BCCIP suppresses tumor initiation but is required for tumor progression.
BCCIP suppresses tumor initiation but is required for tumor progression.
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DOI：
10.1158/0008-5472.can-13-1766
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发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Shen Z
中科院分区：
文献类型：
--
作者：
Huang YY;Dai L;Gaines D;Droz-Rosario R;Lu H;Liu J;Shen Z
基因组看守基因的功能障碍导致基因组不稳定和肿瘤发生。由于许多看守基因对细胞活力也是必不可少的，这些基因功能的永久丧失将阻止肿瘤的进一步发展。重要的看守基因如何促进肿瘤发生尚未完全了解。在这里，我们报告了一个“打了就跑”的作用模式，一个重要的看守基因在肿瘤发生。使用BRCA2相互作用蛋白BCCIP作为平台，我们发现条件性BCCIP敲除和伴随的p53缺失导致髓母细胞瘤的快速发展，其具有涉及Sonic hedgehog（Shh）通路的广泛的改变，与BCCIP对基因组完整性的看护责任一致。令人惊讶的是，进展的肿瘤自发地失去了转基因BCCIP敲低盒并恢复了BCCIP表达。因此，BCCIP的瞬时下调，但不一定是永久性突变，足以启动肿瘤发生。一旦恶性转化已经完成，自主癌症生长已经建立，BCCIP逆转其作用从肿瘤起始抑制剂成为一个必要的进展。这证实了一种新型的肿瘤抑制因子，它不同于在肿瘤发生过程中经常被永久废除的经典肿瘤抑制因子。这对研究非诱变性或瞬时调控的必需看守基因如何参与肿瘤发生具有重要意义。我们进一步表明，BCCIP代表了一类矛盾的肿瘤发生的调节剂，作为启动抑制剂，但要求进展（SIRP）。
Dysfunctions of genome caretaker genes contribute to genomic instability and tumor initiation. Because many of the caretaker genes are also essential for cell viability, permanent loss of function of these genes would prohibit further tumor progression. How essential caretaker genes contribute to tumorigenesis is not fully understood. Here, we report a “hit-and-run” mode of action for an essential caretaker gene in tumorigenesis. Using a BRCA2-interacting protein BCCIP as a platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alternations involving the Sonic hedgehog (Shh) pathway, consistent with a caretaker responsibility of BCCIP on genomic integrity. Surprisingly, the progressed tumors have spontaneously lost the transgenic BCCIP knockdown cassette and restored BCCIP expression. Thus, a transient down-regulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. Once the malignant transformation has been accomplished and autonomous cancer growth has been established, BCCIP reverses its role from a tumor initiation suppressor to become a requisite for progression. This exemplifies a new type of tumor suppressor, which is distinct from the classical tumor suppressors that are often permanently abrogated during tumorigenesis. It has major implications on how a non-mutagenic or transient regulation of essential caretaker gene contributes to tumorigenesis. We further suggest that BCCIP represents a paradoxical class of modulators for tumorigenesis, as a Suppressor for Initiation but a Requisite for Progression (SIRP).