TP53 Mutation by CRISPR System Enhances the Malignant Potential of Colon Cancer
Tumor protein p53 (TP53) mutation is a well-known occurrence at the late phase of carcinogenesis during the adenoma-carcinoma sequence of a sporadic colon cancer. Although numerous reports about clinical information of the patients with colon cancer have suggested that mutation might be related to v...
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Published in | Molecular cancer research Vol. 17; no. 7; pp. 1459 - 1467 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.07.2019
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Subjects | |
Online Access | Get full text |
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Summary: | Tumor protein p53 (TP53) mutation is a well-known occurrence at the late phase of carcinogenesis during the adenoma-carcinoma sequence of a sporadic colon cancer. Although numerous reports about clinical information of the patients with colon cancer have suggested that
mutation might be related to various types of malignant potential, the direct effects of this mutation on the malignant potential of colon cancer remain unknown. Notably, no previous report has described a relationship between
mutation and cancer stemness. We therefore aimed to assess the function of a TP53 mutant induced by the CRISPR-Cas9 system in colon cancer cells. In this study, two
mutations, corresponding to exon 3 (TP53E3) and 10 (TP53E10), were generated in LS174T cells derived from a wild-type TP53 human colon cancer via a lentiviral CRISPR-Cas9 system. The loss of function of TP53 resulting from both mutations manifested as resistance to Nutlin3a-induced apoptosis and the downregulation of target genes of TP53. TP53 mutants exhibited an enhanced malignant potential, characterized by accelerated cell growth, invasiveness, chemoresistance, and cancer stemness. Interestingly, TP53E10 but not TP53E3 cells exhibited aberrant transcriptional activity of regenerating family member 1-α (
) and expression of REG1A, resulting in the acquisition of enhanced malignant potential. In conclusion, we demonstrated for the first time that
genomic mutation into human colon cancer cells affects the malignant potential. IMPLICATIONS: These findings suggest that both a loss of function and an aberrant gain of function of TP53 might promote high malignant potentials at the late phase of carcinogenesis in colon cancer. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1541-7786 1557-3125 |
DOI: | 10.1158/1541-7786.MCR-18-1195 |