Abstract
Colorectal cancer (CRC) is a kind of solid tumor and the third most common cancer type in the world. It is a heterogeneous disease characterized by genetic and epigenetic aberrations. The TP53 mutation is the key step driving the transition from adenoma to adenocarcinoma. The functional roles of TP53 mutation in tumor development have been comprehensively investigated. In CRC, TP53 mutation was associated with poor prognosis and chemoresistance. A gain of function (GOF) of p53 mutants promotes cell proliferation, migration and invasion through multiple mechanisms. Restoring wild type p53 function, depleting p53 mutants, or intervention by targeting the oncogenic downstreams provides potential therapeutic strategies. In this review, we comprehensively summarize the GOF of p53 mutants in CRC progression as well as in some other solid tumors, and discuss the current strategies targeting p53 mutants in malignancies.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide [1]
More than 96% of TP53 mutations are mainly located in exons 5, 6, 7, 8 and 4, and 93% of TP53 mutations cluster are between codon 100 and 300, which is regarded as the DNA-binding domain
CRC is a heterogeneous disease with high recurrence rates and it is hard to achieve a better therapeutic effect by solely targeting p53 mutants
Summary
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide [1]. The loss of genomic stability drives the development of CRC by facilitating the acquisition of multiple tumor-associated mutations. These mutations control the capability of inhibiting tumor-suppressive genes and activating oncogenes, which have long been considered crucial events in CRC carcinogenesis. The APC somatic mutations rates increasingly with the disease progression, forming dysplastic aberrant crypt foci to adenomas and to sporadic carcinoma, with 5%, 30%–70% and 72%, respectively. It suggests that functional loss of APC is the initiating event in CRC [2,3,4]. Some promising compounds are being tested in clinical trials and may be approved and employed for the treatment of CRC patients in the near future
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