘤有关的钙/蛋白激酶 C 机制 (12) 以及有助于细胞极性和运动性的 Rac/Rho 相关过程 (13)。所有这些信号转导事件均由七次跨膜蛋白卷曲 (Fzd) 家族中的 Wnt 受体介导。此外，脂蛋白受体相关蛋白 5 和 6 (LRP5/6) 作为 Wnt 辅助受体发挥作用，特别是在 h-catenin 通路中（图 1）。 sFRP 具有保守的 Fzd 型富含半胱氨酸的结构域，可结合 Wnt，并且通常它们可能通过阻止 Wnt/Fzd 相互作用来拮抗 Wnt 信号传导。五个 SFRP 基因中的四个包含密集的 CpG 岛 (14)，越来越多的文献表明这些基因在癌症中通常被沉默，主要是通过启动子高甲基化 (3)。 sFRP-1 基因沉默的发生率特别高，无论是肿瘤类型的多样性还是个体类型内的频率 (3)。乳腺癌中 sFRP-1 表达的丧失与生存率降低有关 (15)，而结直肠肿瘤细胞系中表达的恢复会导致肿瘤表型减弱，表现为减弱……
In this issue of Clinical Cancer Research, Gumz et al. report on the loss of secreted frizzled-related protein-1 (sFRP-1) in clear cell renal cell carcinoma (RCC; ref. 1). sFRP-1 is a member of a family of proteins that bind Wnts and can inhibit Wnt signaling during embryonic development and in the adult homeostasis (2, 3). Inappropriate Wnt signaling is a well-established mechanism of oncogenesis in several malignancies, and in these contexts, sFRPs have been viewed as potential tumor suppressors. Consistent with this hypothesis, the chromosomal loci of sFRPs have been associated with loss of heterozygosity in various tumor types (4, 5). Moreover, several studies have documented the loss of SFRP expression in cancer due to promoter hypermethylation (3). Recent literature, including the article by Gumz et al.(1), indicates that silencing of SFRP expression, particularly SFRP1, is very common in RCC (6, 7). Importantly, Gumz et al. show that restoration of SFRP1 expression not only reduced the expression of Wnt target genes, but also markedly inhibited tumor cell growth in culture, soft agar, and xenografts in athymic nude mice (1). These findings strongly suggest that loss of sFRP-1 has a pivotal role in RCC, and that restoration of its expression could be of therapeutic benefit. Furthermore, analysis of SFRP gene hypermethylation may have diagnostic and prognostic value in the detection and management of RCC (6), which now claims more than 13,000 lives each year in the US alone (8). Wnts have many diverse functions during embryogenesis, including a critical role in kidney development (9), and they contribute to stem cell renewal in the adult (2). Constitutive activation of the canonical Wnt/h-catenin pathway is common in many cancers, in which it is thought to be an early event in tumorigenesis, particularly in colorectal cancer (2). Stimulation of this pathway inhibits the degradation of cytosolic h-catenin, facilitating its accumulation in the nucleus where it associates with members of the T cell factor/lymphoid enhancer factor (TCF/LEF) family to function as a transcriptional activator (Fig. 1). Although activation of the pathway in cancer is usually attributed to deregulation of downstream effectors (eg, h-catenin) or suppressors [eg, adenomatous polyposis coli (APC) protein or Axin], autocrine mechanisms also have been described (10). Maximal stimulation probably involves a combination of both mechanisms (11). Other Wnt signaling cascades have been well-characterized, including a calcium/protein kinase C mechanism implicated in metastatic melanoma (12) as well as a Rac/Rho-associated process that contributes to cell polarity and motility (13). All of these signaling events are mediated by Wnt receptors in the Frizzled (Fzd) family of seven-pass transmembrane proteins. In addition, the lipoprotein receptor–related proteins 5 and 6 (LRP5/6) function as Wnt coreceptors, specifically in the h-catenin pathway (Fig. 1). sFRPs possess a conserved Fzd-type cysteine-rich domain that binds Wnts and typically they antagonize Wnt signaling, presumably by preventing Wnt/Fzd interactions. Four of the five SFRP genes contain dense CpG islands (14), and a growing literature indicates that these genes often are silenced in cancer, primarily by promoter hypermethylation (3). The incidence of gene silencing is particularly high for sFRP-1, both with regard to the diversity of tumor types and the frequency within an individual type (3). Loss of sFRP-1 expression in breast cancer has been associated with decreased survival (15), and restoration of expression in colorectal tumor cell lines resulted in an attenuated tumor phenotype, manifested as diminished …