期刊
EMBO MOLECULAR MEDICINE
卷 2, 期 11, 页码 472-486出版社
WILEY
DOI: 10.1002/emmm.201000101
关键词
Apc; colorectal cancer; p21; renal carcinoma; senescence
资金
- Cancer Research UK
- MRC [G0301154] Funding Source: UKRI
- Cancer Research UK [12481] Funding Source: researchfish
- Medical Research Council [G0301154] Funding Source: researchfish
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.
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