p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium
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DOI：
10.1002/emmm.201000101
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发表时间：
2010-11-01
影响因子：
11.1
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
--
作者：
Cole, Alicia M.;Ridgway, Rachel A.;Sansom, Owen J.
衰老被认为是许多人类恶性肿瘤（包括结直肠癌（CRC））中肿瘤抑制的重要机制。然而，我们对癌症中发生的潜在突变如何导致衰老及其在体内的相关性仍然知之甚少。 Apc 基因在大约 80% 的 CRC 中作为起始事件发生突变，但在其他地方很少发生。在这项研究中，我们检查了 Apc 损失诱导肠上皮细胞与肾上皮细胞衰老的能力。在肾上皮细胞内，Apc 功能的丧失会导致衰老的诱导，然而，通过 Apc 和 p21 或 Ink4A 基因联合缺失来绕过衰老，会迅速引发肾癌。在肠上皮内，Apt 的缺失不会引起衰老。此外，Apc 和 p21 或 Ink4A 的联合缺失对肿瘤发生没有影响。总而言之，这些结果表明，体内 Apc 损失会以上下文相关的方式调用衰老程序，并暗示衰老可能是肾脏肿瘤发生的关键障碍。然而，在结直肠癌中，逃避衰老可能只是其他突变引发的癌症的一个障碍。
Senescence has been implicated as an important mechanism of tumour suppression in a number of human malignancies, including colorectal cancer (CRC). However, we still have a relatively poor understanding of how the underlying mutations that occur in cancer cause senescence and its relevance in vivo. The Apc gene is mutated in approximately 80% of CRC as the initiating event, but rarely elsewhere. In this study we have examined the capacity of Apc loss to induce senescence in the intestinal epithelium compared to the renal epithelium. within the renal epithelium, loss of Apc function led to an induction of senescence, however, bypassing senescence through combined Apc and p21 or Ink4A gene deletion rapidly initiated renal carcinoma. Within the intestinal epithelium, loss of Apt did not induce senescence. Moreover, combined Apc and p21 or Ink4A loss had no impact upon tumourigenesis. Taken together, these results show that Apc loss in vivo invokes a senescence program in a context-dependent fashion, and implies senescence may play a key barrier to tumourigenesis in the kidney. However, in CRC, escape from senescence is likely to only be a barrier in cancers initiated by other mutations.