TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome
TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome
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DOI：
10.1172/jci80937
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
Mishra, Lopa
中科院分区：
文献类型：
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作者：
Chen, Jian;Yao, Zhi-Xing;Mishra, Lopa
贝克维斯-魏德曼综合征（BWS）是一种人类干细胞疾病，患有这种疾病的人患肿瘤的风险大大增加（约为800倍）。tgf - β信号的SMAD适配器β 2-spectrin（由SPTBN1编码的β 2SP）的表观遗传沉默与BWS有因果关系；然而，tgf - β缺乏在bws相关肿瘤转化中的作用尚不清楚。在这里，我们报道了双杂合Sptbn1(+/-) Smad3（+/-）小鼠，具有tgf - β信号缺陷，发展为与BWS患者表型相似的多发性肿瘤。此外，肿瘤发生相关基因IGF2和端粒酶逆转录酶（TERT）在BWS患者和tgf - β缺陷小鼠的成纤维细胞中过表达。我们进一步决定。染色质绝缘体ccctc结合因子（CTCF）是tgf - β诱导的，并通过与p2SP和SMAD3的相互作用促进tgf - β介导的TERT转录抑制。在tgf - β缺陷小鼠和BWS中，这种调节被取消，导致TERT过表达。11p15.5染色体上IGF2/H19位点和CDKIWC/KCNO1位点的印迹是由CTCF介导的，而这种调控在BWS中缺失，导致生长促进基因的异常过表达。因此，我们提出ctcf依赖性肿瘤促进基因（如IGF2和TERT）印迹的缺失是由tgf - β通路缺陷造成的，并且至少在一定程度上导致了bws相关肿瘤的发生以及经常与SPTBNI和SMAD3突变相关的散发性人类癌症。
Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (similar to 800-fold) of developing tumors. Epigenetic silencing of beta 2-spectrin (beta 2SP, encoded by SPTBN1), a SMAD adaptor for TGF-beta signaling, is causally associated with BWS; however, a role of TGF-beta deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1(+/-) Smad3(+/-) mice, which have defective TGF-beta signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-beta-defective mice. We further determined.that chromatin insulator CCCTC-binding factor (CTCF) is TGF-beta inducible and facilitates TGF-beta-mediated repression of TERT transcription via interactions with p2SP and SMAD3. This regulation was abrogated in TGF-beta-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKIWC/KCNO1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-beta pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBNI and SMAD3 mutations.